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1.
Nucleic Acids Res ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33577686

RESUMO

Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.

2.
J Card Surg ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33604903

RESUMO

OBJECTIVE: To compare the midterm outcomes of patients with isolated left anterior descending disease (iLAD) who underwent robotically assisted coronary artery bypass graft (R-CABG) and percutaneous coronary intervention (PCI) with drug eluting stents (DES). METHOD: Clinic data was collected in 223 patients who underwent R-CABG in our hospital between July, 2007 to November, 2014. Cardiology Database System of our hospital was used to identify 4047 patients who underwent PCI with DES for LAD lesion between April, 2011 to November, 2014. Total 496 patients received DES and 108 patients underwent R-CABG after screening. Patients were propensity matched into 108 R-CABG and DES pairs according to vital statistic. Mortality, myocardial infarction (MI), stroke, repeat target lesion revascularization (r-TLR), main adverse cardiac and cerebral events (MACCE), and angina relief were compared across pairs. RESULT: Kaplan-Meier estimates for R-CABG and DES had no significant difference in mortality (p = 1.00), MI (p = .32), Stroke (p = .80), and MACCE (p = .47), but the rate of r-TLR (p = .03) were lower in R-CABG group. Patients who underwent R-CABG had better angina relief (p = .02), lower rate of arrhythmia (p < .001), and recurrent angina (p = .02) after operation compared patients received DES. CONCLUSION: R-CABG offers lower r-TLR rate and better angina relief compared with DES for revascularization in patients with isolated proximal LAD stenosis and there was no difference in mortality, MI, stroke, and MACCE between them.

3.
Medicine (Baltimore) ; 100(1): e24173, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429802

RESUMO

BACKGROUND: Whether the addition of Chinese herbal medicine (CHM) in routine western medicines for post-stroke depression yields additional therapeutic effects still remains to be controversial. This study aimed to assess the efficacy and safety of combination of CHM with routine western medicines versus routine western medicines alone in patients with post-stroke depression (PSD). METHODS: Electronic databases such as PubMed, EmBase, Cochrane library, and China National Knowledge Infrastructure were systematically searched from inception till October 2019. Studies designed as randomized controlled trials (RCTs) and that investigated the therapeutic effects of CHM plus routine western medicines (CHM group) versus routine western medicines alone (control group) in PSD patients were eligible. The relative risk (RR) and weighted mean difference (WMD) with 95% confidence interval (CI) were used to assess the categories and continuous data using random-effects model. Software STATA was applied to perform statistical analysis (Version 10.0; StataCorp, TX,). RESULTS: A total of 18 RCTs involving a total of 1,367 PSD patients were selected for final analysis. The effective rate in CHM group was significantly higher than that in control group (RR: 1.18; 95%CI: 1.12-1.24; P < .001). Moreover, patients in CHM group showed association with lower Hamilton Depression Rating Scale (WMD: -3.17; 95%CI: -4.12 to -2.22; P < .001) and Scandinavian Stroke Scale (WMD: -3.84; 95%CI: -5.73 to -1.96; P < .001) than those in control group. Furthermore, patients in CHM were associated with high level of Barthel Index than those in control group (WMD: 11.06; 95%CI: 4.01 to 18.10; P = .002). Finally, patients in CHM group had lower risk of gastrointestinal (RR: 0.49; 95%CI: 0.31-0.77; P = .002) and neurological (RR: 0.50; 95%CI: 0.33-0.75; P = .001) adverse events than those in control group. CONCLUSIONS: The study findings revealed that addition of CHM to routine therapies could improve the therapeutic effects and reduce gastrointestinal or neurological adverse events.


