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1.
Nanoscale ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609394

RESUMO

Orientation analyses of macromolecules or artificial particles are vital for both fundamental research and practical bio-applications. An accurate approach is monitoring the polarization spectroscopy of lanthanide-doped nanocrystalline materials. However, nanomaterials are often far from ideal for the colloidal and polarization luminescence properties. In the present study, we synthesize well-dispersed LaPO4:Eu3+ nanomaterials in an anisotropic rod shape. Microwave heating with excess addition of phosphate precursor invokes a rapid phase transition of rhabdophane into monazite. The colloidal stability of the nanorod suspension is outstanding, demonstrated by showing liquid crystalline behaviors. The monazite nanorods are also superior in luminescence efficiency with limited defects. The emission spectrum of Eu3+ consists of well-defined lines with prominent polarization dependencies for both the forced electric dipole transitions and the magnetic dipole transitions. All the results demonstrate that the synthesized monazite nanorods can serve as an accurate probe in orientation analyses and potential applications, such as in microfluidics and biological detections.

2.
Nature ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34619745

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces B cell responses that continue to evolve for at least one year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern1. As a result, vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals with currently available mRNA vaccines produces high levels of plasma neutralizing activity against all variants tested1,2. Here we examine memory B cell evolution 5 months after vaccination with either Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) mRNA vaccines in a cohort of SARS-CoV-2 naive individuals. Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge 5 months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response. While individual memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination, the overall neutralizing potency of plasma is greater following vaccination. These results suggest that boosting vaccinated individuals with currently available mRNA vaccines will increase plasma neutralizing activity but may not produce antibodies with equivalent breadth to those obtained by vaccinating convalescent individuals.

3.
Exp Cell Res ; 408(1): 112854, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34597678

RESUMO

Metastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we investigated the mechanistic role of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis. First, we explored the potential role of NFATc1 in CRC using bioinformatics and hypothesized that NFATc1 might play different roles at different stages of CRC development. Then, we examined the relative expression of NFATc1 in 25 CRC tissues and adjacent normal tissues, and further analyzed the correlation between NFATc1 expression levels and clinical stages in 120 CRC patients. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models. Our results showed that the expression of NFATc1 was increased in metastatic CRC tissues and positively associated with clinical stages (stage I vs. stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was verified as the direct transcriptional target of NFATc1 and interacted with SLUG to promote EMT. Remarkably, our lung and liver metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo. Taken together, our findings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn interacts with SLUG to mediate EMT to promote CRC metastasis. Thus, making NFATc1 a promising therapeutic target in the treatment of metastatic CRC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34482587

RESUMO

AIM: To evaluate the efficacy and safety of autologous platelet-rich fibrin (PRF) for the treatment of infertility with intrauterine adhesions. METHODS: Forty patients who suffered from infertility with intrauterine adhesions (IUAs) were enrolled in this prospective trial from October 2018 to December 2019. They were randomly divided into a PRF group and a control group. Both groups underwent transcervical resection of adhesions (TCRA) during the follicular phase. PRF group: PRF prepared from autologous venous blood was placed in the uterine cavity after TCRA and after the first menstrual re-fluid; control group: no PRF insertion. After the second menstrual re-fluid, both groups underwent hysteroscopy to reevaluate adhesion severity. Pregnancy rate, intrauterine adhesion score, menstrual volume and duration, and endometrial thickness were assessed and adverse events were recorded. RESULTS: (1) PRF group pregnancy rate was significantly higher than the control group (55.0% vs. 20.0%). Mean follow-up time was (17.63 ± 2.33) months. All patients fell pregnant naturally. Four (PRF) and one (control) patients delivered live births without placental complications. (2) Intrauterine adhesion scores decreased compared with treatment-before. (3) In the pictorial blood loss assessment chart, score and menstrual duration during the 3rd menstrual cycle showed significant improvements for both groups. (4) Endometrial thickness also showed an increasing trend, and subendometrial bloodflow improved. (5) No treatment-related serious adverse events were noted. CONCLUSION: Placing PRF into the uterine cavity of infertility patients with IUAs following TCRA is a safe and effective therapeutic method.

