Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 77
Filtrar
1.
Macromol Rapid Commun ; : e2100449, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34624165

RESUMO

Processable microporous organic polymers (MOPs) attract incomparable research interests becuase their vairous types such as monoliths and membranes are for practical application. Most of processable MOPs usually need the harsh conditions such as the use of expensive metal catalysts, specialized stereospecific monomers etc., which restrict the sustainable and real applications of processable MOPs. Therefore, the economical mass production of processable MOPs remains a formidable challenge. Herein, we report that a novel strategy for constructing processable hypercrosslinked polymers (HCPs) need two steps synthesis of pre-crosslinking and deep-crosslinking using divinylbenzene (DVB) as self-crosslinking monomer under the catalysis of a small amount of FeCl3 . The resulting HCPs monoliths possess high BET surface area of 1033-1056 m2 g-1 with hierarchical porosity, and show excellent mechanical strength up to 65 MPa. It is, to the best of our knowledge, the first report of using aromatic vinyl monomers as self-crosslinking monomers to generate HCPs monoliths with high surface area, yielding no by-products and high mechanical strength. This article is protected by copyright. All rights reserved.

2.
Environ Sci Technol ; 55(17): 11538-11548, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34488351

RESUMO

Sulfur dioxide (SO2) measured by satellites is widely used to estimate anthropogenic emissions. The Sentinel-5 Precursor (S-5P) operational SO2 product is overestimated compared to the ground-based multiaxis differential optical absorption spectroscopy (MAX-DOAS) measurements in China and shows an opposite variation to the surface measurements, which limits the application of TROPOspheric monitoring instrument (TROPOMI) products in emissions research. Radiometric calibration, a priori profiles, and fitting windows might cause the overestimation of S-5P operational SO2 product. Here, we improve the optimal-estimation-based algorithm through several calibration methods. The improved retrieval agrees reasonably well with the ground-based measurements (R > 0.70, bias <13.7%) and has smaller biases (-28.9%) with surface measurements over China and India. It revealed that the SO2 column in March 2020 decreased by 51.6% compared to March 2019 due to the lockdown for curbing the spread of the COVID-19 pandemic, and there was a decrease of 50% during the lockdown than those after the lockdown, similar to the surface measurement trend, while S-5P operational SO2 product showed an unrealistic increase of 19%. In India, the improved retrieval identified obvious "hot spots" and observed a 30% decrease of SO2 columns during the lockdown.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Pandemias , SARS-CoV-2
3.
Nat Commun ; 12(1): 5011, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408149

RESUMO

Sequence-based contact prediction has shown considerable promise in assisting non-homologous structure modeling, but it often requires many homologous sequences and a sufficient number of correct contacts to achieve correct folds. Here, we developed a method, C-QUARK, that integrates multiple deep-learning and coevolution-based contact-maps to guide the replica-exchange Monte Carlo fragment assembly simulations. The method was tested on 247 non-redundant proteins, where C-QUARK could fold 75% of the cases with TM-scores (template-modeling scores) ≥0.5, which was 2.6 times more than that achieved by QUARK. For the 59 cases that had either low contact accuracy or few homologous sequences, C-QUARK correctly folded 6 times more proteins than other contact-based folding methods. C-QUARK was also tested on 64 free-modeling targets from the 13th CASP (critical assessment of protein structure prediction) experiment and had an average GDT_TS (global distance test) score that was 5% higher than the best CASP predictors. These data demonstrate, in a robust manner, the progress in modeling non-homologous protein structures using low-accuracy and sparse contact-map predictions.