Assuntos
Depressão/tratamento farmacológico , Depressão/etiologia , Medicina Tradicional Chinesa/normas , Acidente Vascular Cerebral/complicações , Depressão/psicologia , Humanos , Medicina Tradicional Chinesa/métodos , Medicina Tradicional Chinesa/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Acidente Vascular Cerebral/psicologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-33302613

RESUMO

BACKGROUND: To assess the safety and effectiveness, clinical experience with totally robotic mitral valve replacement (TE-MVR) for treating valvular heart disease was summarized and analyzed, and patients' recovery conditions were followed-up. METHODS: The clinical data of 47 patients who received TE-MVR in our hospital between October 2008 and December 2015 were retrospectively analyzed. Among the patients, there are 26 men and 21 women. The mean age was 47.53±10.80 years. We followed up the transesophageal echocardiography (TTE) data of post-discharge patients and analyzed the operation results to determine the surgical effects of TE-MVR. The surgeries were mainly performed with the da Vinci Si robotic surgical system. RESULTS: Thirty-five mechanical valves and twelve bioprosthetic valves were implanted. The cardiopulmonary bypass and aortic cross-clamping times were 122.02±25.45 min and 85.68±20.70 min, respectively. There was no operative mortality. The perioperative complication could only be found in one case, which was pleural effusion. All the TTE results were satisfying before discharge. No paravalvular leakage or prosthetic valve dysfunction was detected. All 47 patients were discharged successfully. During the long-term follow-up (28-110 months), 42 patients were followed-up (89.4%). Most of their heart function was NYHA class I and II. The postoperative TTE showed that the left atrial diameter and left ventricle diameter were decreased (P<0.01). CONCLUSIONS: TE-MVR is reliable and effective, and the postoperative follow-up results revealed good heart function. Patients will obtain benefits from TE-MVR, such as small trauma and rapid recovery. Thus, it is a good minimally-invasive surgery of choice.

5.
Nat Commun ; 11(1): 5752, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188207

RESUMO

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Antivirais/farmacologia , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Macaca mulatta , Masculino , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/prevenção & controle , Receptores de IgG/genética , Receptores de IgG/imunologia , Receptores Virais/metabolismo , Células Vero , Ligação Viral
6.
Emerg Microbes Infect ; 9(1): 2606-2618, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33241728

RESUMO

The ongoing COVID-19 pandemic is causing huge impact on health, life, and global economy, which is characterized by rapid spreading of SARS-CoV-2, high number of confirmed cases and a fatality/case rate worldwide reported by WHO. The most effective intervention measure will be to develop safe and effective vaccines to protect the population from the disease and limit the spread of the virus. An inactivated, whole virus vaccine candidate of SARS-CoV-2 has been developed by Wuhan Institute of Biological Products and Wuhan Institute of Virology. The low toxicity, immunogenicity, and immune persistence were investigated in preclinical studies using seven different species of animals. The results showed that the vaccine candidate was well tolerated and stimulated high levels of specific IgG and neutralizing antibodies. Low or no toxicity in three species of animals was also demonstrated in preclinical study of the vaccine candidate. Biochemical analysis of structural proteins and purity analysis were performed. The inactivated, whole virion vaccine was characterized with safe double-inactivation, no use of DNases and high purity. Dosages, boosting times, adjuvants, and immunization schedules were shown to be important for stimulating a strong humoral immune response in animals tested. Preliminary observation in ongoing phase I and II clinical trials of the vaccine candidate in Wuzhi County, Henan Province, showed that the vaccine is well tolerant. The results were characterized by very low proportion and low degree of side effects, high levels of neutralizing antibodies, and seroconversion. These results consistent with the results obtained from preclinical data on the safety.

