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3.
bioRxiv ; 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35118473

RESUMO

The 2019 coronavirus disease (COVID-19) pandemic has had devastating impacts on our global health. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, has continued to mutate and spread worldwide despite global vaccination efforts. In particular, the Omicron variant, first identified in South Africa in late November 2021, has now overtaken the Delta variant and become the dominant strain worldwide. Compared to the original strain identified in Wuhan, Omicron features 50 genetic mutations, with 15 mutations in the receptor-binding domain (RBD) of the spike protein, which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor for viral entry. However, it is not completely understood how these mutations alter the interaction and binding strength between the Omicron RBD and ACE2. In this study, we used a combined steered molecular dynamics (SMD) simulation and experimental microscale thermophoresis (MST) approach to quantify the interaction between Omicron RBD and ACE2. We report that the Omicron brings an enhanced RBD-ACE2 interface through N501Y, Q493K/R, and T478K mutations; the changes further lead to unique interaction patterns, reminiscing the features of previously dominated variants, Alpha (N501Y) and Delta (L452R and T478K). Our MST data confirmed that the Omicron mutations in RBD are associated with a five-fold higher binding affinity to ACE2 compared to the RBD of the original strain. In conclusion, our result could help explain the Omicron variant’s prevalence in human populations, as higher interaction forces or affinity for ACE2 likely promote greater viral binding and internalization, leading to increased infectivity.

5.
Nat Commun ; 13(1): 485, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35079011

RESUMO

Nitrogen (N), one of the most important plant nutrients, plays crucial roles in multiple plant developmental processes. Spikelets are the primary sink tissues during reproductive growth, and N deficiency can cause floral abortion. However, the roles of N nutrition in meiosis, the crucial step in plant sexual reproduction, are poorly understood. Here, we identified an N-dependent meiotic entrance mutant with loss of function of ELECTRON TRANSFER FLAVOPROTEIN SUBUNIT ß (ETFß) in rice (Oryza sativa). etfß displayed meiosis initiation defects, excessive accumulation of branched-chain amino acids (BCAAs) and decrease in total N contents in spikelets under N starvation, which were rescued by applying excess exogenous inorganic N. Under N starvation, ETFß, through its involvement in BCAA catabolism, promotes N reutilization and contributes to meeting N demands of spikelets, highlighting the impact of N nutrition on meiosis initiation. We conclude that N nutrition contributes to plant fertility by affecting meiosis initiation.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Flavoproteínas Transferidoras de Elétrons/metabolismo , Regulação da Expressão Gênica de Plantas , Meiose , Nitrogênio/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Flavoproteínas Transferidoras de Elétrons/genética , Fertilidade , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/genética
7.
Cytometry A ; 101(2): 150-158, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34173319

RESUMO

Human basophils are terminally differentiated granulocytes that are least abundant in the peripheral blood but play important roles in allergic diseases. Studies on human basophils are limited by the high cost on the isolation of human basophils by magnetic-activated cell sorting (MACS) for negative depletion of non-basophils, followed by CD123-based positive selection of basophils. Moreover, such CD123-based purification of basophils may be limited by blocking of the binding of IL-3/anti-CD123 to the surface CD123. Here we identified SSClow CD4- CD127- HLA-DR- CRTH2high as unique markers for the identification of human basophils through stringent flow cytometric analysis of leukocytes from buffy coat. We established an efficient and cost-effective method for isolating human basophils from buffy coat based on positive magnetic selection of CRTH2+ cells followed by flow cytometric sorting of SSClow CD4- CD127- HLA-DR- CRTH2high cells. Approximately 1 to 1.5 million basophils were isolated from one buffy coat with a purity of >97%. Basophils purified by this method were viable and efficiently responded to key regulators of basophils including IL-3 and anti-IgE. This method can be used for purifying human basophils for subsequent functional studies.


Assuntos
Basófilos , Subunidade alfa de Receptor de Interleucina-3 , Análise Custo-Benefício , Antígenos HLA-DR , Humanos , Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-3/metabolismo
8.
Int J Med Inform ; 161: 104733, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35299099

RESUMO

PURPOSE: To develop and validate machine learning (ML) models for cancer-associated deep vein thrombosis (DVT) and to compare the performance of these models with the Khorana score (KS). METHODS: We randomly extracted data of 2100 patients with cancer between Jan. 1, 2017, and Oct. 31, 2019, and 1035 patients who underwent Doppler ultrasonography were enrolled. Univariate analysis and Lasso regression were applied to select important predictors. Model training and hyperparameter tuning were implemented on 70% of the data using a ten-fold cross-validation method. The remaining 30% of the data were used to compare the performance with seven indicators (area under the receiver operating characteristic curve [AUC], sensitivity, specificity, accuracy, balanced accuracy, Brier score, and calibration curve), among all five ML models (linear discriminant analysis [LDA], logistic regression [LR], classification tree [CT], random forest [RF], and support vector machine [SVM]), and the KS. RESULTS: The incidence of cancer-associated DVT was 22.3%. The top five predictors were D-dimer level, age, Charlson Comorbidity Index (CCI), length of stay (LOS), and previous VTE (venous thromboembolism) history according to RF. Only LDA (AUC = 0.773) and LR (AUC = 0.772) outperformed KS (AUC = 0.642), and combination with D-dimer showed improved performance in all models. A nomogram and web calculator https://webcalculatorofcancerassociateddvt.shinyapps.io/dynnomapp/ were used to visualize the best recommended LR model. CONCLUSION: This study developed and validated cancer-associated DVT predictive models using five ML algorithms and visualized the best recommended model using a nomogram and web calculator. The nomogram and web calculator developed in this study may assist doctors and nurses in evaluating individualized cancer-associated DVT risk and making decisions. However, other prospective cohort studies should be conducted to externally validate the recommended model.