5.
J Clin Epidemiol ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34416326

RESUMO

OBJECTIVE: This study aimed to systematically review the methodological and reporting quality of clinical practice guidelines (CPGs) developed in China and published in medical journals between 2014 and 2018. STUDY DESIGN AND SETTING: We conducted a comprehensive search in multiple databases: MEDLINE (via PubMed), Embase, CBM (China Biology Medicine), CNKI (China National Knowledge Infrastructure) and Wanfang Data. We included all clinical practice guidelines developed in China between 2014 and 2018. The AGREE II tool and the RIGHT checklist were used to appraise the methodological quality and reporting quality of the included guidelines, respectively. RESULTS: We identified 17,188 records, and included finally 573 CPGs. Most (n=507, 88.5%) were published in Chinese, and 508 (88.7%) were about Western medicine. Only 62 (10.8%) of the guidelines used the GRADE approach. The mean overall score of methodological quality over all guidelines was 19.4%, and the mean scores for the AGREE II domains were 28.6% (Scope and purpose), 17.0% (Stakeholder involvement), 11.7% (Rigor of development), 32.2% (Clarity of presentation), 14.2% (Applicability) and 12.8% (Editorial independence). The mean overall score for reporting quality over all guidelines was 30.2%, with the following mean scores for each RIGHT domain: 55.6% (Basic information), 43.8% (Background), 14.5% (Evidence), 29.2% (Recommendations), 10.7% (Review and quality assurance), 12.6% (Funding and declaration of interest) and 8.4% (Other information). Subgroup analyses found that both the methodological and reporting quality were generally higher among CPGs that used evidence grading systems or reported receiving funding. CONCLUSION: Both the methodological quality and the reporting quality of CPGs developed in China have improved over time, but are still below the international average.

6.
Oxid Med Cell Longev ; 2021: 9993704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34426761

RESUMO

Background: Postoperative abdominal adhesion remains one of the frequent complications after abdominal surgery and lacks effective intervention. Peritoneal mesothelial cell injury and healing play crucial roles in the process of adhesion formation, and identifying this mechanism might provide new insight into possible new therapeutic strategies for this disease. Transmembrane and immunoglobulin domain-containing 1 (TMIGD1) has been proven to protect renal epithelial cells from injury induced by oxidative stress and has also been identified as a novel adhesion molecule. Here, we investigated the role of TMIGD1 and its possible mechanism in adhesion formation. Materials and Methods: Immunohistochemistry (IHC), qPCR, and immunofluorescence (IHF) were used to detect the expression of TMIGD1. The grade and tenacity score of adhesion were used to evaluate the adhesion formation conditions. A TMIGD1-overexpressing HMrSV5 cell line was established. MTT assay, Western blotting, Annexin V apoptosis analysis, and CK19 staining were used to measure mesothelial cell viability, apoptosis, and completeness. ROS and MDA detection were used to measure mesothelial cell oxidative stress levels. JC-1 staining, IHF, and transmission electron microscopy were performed to assess mitochondrial function. Scratch-wound and adhesion assays were used to evaluate the adhesion ability of mesothelial cells. Results: First, we showed that TMIGD1 was decreased in mouse abdominal adhesion tissue and peritoneal mesothelial cells. Second, TMIGD1 overexpression inhibited adhesion formation. Third, TMIGD1 overexpression protected mesothelial cells from hydrogen peroxide- (H2O2-) induced oxidative stress injury. Fourth, TMIGD1 overexpression alleviated oxidative stress by protecting the mitochondrial function of mesothelial cells. In addition, TMIGD1 overexpression enhanced mesothelial cell adhesion. Conclusion: Our findings suggest that TMIGD1 protects mesothelial cells from oxidative stress injury by protecting their mitochondrial function, which is decreased in regular abdominal adhesion tissue. In addition, TMIGD1 enhances peritoneal mesothelial cell adhesion to promote healing.