Assuntos
Biologia Computacional/métodos , Proteínas/química , Bases de Dados de Proteínas , Modelos Moleculares , Método de Monte Carlo , Conformação Proteica , Dobramento de Proteína , Proteínas/genética , Software
4.
Proteins ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382712

RESUMO

This article reports and analyzes the results of protein contact and distance prediction by our methods in the 14th Critical Assessment of techniques for protein Structure Prediction (CASP14). A new deep learning-based contact/distance predictor was employed based on the ensemble of two complementary coevolution features coupling with deep residual networks. We also improved our multiple sequence alignment (MSA) generation protocol with wholesale meta-genome sequence databases. On 22 CASP14 free modeling (FM) targets, the proposed model achieved a top-L/5 long-range precision of 63.8% and a mean distance bin error of 1.494. Based on the predicted distance potentials, 11 out of 22 FM targets and all of the 14 FM/template-based modeling (TBM) targets have correctly predicted folds (TM-score >0.5), suggesting that our approach can provide reliable distance potentials for ab initio protein folding.

5.
Cardiovasc Res ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375400

RESUMO

AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodeling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodeling, as they exhibited lower mortality, better cardiac function, shorter scar length and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin (α-SMA) myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 (CXCR2) antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodeling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodeling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI. TRANSLATIONAL PERSPECTIVE: We established EDIL3 as a critical regulator of neutrophil recruitment and macrophage polarization during post-MI cardiac remodeling. EDIL3 may be a candidate prognostic biomarker and drug target for cardiovascular diseases. The novel pathways and mechanisms revealed in this study has renewed our understanding of the role of leukocyte adhesion inhibitors in cardiovascular disease. Meanwhile, our study reaffirmed the indispensable role of inflammation in the healing process, thereby prompting the reevaluation of post-MI anti-inflammatory treatments.

6.
Circulation ; 144(14): 1145-1159, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34346740

RESUMO

BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection. Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive, impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMCs) have heterogenous embryonic origins, depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. METHODS: We identified an LDS family with a dominant pathogenic variant in the TGFBR1 gene (TGFBR1A230T) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human induced pluripotent stem cells from a subject with normal aorta to generate human induced pluripotent stem cells carrying TGFBR1A230T, and corrected the mutation in patient-derived human induced pluripotent stem cells using CRISPR-Cas9 gene editing. After their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell lineages, we used conventional molecular techniques and single-cell RNA sequencing to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments using activin A and rapamycin. RESULTS: Our results indicate the TGFBR1A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in neural crest stem cell-SMC. Single-cell RNA sequencing results implicate defective differentiation even in TGFBR1A230T/+ CPC-SMC including disruption of SMC contraction and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1A230T selectively disrupted SMAD3 (SMAD family member 3) and AKT (AKT serine/threonine kinase) activation in CPC-SMC, and led to increased cell proliferation. Consistently, single-cell RNA sequencing revealed molecular similarities between a loss-of-function SMAD3 mutation (SMAD3c.652delA/+) and TGFBR1A230T/+. Last, combination treatment with activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression and function, and rescued the mechanical properties of mutant CPC-SMC tissue constructs. CONCLUSIONS: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with activin A and rapamycin that can rescue the SMC defects caused by the variant.

7.
Environ Pollut ; 289: 117899, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358865

RESUMO

To prevent the spread of the COVID-19 epidemic, the Chinese megacity Wuhan has taken emergent lockdown measures starting on January 23, 2020. This provided a natural experiment to investigate the response of air quality to such emission reductions. Here, we decoupled the influence of meteorological and non-meteorological factors on main air pollutants using generalized additive models (GAMs), driven by data from the China National Environmental Monitoring Center (CNEMC) network. During the lockdown period (Jan. 23 - Apr. 8, 2020), PM2.5, PM10, NO2, SO2, and CO concentrations decreased significantly by 45 %, 49 %, 56 %, 39 %, and 18 % compared with the corresponding period in 2015-2019, with contributions by S(meteos) of 15 %, 17 %, 13 %, 10 %, and 6 %. This indicates an emission reduction of NOx at least 43 %. However, O3 increased by 43 % with a contribution by S(meteos) of 6 %. In spite of the reduced volatile organic compound (VOC) emissions by 30 % during the strict lockdown period (Jan. 23 - Feb. 14, 2020), which likely reduced the production of O3, O3 concentrations increased due to a weakening of the titration effect of NO. Our results suggest that conventional emission reduction (NOx reduction only) measures may not be sufficient to reduce (or even lead to an increase of) surface O3 concentrations, even if reaching the limit, and VOC-specific measures should also be taken.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/prevenção & controle , China , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Material Particulado/análise , SARS-CoV-2
8.
Int J Med Robot ; 17(5): e2304, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34197045