Assuntos
Neoplasias , Trombose Venosa , Humanos , Modelos Logísticos , Aprendizado de Máquina , Neoplasias/complicações , Neoplasias/epidemiologia , Estudos Prospectivos , Trombose Venosa/diagnóstico , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia
9.
J Chem Theory Comput ; 17(12): 7972-7979, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34856802

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. It is known that the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, initiating the entry of SARS-CoV-2. Since its emergence, a number of SARS-CoV-2 variants have been reported, and the variants that show high infectivity are classified as variants of concern according to the United States Centers for Disease Control and Prevention. In this study, we performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). We report that RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484 K, and N501Y) or Delta (L452R and T478 K) variants. Among all variants investigated in this work, RBD of the Epsilon (L452R) variant is relatively easily detached from ACE2. Our results from both SMD simulations and MST experiments indicate what makes each variant more contagious in terms of RBD and ACE2 interactions. This study could shed light on developing new drugs to inhibit SARS-CoV-2 entry effectively.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , SARS-CoV-2/química , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , COVID-19/metabolismo , Células HEK293 , Humanos , Ligação Proteica , SARS-CoV-2/classificação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus
11.
J Chem Inf Model ; 61(11): 5336-5342, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34757752

RESUMO

Rational drug design involves a task of finding ligands that would bind to a specific target protein. This work presents CHARMM-GUI Ligand Designer that is an intuitive and interactive web-based tool to design virtual ligands that match the shape and chemical features of a given protein binding site. Ligand Designer provides ligand modification capabilities with 3D visualization that allow researchers to modify and redesign virtual ligands while viewing how the protein-ligand interactions are affected. Virtual ligands can also be parameterized for further molecular dynamics (MD) simulations and free energy calculations. Using 8 targets from 8 different protein classes in the directory of useful decoys, enhanced (DUD-E) data set, we show that Ligand Designer can produce similar ligands to the known active ligands in the crystal structures. Ligand Designer also produces stable protein-ligand complex structures when tested using short MD simulations. We expect that Ligand Designer can be a useful and user-friendly tool to design small molecules in any given potential ligand binding site on a protein of interest.


Assuntos
Simulação de Dinâmica Molecular , Proteínas , Sítios de Ligação , Ligantes , Ligação Proteica , Proteínas/metabolismo
12.
Front Plant Sci ; 12: 757152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675957

RESUMO

Manipulation of the distribution and frequency of meiotic recombination events to increase genetic diversity and disrupting genetic interference are long-standing goals in crop breeding. However, attenuation of genetic interference is usually accompanied by a reduction in recombination frequency and subsequent loss of plant fertility. In the present study, we generated null mutants of the ZEP1 gene, which encodes the central component of the meiotic synaptonemal complex (SC), in a hybrid rice using CRISPR/Cas9. The null mutants exhibited absolute male sterility but maintained nearly unaffected female fertility. By pollinating the zep1 null mutants with pollen from indica rice variety 93-11, we successfully conducted genetic analysis and found that genetic recombination frequency was greatly increased and genetic interference was completely eliminated in the absence of ZEP1. The findings provided direct evidence to support the controversial hypothesis that SC is involved in mediating interference. Additionally, the remained female fertility of the null mutants makes it possible to break linkage drag. Our study provides a potential approach to increase genetic diversity and fully eliminate genetic interference in rice breeding.

15.
J Chem Theory Comput ; 17(10): 6559-6569, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34529436

RESUMO

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work and performed all-atom molecular dynamics simulations to gain insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.


Assuntos
Anticorpos Neutralizantes/química , Glicoproteína da Espícula de Coronavírus/química , Anticorpos Neutralizantes/imunologia , Reações Antígeno-Anticorpo , COVID-19 , Simulação por Computador , Glicosilação , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Polissacarídeos/química , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
17.
Eur J Oncol Nurs ; 54: 102023, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34500318