7.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(11): 1557-1563, 2020 Nov 30.
Artigo em Chinês | MEDLINE | ID: mdl-33243731

RESUMO

OBJECTIVE: To compare the mid- and long-term outcomes of patients receiving mitral valve replacement through robotically assisted and conventional median sternotomy approach. METHODS: The data of 47 patients who underwent da Vinci robotic mitral valve replacement in our hospital between January, 2007 and December, 2015 were collected retrospectively (robotic group). From a total of 286 patients undergoing mitral valve replacement through the median thoracotomy approach between March, 2002 and June, 2014, 47 patients were selected as the median sternotomy group for matching with the robotic group at a 1:1 ratio. The perioperative data and follow-up data of the patients were collected, and the quality of life (QOL) of the patients at 30 days and 6 months was evaluated using the Quality of Life Short Form Survey (SF-12). The time of returning to work postoperatively and the patients' satisfaction with the surgical incision were compared between the two groups. RESULTS: All the patients in both groups completed mitral valve replacement successfully, and no death occurred during the operation. In the robotic group, only one patient experienced postoperative complication (pleural effusion); in median sternotomy group, one patient received a secondary thoracotomy for management of bleeding resulting from excessive postoperative drainage, and one patient died of septic shock after the operation. The volume of postoperative drainage, postoperative monitoring time, ventilation time, and postoperative hospital stay were significantly smaller or shorter in the robotic group than in the thoracotomy group (P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups. Assessment of the patients at 30 days after the operation showed a better quality of life in the robotic group, but the difference between the two groups tended to diminish at 6 months. The patients in the robotic group reported significantly better satisfaction with the incision than those in the thoracotomy group (P < 0.001). At 6 months after the operation, the patients in the robotic group showed significantly faster recovery of work and daily activities than those in the thoracotomy group. CONCLUSIONS: Robotically assisted mitral valve replacement is safe and reliable. Compared with the median sternotomy approach, the robotic approach is less invasive and promotes faster postoperative recovery of the patients, who have better satisfaction with the quality of life and wound recovery.

8.
BMC Urol ; 20(1): 156, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028271

RESUMO

BACKGROUND: Large paraganglioma of the Zuckerkandl organ (POZ) is extremely rare. The patient can occasionally be paucisymptomatic, further obscuring the diagnosis and carrying high mortality. Recommended treatment for large paraganglioma (PGL) is open surgical removal. We report a case of successful laparoscopic resection of a large POZ with normal blood pressure in a 45-year-old man. CASE PRESENTATION: A 45-year-old man was hospitalized because of hyperglycemia. Computed tomography of the abdomen and the serum and urinary catecholamine levels confirmed the diagnosis of large POZ. But his blood pressure was normal and he underwent laparoscopic tumor excision successfully. During 6 months follow-up after laparoscopy, serum and urinary catecholamines were normal but glycaemia remained high level. DNA analysis of the succinate dehydrogenase complex subunits B (SDHB) and SDHD revealed no mutation. CONCLUSIONS: POZ is an unusual mass and preoperative diagnosis can be difficult in clinically silent cases. PGL cannot be excluded in patients with normal blood pressure. Even a large POZ can be excised laparoscopically by following proper techniques.

9.
J Mol Biol ; 432(23): 6146-6156, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33058871

RESUMO

Forkhead box G1 (FOXG1) is a transcription factor mainly expressed in the brain that plays a critical role in the development and regionalization of the forebrain. Aberrant expression of FOXG1 has implications in FOXG1 syndrome, a serious neurodevelopmental disorder. Here, we report the crystal structure of the FOXG1 DNA-binding domain (DBD) in complex with the forkhead consensus DNA site DBE2 at the resolution of 1.6 Å. FOXG1-DBD adopts a typical winged helix fold. Compared to those of other FOX-DBD/DBE2 structures, the N terminus, H3 helix and wing2 region of FOXG1-DBD exhibit differences in DNA recognition. The FOXG1-DBD wing2 region adopts a unique architecture composed of two ß-strands that differs from all other known FOX-DBD wing2 folds. Mutation assays revealed that the disease-causing mutations within the FOXG1-DBD affect DNA binding, protein thermal stability, or both. Our report provides initial insight into how FOXG1 binds DNA and sheds light on how disease-causing mutations in FOXG1-DBD affect its DNA-binding ability.