RESUMO

BACKGROUND: This paper describes a case of a patient with situs inversus totalis (SIT) and dextrocardia in which robotic atrial septal defect (ASD) repair was successfully performed in a beating heart. METHODS AND RESULTS: A 45-year-old female patient who had SIT and dextrocardia was diagnosed with secundum ASD 5 years ago. Because of progressive dyspnoea, fatigue, and obvious cough, she came to our hospital for surgical treatment. Transthoracic echocardiography showed the defect located in the middle and lower segments of the atrial septum with a maximum diameter of 27 mm, with a left-to-right shunt. Transcatheter ASD closure could not be performed because there was not enough tissue surrounding the defect. After communicating with the patient, we performed robotic ASD repair in a beating heart using the da Vinci surgical system. The operation was successful, and the patient recovered quickly. CONCLUSION: As a minimally invasive approach, robotic cardiac surgery has many advantages and is feasible and safe in suitable patients.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Dextrocardia , Comunicação Interatrial , Procedimentos Cirúrgicos Robóticos , Robótica , Dextrocardia/complicações , Dextrocardia/cirurgia , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/cirurgia , Humanos , Pessoa de Meia-Idade
9.
Proteins ; 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34331351

RESUMO

In this article, we report 3D structure prediction results by two of our best server groups ("Zhang-Server" and "QUARK") in CASP14. These two servers were built based on the D-I-TASSER and D-QUARK algorithms, which integrated four newly developed components into the classical protein folding pipelines, I-TASSER and QUARK, respectively. The new components include: (a) a new multiple sequence alignment (MSA) collection tool, DeepMSA2, which is extended from the DeepMSA program; (b) a contact-based domain boundary prediction algorithm, FUpred, to detect protein domain boundaries; (c) a residual convolutional neural network-based method, DeepPotential, to predict multiple spatial restraints by co-evolutionary features derived from the MSA; and (d) optimized spatial restraint energy potentials to guide the structure assembly simulations. For 37 FM targets, the average TM-scores of the first models produced by D-I-TASSER and D-QUARK were 96% and 112% higher than those constructed by I-TASSER and QUARK, respectively. The data analysis indicates noticeable improvements produced by each of the four new components, especially for the newly added spatial restraints from DeepPotential and the well-tuned force field that combines spatial restraints, threading templates, and generic knowledge-based potentials. However, challenges still exist in the current pipelines. These include difficulties in modeling multi-domain proteins due to low accuracy in inter-domain distance prediction and modeling protein domains from oligomer complexes, as the co-evolutionary analysis cannot distinguish inter-chain and intra-chain distances. Specifically tuning the deep learning-based predictors for multi-domain targets and protein complexes may be helpful to address these issues.

11.
Hypertension ; 78(1): 16-29, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34058852

RESUMO

Increasing evidence has suggested that noncoding RNAs (ncRNAs) have vital roles in cardiovascular tissue homeostasis and diseases. As a main subgroup of ncRNAs, long ncRNAs (lncRNAs) have been reported to play important roles in lipid metabolism, inflammation, vascular injury, and angiogenesis. They have also been implicated in many human diseases including atherosclerosis, arterial remodeling, hypertension, myocardial injury, cardiac remodeling, and heart failure. Importantly, it was reported that lncRNAs were dysregulated in the development and progression of cardiovascular diseases (CVDs). A variety of studies have demonstrated that lncRNAs could influence gene expression at transcription, post-transcription, translation, and post-translation level. Particularly, emerging evidence has confirmed that the crosstalk among lncRNAs, mRNA, and miRNAs is an important underlying regulatory mechanism of lncRNAs. Nevertheless, the biological functions and molecular mechanisms of lncRNAs in CVDs have not been fully explored yet. In this review, we will comprehensively summarize the main findings about lncRNAs and CVDs, highlighting the most recent discoveries in the field of lncRNAs and their pathophysiological functions in CVDs, with the aim of dissecting the intrinsic association between lncRNAs and common risk factors of CVDs including hypertension, high glucose, and high fat. Finally, the potential of lncRNAs functioning as the biomarkers, therapeutic targets, as well as specific diagnostic and prognostic indicators of CVDs will be discussed in this review.