RESUMO

PURPOSE: Early detection and intervention of lymphedema is essential for improving the quality of life of breast cancer survivors. Previous studies have shown that patients have symptoms such as arm tightness and arm heaviness before experiencing obvious limb swelling. Thus, this study aimed to develop a symptom-warning model for the early detection of breast cancer-related lymphedema. METHODS: A cross-sectional study was conducted at a tertiary hospital in Beijing between April 2017 and December 2018. A total of 24 lymphedema-associated symptoms were identified as candidate predictors. Circumferential measurements were used to diagnose lymphedema. The data were randomly split into training and validation sets with a 7:3 ratio to derive and evaluate six machine learning models. Both the discrimination and calibration of each model were assessed on the validation set. RESULTS: A total of 533 patients were included in the study. The logistic regression model showed the best performance for early detection of lymphedema, with AUC = 0.889 (0.840-0.938), sensitivity = 0.771, specificity = 0.883, accuracy = 0.825, and Brier scores = 0.141. Calibration was also acceptable. It has been deployed as an open-access web application, allowing users to estimate the probability of lymphedema individually in real time. The application can be found at https://apredictiontoolforlymphedema.shinyapps.io/dynnomapp/. CONCLUSION: The symptom-warning model developed by logistic regression performed well in the early detection of lymphedema. Integrating this model into an open-access web application is beneficial to patients and healthcare providers to monitor lymphedema status in real-time.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Linfedema , Neoplasias da Mama/complicações , Estudos Transversais , Feminino , Humanos , Linfedema/diagnóstico , Linfedema/etiologia , Qualidade de Vida
18.
bioRxiv ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34341794

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. It is known that the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, initiating the entry of SARS-CoV-2. Since its emergence, a number of SARS-CoV-2 variants have been reported, and the variants that show high infectivity are classified as the variants of concern according to the US CDC. In this study, we performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). We report that the RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484K, and N501Y) or Delta (L452R and T478K) variant. Among all variants investigated in this work, the RBD of the Epsilon (L452R) variant is relatively easily detached from ACE2. Our results combined SMD simulations and MST experiments indicate what makes each variant more contagious in terms of RBD and ACE2 interactions. This study could help develop new drugs to inhibit SARS-CoV-2 entry effectively.

19.
Eur J Oncol Nurs ; 53: 101943, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281789

RESUMO

PURPOSE: Our study aims to investigate dietary intake characteristics and their association with skeletal muscle mass in head and neck cancer patients treated with radiotherapy. METHODS: From March 2017 to August 2018, patients with head and neck cancer who received radiotherapy at our affiliated hospital were enrolled. Dietary intake was assessed through 24-hr dietary recall and skeletal muscle mass was evaluated by bioelectrical impedance analysis at three-time points. Appendicular skeletal muscle mass was adjusted for height squared defined sarcopenia and correlated with dietary intake by generalized estimating equations (GEE). RESULTS: This study sample comprised 287 patients [median age: 54 years; 187 (65.2%) men]. Median dietary intake at post-treatment was 14.95 kcal/kg/day energy and 0.63 g/kg/day protein. Skeletal muscle mass decreased significantly in all patients. The prevalence of sarcopenia increased from 24.4% before treatment to 46.7% at the end of treatment. Exploratory univariate GEE analysis revealed that radiotherapy time-point, male-gender, age ≥60 and decreased dietary energy intake significantly impacted on muscle loss represented by the appendicular skeletal muscle index. After controlling covariates, dietary energy intake was only positively associated with muscle loss in women (P = 0.013, 95% CI = 0.003-0.027) but not in men (P = 0.788, 95% CI = -0.007-0.009). CONCLUSION: While the loss in skeletal muscle is more prevalent in men receiving radiotherapy, the effects of dietary energy intake were only associated with women. A prospective randomized clinical trial is required to identify the appropriate amount of dietary energy supplement by gender in cancer patients treated with radiotherapy.


Assuntos
Neoplasias de Cabeça e Pescoço , Sarcopenia , Ingestão de Alimentos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Prevalência , Estudos Prospectivos , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Sarcopenia/patologia
20.
J Int Med Res ; 49(7): 3000605211033495, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34292764

RESUMO

OBJECTIVE: To investigate the predictive value of hyperhomocysteinaemia (HHcy) for obstructive coronary artery disease (CAD) in an Asian population in northern China. METHODS: This retrospective study enrolled patients at their first cardiac assessment and assigned them to an obstructive CAD group or a non-obstructive CAD group according to the coronary angiography results. HHcy was defined as a homocysteine (Hcy) level > 15 µmol/l. RESULTS: This study enrolled 2987 participants: 1172 in the non-obstructive CAD group and 1815 in the obstructive CAD group. Hcy level in the obstructive CAD group was significantly higher than in the non-obstructive CAD group. The proportion of patients with HHcy in the obstructive CAD group was significantly greater than in the non-obstructive CAD group. Multivariate logistic regression analysis demonstrated that HHcy was independently correlated with obstructive CAD in both young (aged ≤ 55 years) and old patients (aged > 55 years). HHcy showed a higher sensitivity (93.1%), specificity (86.1%) and accuracy (90.0%) for obstructive CAD. The odds ratio for HHcy was 84.2. The Kappa value (0.8) showed substantial agreement between obstructive CAD and HHcy. CONCLUSIONS: HHcy was associated with obstructive CAD and may be a potentially independent risk factor for obstructive CAD with good predictive value.


Assuntos
Doença da Artéria Coronariana , Hiper-Homocisteinemia , China , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Homocisteína , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/diagnóstico , Estudos Retrospectivos , Fatores de Risco
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