10.
Emerg Microbes Infect ; 9(1): 2013-2019, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32867625

RESUMO

COVID-19 is a new respiratory illness caused by SARS-CoV-2, and has constituted a global public health emergency. Cat is susceptible to SARS-CoV-2. However, the prevalence of SARS-CoV-2 in cats remains largely unknown. Here, we investigated the infection of SARS-CoV-2 in cats during COVID-19 outbreak in Wuhan by serological detection methods. A cohort of serum samples were collected from cats in Wuhan, including 102 sampled after COVID-19 outbreak, and 39 prior to the outbreak. Fifteen sera collected after the outbreak were positive for the receptor binding domain (RBD) of SARS-CoV-2 by indirect enzyme linked immunosorbent assay (ELISA). Among them, 11 had SARS-CoV-2 neutralizing antibodies with a titer ranging from 1/20 to 1/1080. No serological cross-reactivity was detected between SARS-CoV-2 and type I or II feline infectious peritonitis virus (FIPV). In addition, we continuously monitored serum antibody dynamics of two positive cats every 10 days over 130 days. Their serum antibodies reached the peak at 10 days after first sampling, and declined to the limit of detection within 110 days. Our data demonstrated that SARS-CoV-2 has infected cats in Wuhan during the outbreak and described serum antibody dynamics in cats, providing an important reference for clinical treatment and prevention of COVID-19.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/veterinária , Pandemias/veterinária , Pneumonia Viral/veterinária , Animais , Gatos , China , Infecções por Coronavirus/epidemiologia , Coronavirus Felino/imunologia , Reações Cruzadas/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Imunoglobulina G/sangue , Proteínas do Nucleocapsídeo/imunologia , Fosfoproteínas , Pneumonia Viral/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia
11.
J Card Surg ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32939788

RESUMO

OBJECTIVE: This study aimed to evaluate the role of surgical left atrial appendage (LAA) exclusion in the prevention of stroke after mitral valve replacement (MVR). METHODS: We retrospectively reviewed clinical data of 860 patients who received MVR in our center from January 2008 to January 2013. The patients were randomly assigned to two surgical groups, namely LAA exclusion group (n = 521) and LAA nonexclusion group (n = 339) according to whether concurrent surgical exclusion of the LAA was to be undertaken or not before surgery in a blind fashion. MVR was performed by two experienced surgeons. The LAA was explored during the operation and mural thrombus removed in all cases. The LAA was left intact in nonocclusion group whereas the neck of the LAA was closed with a two-layer continued suture in exclusion group. The incidence of early postoperative ischemic stroke between the two groups was compared. RESULTS: The patients' age was 53 ± 12 years, with 48.1% male and 67.9% with rheumatic disease. Mural thrombosis was seen in 18.8% of the patients and atrial fibrillation (AF) coexisted in 62.4%. All operations were successfully performed and no difference was noted in in-hospital mortality, re-exploration for bleeding, and other major complications between the two groups. The incidence of ischemic stroke in LAA exclusion group was significantly lower than in nonexclusion group (0.6% vs. 2.7%, p = .011). The subgroup multivariate analysis showed that LAA exclusion significantly reduced the risk of postoperative stroke in patients with AF (odds ratio [OR] = 0.070, 95% confidence interval [CI]: 0.006-0.705, p = .025) but not in non-AF patients (OR = 1.902, 95% CI: 0.171-21.191, p = .601). CONCLUSIONS: Concurrent LAA exclusion during MVR is a safe and effective way to reduce postoperative ischemic stroke, particularly in patients with AF.