7.
Toxins (Basel) ; 13(8)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34437425

RESUMO

The spider peptide toxins HNTX-III and JZTX-I are a specific inhibitor and activator of TTX-S VGSCs, respectively. They play important roles in regulating MAT-LyLu cell metastasis in prostate cancer. In order to identify key biomarkers involved in the regulation of MAT-LyLu cell metastasis, iTRAQ-based quantitative phosphoproteomics analysis was performed on cells treated with HNTX-III, JZTX-I and blank. A total of 554 unique phosphorylated proteins and 1779 distinct phosphorylated proteins were identified, while 55 and 36 phosphorylated proteins were identified as differentially expressed proteins in HNTX-III and JZTX-I treated groups compared with control groups. Multiple bioinformatics analysis based on quantitative phosphoproteomics data suggested that the differentially expressed phosphorylated proteins and peptides were significantly associated with the migration and invasion of prostate tumors. Specifically, the toxins HNTX-III and JZTX-I have opposite effects on tumor formation and metastasis by regulating the expression and phosphorylation level of causal proteins. Herein, we highlighted three key proteins EEF2, U2AF2 and FLNC which were down-regulated in HNTX-III treated cells and up-regulated in JZTX-I treated cells. They played significant roles in cancer related physiological and pathological processes. The differentially expressed phosphorylated proteins identified in this study may serve as potential biomarkers for precision medicine for prostate cancer in the near future.

8.
Sci Robot ; 6(57)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433656

RESUMO

Fibers capable of generating axial contraction are commonly seen in nature and engineering applications. Despite the broad applications of fiber actuators, it is still very challenging to fabricate fiber actuators with combined large actuation strain, fast response speed, and high power density. Here, we report the fabrication of a liquid crystal elastomer (LCE) microfiber actuators using a facile electrospinning technique. Owing to the extremely small size of the LCE microfibers, they can generate large actuation strain (~60 percent) with a fast response speed (<0.2 second) and a high power density (400 watts per kilogram), resulting from the nematic-isotropic phase transition of liquid crystal mesogens. Moreover, no performance degradation is detected in the LCE microfibers after 106 cycles of loading and unloading with the maximum strain of 20 percent at high temperature (90 degree Celsius). The small diameter of the LCE microfiber also results in a self-oscillatory behavior in a steady temperature field. In addition, with a polydopamine coating layer, the actuation of the electrospun LCE microfiber can be precisely and remotely controlled by a near-infrared laser through photothermal effect. Using the electrospun LCE microfiber actuator, we have successfully constructed a microtweezer, a microrobot, and a light-powered microfluidic pump.

9.
Nat Commun ; 12(1): 4196, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234131

RESUMO

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.


Assuntos
Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , COVID-19/imunologia , Epitopos , Antígenos HLA/imunologia , Humanos , Evasão da Resposta Imune/genética , Modelos Moleculares , Mutação , Testes de Neutralização , Domínios Proteicos , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química
10.
Huan Jing Ke Xue ; 42(8): 3931-3942, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34309280