12.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803409

RESUMO

Protein engineering is actively pursued in industrial and laboratory settings for high thermostability. Among the many protein engineering methods, rational design by bioinformatics provides theoretical guidance without time-consuming experimental screenings. However, most rational design methods either rely on protein tertiary structure information or have limited accuracies. We proposed a primary-sequence-based algorithm for increasing the heat resistance of a protein while maintaining its functions. Using adenylate kinase (ADK) family as a model system, this method identified a series of amino acid sites closely related to thermostability. Single- and double-point mutants constructed based on this method increase the thermal denaturation temperature of the mesophilic Escherichia coli (E. coli) ADK by 5.5 and 8.3 °C, respectively, while preserving most of the catalytic function at ambient temperatures. Additionally, the constructed mutants have improved enzymatic activity at higher temperature.


Assuntos
Adenilato Quinase/química , Proteínas de Escherichia coli/química , Escherichia coli/enzimologia , Temperatura Alta , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Estabilidade Enzimática , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo
13.
PLoS Comput Biol ; 17(3): e1008865, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33770072

RESUMO

The topology of protein folds can be specified by the inter-residue contact-maps and accurate contact-map prediction can help ab initio structure folding. We developed TripletRes to deduce protein contact-maps from discretized distance profiles by end-to-end training of deep residual neural-networks. Compared to previous approaches, the major advantage of TripletRes is in its ability to learn and directly fuse a triplet of coevolutionary matrices extracted from the whole-genome and metagenome databases and therefore minimize the information loss during the course of contact model training. TripletRes was tested on a large set of 245 non-homologous proteins from CASP 11&12 and CAMEO experiments and outperformed other top methods from CASP12 by at least 58.4% for the CASP 11&12 targets and 44.4% for the CAMEO targets in the top-L long-range contact precision. On the 31 FM targets from the latest CASP13 challenge, TripletRes achieved the highest precision (71.6%) for the top-L/5 long-range contact predictions. It was also shown that a simple re-training of the TripletRes model with more proteins can lead to further improvement with precisions comparable to state-of-the-art methods developed after CASP13. These results demonstrate a novel efficient approach to extend the power of deep convolutional networks for high-accuracy medium- and long-range protein contact-map predictions starting from primary sequences, which are critical for constructing 3D structure of proteins that lack homologous templates in the PDB library.


Assuntos
Redes Neurais de Computação , Proteínas , Análise de Sequência de Proteína/métodos , Biologia Computacional , Conformação Proteica , Dobramento de Proteína , Proteínas/química , Proteínas/metabolismo , Reprodutibilidade dos Testes
14.
Sci Total Environ ; 764: 142886, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33757247