13.
Mol Ecol ; 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32812678

RESUMO

Marine planktonic bacteria and archaea commonly exhibit pronounced seasonal succession in community composition. But the existence of seasonality in their assembly processes and between-domain differences in underlying mechanism are largely unassessed. Using a high-coverage sampling strategy (including single sample for each station during four cruises in different seasons), 16S rRNA gene sequencing, and null models, we investigated seasonal patterns in the processes governing spatial turnover of bacteria and archaea in surface coastal waters across a sampling grid over ~300 km in the East China Sea. We found that archaea only bloomed in prokaryotic communities during autumn and winter cruises. Seasonality mostly overwhelmed spatial variability in the compositions of both domains. Bacterial and archaeal communities were dominantly governed by deterministic and stochastic assembly processes, respectively, in autumn cruise, probably due to the differences in niche breadths (bacteria < archaea) and relative abundance (bacteria > archaea). Stochasticity dominated assembly mechanisms of both domains but was driven by distinct processes in winter cruise. Determinism-dominated assembly mechanisms of bacteria rebounded in spring and summer cruises, reflecting seasonal variability in bacterial community assembly. This could be attributed to seasonal changes in bacterial niche breadths and habitat heterogeneity across the study area. There were seasonal changes in environmental factors mediating the determinism-stochasticity balance of bacterial community assembly, holding a probability of the existence of unmeasured mediators. Our results suggest contrasting assembly mechanisms of bacteria and archaea in terms of determinism-vs.-stochasticity pattern and its seasonality, highlighting the importance of seasonal perspective on microbial community assembly in marine ecosystems.

14.
Front Genet ; 11: 674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760423

RESUMO

Patients with carcinoma of unknown primary (CUP) account for 3-5% of all cancer cases. A large number of metastatic cancers require further diagnosis to determine their tissue of origin. However, diagnosis of CUP and identification of its primary site are challenging. Previous studies have suggested that molecular profiling of tissue-specific genes could be useful in inferring the primary tissue of a tumor. The purpose of this study was to evaluate the performance somatic mutations detected in a tumor to identify the cancer tissue of origin. We downloaded the somatic mutation datasets from the International Cancer Genome Consortium project. The random forest algorithm was used to extract features, and a classifier was established based on the logistic regression. Specifically, the somatic mutations of 300 genes were extracted, which are significantly enriched in functions, such as cell-to-cell adhesion. In addition, the prediction accuracy on tissue-of-origin inference for 3,374 cancer samples across 13 cancer types reached 81% in a 10-fold cross-validation. Our method could be useful in the identification of cancer tissue of origin, as well as the diagnosis and treatment of cancers.

15.
JAMA ; 324(10): 951-960, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32789505

RESUMO

Importance: A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. Objective: To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China. Interventions: In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 µg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 µg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]). Design, Setting, and Participants: Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020. Main Outcomes and Measures: The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups. Conclusions and Relevance: In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunogenicidade da Vacina , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Humanos , Injeções Intramusculares , Masculino , Pneumonia Viral/imunologia , Propiolactona , Vacinas de Produtos Inativados/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Adulto Jovem
16.
Cell Res ; 30(8): 670-677, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32636454

RESUMO

The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.


Assuntos
Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Macaca mulatta/virologia , Pneumonia Viral/patologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/virologia , Feminino , Imuno-Histoquímica , Masculino , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/virologia , RNA Viral/genética , Radiografia Torácica , Reação em Cadeia da Polimerase em Tempo Real , Carga Viral , Replicação Viral
17.
Artigo em Inglês | MEDLINE | ID: mdl-32637398