RESUMO

Based on the rice-vegetable crop rotation model, in-situ measurements of nitrous oxide (N2O) and methane (CH4) emissions were conducted in double-cropping rice fields in Hainan to determine the impact of coconut chaff biochar on greenhouse gas emissions. The experiment involved four treatments:conventional farming fertilization (CON), nitrogen fertilizer combined with 20 t ·hm-2 biochar (B1), nitrogen fertilizer combined with 40 t ·hm-2 biochar (B2), and no nitrogen fertilizer, as the control (CK). The N2O and CH4 emissions were measured using static chamber-gas chromatography during the two paddy seasons, and the global warming potential (GWP) and greenhouse gas intensity (GHGI) were also estimated. The results show that N2O emission dynamics during the early rice season are closely related to the mineral nitrogen content of the soil. The N2O is emitted at the rice seedling and tillering stages after fertilization. The cumulative N2O emission during the early rice season was 0.18-0.76 kg ·hm-2. Compared with the CON treatment, the biochar treatments reduced N2O by 18%-43%, and the B2 treatment resulted in a significant reduction. The addition of biochar may promote the reduction of N2O at the early rice seedling stage and increase N2O emissions by improving the soil NO3--N content at the early rice tillering stage. During the late rice season, N2O is emitted during the heading and maturity stages, and the cumulative N2O emission was 0.17-0.34 kg ·hm-2. The B1 treatment reduced emissions by 37%, and B2 increased emission by only 3%, which is not a significant difference. The peak of CH4 emissions from rice fields appeared in the late phase of the early rice season and prophase of the late rice season. The cumulative emission of CH4 in the early rice season was 3.11-14.87 kg ·hm-2. Compared with CON, the CK treatment increased emission by 39%. The biochar treatment may increase soil aeration and limit the ability of CH4 production in the early rice season, as B1 and B2 treatments reduced CH4 emissions by 28% and 71%. The cumulative CH4 emission in late rice season was 53.1-146.3 kg ·hm-2, and the emission dynamics were significantly positively correlated with NH4+-N content. CK and B1 treatments increased CH4 emissions by 52% and 99%, respectively compared with CON, and the B2 treatment significantly increased CH4 emissions by 176%. Compared with CON, the B1 and B2 treatments increased the yield by 12.0% and 14.3% when applied in the early rice season and by 7.6% and 0.4% when applied in the late rice season, respectively. Due to the increased methane emissions in the late rice season, biochar amendment increased the GWP of the double-cropping rice field, in which the high amount of biochar reached a significant level; different amounts of biochar had no significant effect on the GHGI of the double-cropping rice field. Thus, the application of coconut chaff biochar for the reduction of greenhouse gas emission, from rice fields in hot areas, requires further research.


Assuntos
Óxido Nitroso , Oryza , Agricultura , Carvão Vegetal , China , Cocos , Fertilizantes/análise , Metano/análise , Óxido Nitroso/análise , Solo
11.
Huan Jing Ke Xue ; 42(8): 3943-3952, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34309281

RESUMO

Alternating dry and wet conditions affect the main processes of N2O production, such as nitrification and denitrification. Such conditions are very common in tropical rice-growing areas, such as Hainan. As a type of soil amendment, biochar is widely used to improve physical and chemical properties of soil and to reduce soil greenhouse gas emissions. However, there is a lack of existing in-depth research on the emission reductions of biochar when used in tropical soils that undergo frequently alternating dry and wet conditions. In this experiment, typical paddy soil from northern Hainan was used as the test soil, and corn stalk biochar, carbonized under anaerobic conditions at 400℃, was used as the test biochar. This experiment explored the effects of adding biochar on soil greenhouse gas emissions and microbial-related functional genes under different water management conditions. The experiment comprised a 30 d culture, kept in the dark at 25℃, and a total of six treatments:alternating dry-wet conditions without adding biochar (AWD1), alternating dry-wet conditions with 2% biochar (AWD2), alternating dry-wet conditions with 4% biochar (AWD3), continuous flooding without adding biochar (CF1), continuous flooding with 2% biochar (CF2), and continuous flooding with 4% biochar (CF3). The results showed that:① the addition of biochar under different moisture conditions can reduce N2O emissions in acidic paddy soil (P<0.05, the same below), as the total N2O emissions with the AWD3 treatment were 0.43 mg ·kg-1, which indicates an approximate reduction of 68%, relative to the AWD1 treatment; ② Corn stalk biochar can significantly increase the soil pH under different water management conditions. Compared to the no-biochar treatment, the soil pH increased by 0.5 units on average after cultivation with the addition of biochar, and as the soil NH4+-N content increased, it led to a decrease in Eh. ③ Corn stalk biochar significantly reduces the abundance of ammonia oxidizing bacteria and significantly increases the nosZ gene abundance. However, it decreases the ratio of (nirK+nirS)/nosZ, inhibits the nitrification process, and promotes the reduction of N2O in the denitrification process. Thereby, the addition of corn stalk biochar can reduce N2O emissions. These results show that alternating dry-wet conditions, combined with the addition of corn stalk biochar, are beneficial for reducing N2O emissions in paddy soil, which may have further application in the reduction of agricultural greenhouse gas emissions in northern Hainan.