RESUMO

During the outbreak of the coronavirus disease 2019 (COVID-19) in China in January and February 2020, production and living activities were drastically reduced to impede the spread of the virus, which also caused a strong reduction of the emission of primary pollutants. However, as a major species of secondary air pollutant, tropospheric ozone did not reduce synchronously, but instead rose in some region. Furthermore, higher concentrations of ozone may potentially promote the rates of COVID-19 infections, causing extra risk to human health. Thus, the variation of ozone should be evaluated widely. This paper presents ozone profiles and tropospheric ozone columns from ultraviolet radiances detected by TROPOospheric Monitoring Instrument (TROPOMI) onboard Sentinel 5 Precursor (S5P) satellite based on the principle of optimal estimation method. We compare our TROPOMI retrievals with global ozonesonde observations, Fourier Transform Spectrometry (FTS) observation at Hefei (117.17°E, 31.7°N) and Global Positioning System (GPS) ozonesonde sensor (GPSO3) ozonesonde profiles at Beijing (116.46°E, 39.80°N). The integrated Tropospheric Ozone Column (TOC) and Stratospheric Ozone Column (SOC) show excellent agreement with validation data. We use the retrieved TOC combining with tropospheric vertical column density (TVCD) of NO2 and HCHO from TROPOMI to assess the changes of tropospheric ozone during the outbreak of COVID-19 in China. Although NO2 TVCD decreased by 63%, the retrieved TOC over east China increase by 10% from the 20-day averaged before the lockdown on January 23, 2020 to 20-day averaged after it. Because the production of ozone in winter is controlled by volatile organic compounds (VOCs) indicated by monitored HCHO, which did not present evident change during the lockdown, the production of ozone did not decrease significantly. Besides, the decrease of NOx emission weakened the titration of ozone, causing an increase of ozone.


Assuntos
Poluentes Atmosféricos , COVID-19 , Ozônio , Poluentes Atmosféricos/análise , Pequim , China/epidemiologia , Controle de Doenças Transmissíveis , Surtos de Doenças , Monitoramento Ambiental , Humanos , Ozônio/análise , SARS-CoV-2
15.
J Mol Biol ; 433(10): 166944, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33741411

RESUMO

Genome-wide protein-protein interaction (PPI) determination remains a significant unsolved problem in structural biology. The difficulty is twofold since high-throughput experiments (HTEs) have often a relatively high false-positive rate in assigning PPIs, and PPI quaternary structures are more difficult to solve than tertiary structures using traditional structural biology techniques. We proposed a uniform pipeline, Threpp, to address both problems. Starting from a pair of monomer sequences, Threpp first threads both sequences through a complex structure library, where the alignment score is combined with HTE data using a naïve Bayesian classifier model to predict the likelihood of two chains to interact with each other. Next, quaternary complex structures of the identified PPIs are constructed by reassembling monomeric alignments with dimeric threading frameworks through interface-specific structural alignments. The pipeline was applied to the Escherichia coli genome and created 35,125 confident PPIs which is 4.5-fold higher than HTE alone. Graphic analyses of the PPI networks show a scale-free cluster size distribution, consistent with previous studies, which was found critical to the robustness of genome evolution and the centrality of functionally important proteins that are essential to E. coli survival. Furthermore, complex structure models were constructed for all predicted E. coli PPIs based on the quaternary threading alignments, where 6771 of them were found to have a high confidence score that corresponds to the correct fold of the complexes with a TM-score >0.5, and 39 showed a close consistency with the later released experimental structures with an average TM-score = 0.73. These results demonstrated the significant usefulness of threading-based homologous modeling in both genome-wide PPI network detection and complex structural construction.


Assuntos
Proteínas de Escherichia coli/genética , Escherichia coli/genética , Proteínas de Choque Térmico HSP70/genética , Fosfotransferases/genética , Proteoma/genética , Fatores de Transcrição/genética , Teorema de Bayes , Análise por Conglomerados , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/metabolismo , Fosfotransferases/química , Fosfotransferases/metabolismo , Dobramento de Proteína , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Estrutura Quaternária de Proteína , Proteoma/química , Proteoma/metabolismo , Transdução de Sinais , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
16.
J Mol Biol ; 433(11): 166840, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33539887

RESUMO

Numerous human diseases are caused by mutations in genomic sequences. Since amino acid changes affect protein function through mechanisms often predictable from protein structure, the integration of structural and sequence data enables us to estimate with greater accuracy whether and how a given mutation will lead to disease. Publicly available annotated databases enable hypothesis assessment and benchmarking of prediction tools. However, the results are often presented as summary statistics or black box predictors, without providing full descriptive information. We developed a new semi-manually curated human variant database presenting information on the protein contact-map, sequence-to-structure mapping, amino acid identity change, and stability prediction for the popular UniProt database. We found that the profiles of pathogenic and benign missense polymorphisms can be effectively deduced using decision trees and comparative analyses based on the presented dataset. The database is made publicly available through https://zhanglab.ccmb.med.umich.edu/ADDRESS.