RESUMO

With the development of high throughput technologies, there are more and more protein-protein interaction (PPI) networks available, which provide a need for efficient computational tools for network alignment. Network alignment is widely used to predict functions of certain proteins, identify conserved network modules, and study the evolutionary relationship across species or biological entities. However, network alignment is an NP-complete problem, and previous algorithms are usually slow or less accurate in aligning big networks like human vs. yeast. In this study, we proposed a fast yet accurate algorithm called Network Alignment by Integrating Biological Process (NAIGO). Specifically, we first divided the networks into subnets taking the advantage of known prior knowledge, such as gene ontology. For each subnet pair, we then developed a novel method to align them by considering both protein orthologous information and their local structural information. After that, we expanded the obtained local network alignments in a greedy manner. Taking the aligned pairs as seeds, we formulated the global network alignment problem as an assignment problem based on similarity matrix, which was solved by the Hungarian method. We applied NAIGO to align human and Saccharomyces cerevisiae S288c PPI network and compared the results with other popular methods like IsoRank, GRAAL, SANA, and NABEECO. As a result, our method outperformed the competitors by aligning more orthologous proteins or matched interactions. In addition, we found a few potential functional orthologous proteins such as RRM2B in human and DNA2 in S. cerevisiae S288c, which are related to DNA repair. We also identified a conserved subnet with six orthologous proteins EXO1, MSH3, MSH2, MLH1, MLH3, and MSH6, and six aligned interactions. All these proteins are associated with mismatch repair. Finally, we predicted a few proteins of S. cerevisiae S288c potentially involving in certain biological processes like autophagosome assembly.

18.
Biomed Res Int ; 2020: 5279193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685499

RESUMO

Lonicera japonica is a traditional Chinese herbal medicine with antioxidation, anti-inflammatory, antibacterial, and immunoregulation functions. A method to isolate polysaccharides from Lonicera japonica (LJP) has been reported previously by our group. We also reported previously that LJP was consisted of 6 types of monosaccharides and had the characteristic absorption of typical polysaccharides. In this study, we investigated the protective effect of LJP on cardiomyocytes of mice injured by hydrogen peroxide (H2O2). The results showed that LJP can increase the cardiomyocyte viability and the activities of the enzyme (SOD, CAT, GSH-Px, AST, CPK, and LDH) in cardiomyocytes of mice injured by hydrogen peroxide. The results of intracellular ROS contents showed that a high dose (40 µg mL-1) of LJP had the best effects on protecting the cardiomyocytes of mice injured by H2O2. In addition, the measurement results of the cardiomyocyte apoptosis and the activity of caspase-3, caspase-8, and caspase-9 in cardiomyocytes confirmed this conclusion from another perspective.

19.
Cell ; 182(1): 50-58.e8, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32516571

RESUMO

COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Camundongos Transgênicos , Pneumonia Viral/patologia , Animais , Feminino , Humanos , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Pandemias , Peptidil Dipeptidase A/genética , Tropismo Viral , Perda de Peso
20.
Environ Pollut ; 265(Pt B): 115047, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32585552

RESUMO

Terminating harmful algal blooms by using algicidal agents is a strong disturbance event in marine environment, which has powerful structural influences on microbial ecosystems. But, the response of microbial ecosystem to algicidal agent is largely unknown. Here, we conducted Phaeocystis globosa microcosms to investigate the dynamics, assembly processes, and co-occurrence patterns of microbial communities in response to algicidal process induced by a highly efficient algicidal agent, prodigiosin, by using 16S rRNA gene amplicon sequencing. The α-diversity of microbial community showed no obvious changes during the algicidal process in P. globosa microcosm treated with prodigiosin (group PD). Rhodobacteraceae increased significantly (P < 0.05) during algicidal process in PD, and this was mainly due to the lysis of P. globosa cells. Compared to the control group, the temporal turnover rates of common and rare taxa in PD were significantly higher because of the lysis of P. globosa induced by prodigiosin. Neutral processes mainly drove the assembly of microbial communities in all microcosms, even though the algicidal process induced by prodigiosin had no effect on the assembly processes. In addition, the time-decay relationship and co-occurrence network analysis indicate that rare taxa play important roles in maintaining microbial community stability in response to the algicidal process, rather than prodigiosin. These findings suggest that prodigiosin cannot affect the dynamics of microbial communities directly; however, future investigations into the function of microbial communities in response to prodigiosin remain imperative.


Assuntos
Haptófitas , Herbicidas , Microbiota , Proliferação Nociva de Algas , Prodigiosina , RNA Ribossômico 16S
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