Assuntos
Óxido Nitroso , Solo , Carvão Vegetal , Óxido Nitroso/análise , Microbiologia do Solo , Água , Abastecimento de Água
12.
Immunity ; 54(8): 1853-1868.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34331873

RESUMO

Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.


Assuntos
Afinidade de Anticorpos/imunologia , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Mutação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Epitopos/química , Epitopos/imunologia , Humanos , Modelos Moleculares , Testes de Neutralização , Ligação Proteica , Conformação Proteica , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Relação Estrutura-Atividade , Virulência/genética
13.
J Clin Epidemiol ; 139: 57-67, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34186193

RESUMO

OBJECTIVE: To analyze the retraction status and reasons of non-Cochrane systematic reviews (SRs) in medicine. STUDY DESIGN AND SETTING: MEDLINE, Embase, Retraction Watch Database and Google Scholar were systematically searched to find all retracted non-Cochrane SRs. RESULTS: Of 159 non-Cochrane SRs in medicine retracted between 2004 and 2020, more than 70% were led by authors from China and affiliated with hospitals. The largest proportion of retraction notices were issued by the publisher and editor(s) jointly. Fraudulent peer-review was the most common reason for retraction, followed by unreliable data meaning errors in study selection or data analysis. The median time between publication and retraction was 14 months, and SRs retracted due to research misconduct took longer to retract than honest error. CONCLUSION: The total number of retracted SRs is increasing worldwide, in particular in China. The most common reasons for retraction are fraudulent peer-review and unreliable data, and in most cases the SR is retracted more than a year after publication. Better systems of ethical oversight and culture to improve the process of peer review and adherence to the COPE retraction guidance are needed, and authors should strengthen their skills in SR methodology.

14.
Nature ; 595(7866): 278-282, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34098567

RESUMO

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1-3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.


Assuntos
Anticorpos Neutralizantes/imunologia , Camelídeos Americanos/imunologia , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/isolamento & purificação , Sistemas CRISPR-Cas , Camelídeos Americanos/genética , Feminino , Edição de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutação , Testes de Neutralização , SARS-CoV-2/química , SARS-CoV-2/genética , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/isolamento & purificação , Hipermutação Somática de Imunoglobulina/genética
15.
Nature ; 595(7867): 426-431, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34126625

RESUMO

More than one year after its inception, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains difficult to control despite the availability of several working vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination, antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable between 6 and 12 months after infection. Vaccination increases all components of the humoral response and, as expected, results in serum neutralizing activities against variants of concern similar to or greater than the neutralizing activity against the original Wuhan Hu-1 strain achieved by vaccination of naive individuals2,5-8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in the variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand markedly after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Linfócitos B/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Feminino , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo
16.
ACS Nano ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34165280

RESUMO

Ischemic stroke (IS) characterized with high morbidity and mortality rates is considered as one of the most dangerous brain diseases. The timely assessment of IS is crucial for making a clinical decision due to the severity of IS featured with time-dependence. Herein, we develop a highly reactive oxygen species (HROS)-responsive ratiometric near-infrared-II (NIR-II) nanoprobe based on a dye-sensitized system between IR-783 dye and lanthanide-doped nanoparticles. Once intravenously injected into the mice, the probe is rapidly accumulated at a lesion site by recognizing the activated endothelial cell or impaired blood-brain barrier (BBB) in the ischemic area and further responds to HROS, thereby allowing in vivo imaging of the oxidative stress level. The probe is not only able to discriminate the salvageable ischemic tissue from infarcted stroke core by visualizing the enriched degree of the probe at the lesion site but also can grade the salvageable ischemic tissue by analyzing the oxidative stress level. In addition, the ischemia area was clearly delineated by NIR-II luminescence imaging after cerebral ischemia for 30 min, which is significantly earlier than with the magnetic resonance imaging (MRI) method, thereby providing a practical tool for the timely assessing of IS.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33973764