Assuntos
Bases de Dados de Proteínas , Doença/genética , Variação Genética , Dobramento de Proteína , Proteínas/química , Proteínas/metabolismo , Aminoácidos/química , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estabilidade Proteica , Interface Usuário-Computador
17.
J Proteome Res ; 20(2): 1178-1189, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33393786

RESUMO

When the JCVI-syn3.0 genome was designed and implemented in 2016 as the minimal genome of a free-living organism, approximately one-third of the 438 protein-coding genes had no known function. Subsequent refinement into JCVI-syn3A led to inclusion of 16 additional protein-coding genes, including several unknown functions, resulting in an improved growth phenotype. Here, we seek to unveil the biological roles and protein-protein interaction (PPI) networks for these poorly characterized proteins using state-of-the-art deep learning contact-assisted structure prediction, followed by structure-based annotation of functions and PPI predictions. Our pipeline is able to confidently assign functions for many previously unannotated proteins such as putative vitamin transporters, which suggest the importance of nutrient uptake even in a minimized genome. Remarkably, despite the artificial selection of genes in the minimal syn3 genome, our reconstructed PPI network still shows a power law distribution of node degrees typical of naturally evolved bacterial PPI networks. Making use of our framework for combined structure/function/interaction modeling, we are able to identify both fundamental aspects of network biology that are retained in a minimal proteome and additional essential functions not yet recognized among the poorly annotated components of the syn3.0 and syn3A proteomes.


Assuntos
Genes Essenciais , Mapas de Interação de Proteínas , Biologia Computacional , Proteoma/genética
18.
J Proteome Res ; 19(12): 4844-4856, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33175551

RESUMO

Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that binding to ACE2 proteins is the first step for the coronaviruses to invade host cells, we propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets. Built on the optimized binding affinity cutoff, we suggest a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggests a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation, but also, more importantly, it proposes a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Animais , Sítios de Ligação/genética , COVID-19/patologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Mamíferos/genética , Mamíferos/virologia , Pandemias , Ligação Proteica/genética , Domínios Proteicos/genética , SARS-CoV-2/patogenicidade , Zoonoses Virais/genética , Zoonoses Virais/virologia
19.
bioRxiv ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33083802

RESUMO

Progress in cryo-electron microscopy (cryo-EM) has provided the potential for large-size protein structure determination. However, the solution rate for multi-domain proteins remains low due to the difficulty in modeling inter-domain orientations. We developed DEMO-EM, an automatic method to assemble multi-domain structures from cryo-EM maps through a progressive structural refinement procedure combining rigid-body domain fitting and flexible assembly simulations with deep neural network inter-domain distance profiles. The method was tested on a large-scale benchmark set of proteins containing up to twelve continuous and discontinuous domains with medium-to-low-resolution density maps, where DEMO-EM produced models with correct inter-domain orientations (TM-score >0.5) for 98% of cases and significantly outperformed the state-of-the-art methods. DEMO-EM was applied to SARS-Cov-2 coronavirus genome and generated models with average TM-score/RMSD of 0.97/1.4Å to the deposited structures. These results demonstrated an efficient pipeline that enables automated and reliable large-scale multi-domain protein structure modeling with atomic-level accuracy from cryo-EM maps.

20.
bioRxiv ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32935105

RESUMO

Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that the recognition of the binding ACE2 proteins is the first step for the coronaviruses to invade host cells, we proposed a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated on the modeled Spike-RBD/ACE2 complex structures correlate closely with the effectiveness of animal infections as determined by multiple experimental datasets. Built on the optimized binding affinity cutoff, we suggested a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggested a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation; but more importantly, it proposed a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...