RESUMO

Additive manufacturing of electrically responsive soft actuators is of great importance in designing and constructing novel soft robots and soft machines. However, there are very limited options for 3D-printable and electrically responsive soft materials. Herein, we report a strategy of 3D printing polyvinyl chloride (PVC) gel actuators that are electrically controllable. We print a jellyfish-like actuator from PVC ink, which can achieve 130° bending in less than 5 s. With the multi-material 3D printing technique, we have further printed a soft actuator with a stiffness gradient that can generate undulatory motion. As a proof-of-concept demonstration, we show that a 3D-printed PVC gel-based smart window can change its transparency upon the application of voltage. The 3D printing strategy developed in this article may expand the potential applications of electrically responsive soft materials in diverse engineering fields.

18.
Neuropsychopharmacology ; 46(9): 1617-1626, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34007043

RESUMO

Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration.


Assuntos
Transtorno Autístico , Animais , Transtorno Autístico/genética , Reparo do DNA , Metiltransferases , Camundongos , Córtex Pré-Frontal , Transcrição Genética
19.
Cell Death Dis ; 12(4): 361, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824298

RESUMO

Solute carrier family 25 member 20 (SLC25A20) is a mitochondrial-membrane-carrier protein involved in the transport of acylcarnitines into mitochondrial matrix for oxidation. A previous-integrated-proteogenomic study had identified SLC25A20 as one of the top-three prognostic biomarkers in HCC. However, the expression and the biological function of SLC25A20 have not yet been investigated in HCC. In the present study, we found that SLC25A20 expression is frequently down-regulated in HCC cells mainly due to the up-regulation of miR-132-3p. Down-regulation of SLC25A20 is associated with a poor prognosis in patients with HCC. SLC25A20 suppressed HCC growth and metastasis, both in vitro and in vivo, by suppression of G1-S cell transition, epithelial-to-mesenchymal transition (EMT), and induction of cell apoptosis. Mechanistically, SLC25A20 down-regulation promoted HCC growth and metastasis through suppression of fatty-acid oxidation. Altogether, SLC25A20 plays a critical tumor-suppressive role in carcinogenesis of HCC; SLC25A20 may serve as a novel prognostic factor and therapeutic target for patients with HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Metástase Neoplásica/patologia , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia
20.
Sci Rep ; 11(1): 9164, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911146

RESUMO

Lymphocyte cytosolic protein 2 (LCP2) is one of the SLP-76 family of adapters, which are critical intermediates in signal cascades downstream of several receptors. LCP2 regulates immunoreceptor signaling (such as T-cell receptors) and is also required for integrin signaling in neutrophils and platelets. However, the role of LCP2 in the tumor microenvironment is still unknown. In this study, we found a significant increase of mRNA and protein expression of LCP2 in metastatic skin cutaneous melanoma compared to normal skin. The upregulation of LCP2 was associated with good overall survival of patients with metastatic skin cutaneous melanoma, who received pharmacotherapy and radiation. GSEA signaling pathways analysis showed that LCP2 was involved in multiple pathways of immune response and correlation analysis revealed LCP2 was positively correlated with molecules in TCR signaling and 11 immune checkpoints, while LCP2 negatively correlated with 2 immune checkpoints in the metastatic skin cutaneous melanoma. According to the different expressions of LCP2, high LCP2 expression was positively correlated with more tumor-infiltrating CD8+ T cells. Furthermore, Kaplan-Meier plot indicated that LCP2 acted as a prognostic biomarker for progression-free survival of patients with metastatic skin cutaneous melanoma receiving anti-PD1 immunotherapy. In conclusion, our results integrated both the expression and function of LCP2 in melanoma using multiple tools, shedding light on the potential role of LCP2 in melanoma, and suggesting LCP2 serves as a prognostic biomarker and therapeutic target in anti-tumor immunity.

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