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1.
Parasit Vectors ; 14(1): 605, 2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34895309

RESUMO

BACKGROUND: Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure-function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored. METHODS: We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database ( https://vectorbase.org/vectorbase/app ) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases-were generated using the I-TASSER and Phyre protein modeling servers. RESULTS: Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%. CONCLUSIONS: Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.


Assuntos
Aedes/efeitos dos fármacos , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Anopheles/efeitos dos fármacos , Dengue/transmissão , Inseticidas/farmacologia , Malária/transmissão , Mosquitos Vetores/efeitos dos fármacos , Aedes/enzimologia , Aedes/genética , Sequência de Aminoácidos , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/genética , Animais , Anopheles/enzimologia , Anopheles/genética , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Genômica , Humanos , Resistência a Inseticidas , Modelos Estruturais , Mosquitos Vetores/enzimologia , Mosquitos Vetores/genética , Alinhamento de Sequência , Relação Estrutura-Atividade
2.
Environ Pollut ; 291: 118208, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34740291

RESUMO

Increasingly, studies suggest benefits of natural environments or greenness on children's health. However, little is known about cumulative exposure or windows of susceptibility to greenness exposure. Using inverse probability weighting of marginal structural models (IPW/MSM), we estimated effects of greenness exposure from birth through adolescence on executive function and behavior. We analyzed data of 908 children from Project Viva enrolled at birth in 1999-2002 and followed up until early adolescence. In mid-childhood (median 7.7 years) and early adolescence (13.1 years), executive function and behavior were assessed using the Behavior Rating Inventory of Executive Function and the Strengths and Difficulties Questionnaire (SDQ). Greenness was measured at birth, early childhood, mid-childhood, and early adolescence, using the Normalized Difference Vegetation Index. We used inverse probability weighting of marginal structural models to estimate effects of interventions that ensure maximum greenness exposure versus minimum through all intervals; and that ensure maximum greenness only in early childhood (vs. minimum through all intervals). Results of the effects of "maximum (vs. minimum) greenness at all timepoints" did not suggest associations with mid-childhood outcomes. Estimates of "maximum greenness only in early childhood (vs. minimum)" suggested a beneficial association with mid-childhood SDQ (-3.21, 99 %CI: -6.71,0.29 mother-rated; -4.02, 99 %CI: -7.87,-0.17 teacher-rated). No associations were observed with early adolescent outcomes. Our results for "persistent" maximum greenness exposure on behavior, were not conclusive with confidence intervals containing the null. The results for maximum greenness "only in early childhood" may shed light on sensitive periods of greenness exposure for behavior regulation.


Assuntos
Meio Ambiente , Função Executiva , Adolescente , Criança , Pré-Escolar , Humanos , Recém-Nascido , Modelos Estruturais , Probabilidade
3.
An Acad Bras Cienc ; 93(suppl 4): e20210680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34817039

RESUMO

The present study aimed to establish the associations between hopelessness, depression and impulsivity with respect to suicidal ideation and behavior, and to explore the role that impulsivity plays in the mechanism that operates between depression and hopelessness. Through an empirical observational study, with an analytical scope based on a cross-sectional design for a sample of 228 university students and using The Inventory of Suicide Orientation (ISO-30); Beck Depression Inventory (BDI); Beck Hopelessness Scale (BHS); and Barratt Impulsiveness Scale (BIS-11). The results indicated a significant positives correlations between BDI, BHS, BIS and ISO-30. Regression analysis showed that depression, impulsivity and hopelessness explain between 57% and 67% of the variance in the risk of suicidal ideation and behavior. Through the analysis of structural equation modeling, three models were established showing that impulsivity mediates the relationship between depressive symptomatology and suicidal ideation and behavior. This study has implications for mental health intervention and research, in that it emphasizes the importance of impulsivity traits as factors that act as triggers in the association between the presence of depressive symptoms and suicidal behavior.


Assuntos
Comportamento Impulsivo , Ideação Suicida , Estudos Transversais , Humanos , Modelos Estruturais , Escalas de Graduação Psiquiátrica
4.
Nat Commun ; 12(1): 6067, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663821

RESUMO

Living cells are a complex soft material with fascinating mechanical properties. A striking feature is that, regardless of their types or states, cells exhibit a universal power-law rheological behavior which to this date still has not been captured by a single theoretical model. Here, we propose a cellular structural model that accounts for the essential mechanical responses of cell membrane, cytoplasm and cytoskeleton. We demonstrate that this model can naturally reproduce the universal power-law characteristics of cell rheology, as well as how its power-law exponent is related to cellular stiffness. More importantly, the power-law exponent can be quantitatively tuned in the range of 0.1 ~ 0.5, as found in most types of cells, by varying the stiffness or architecture of the cytoskeleton. Based on the structural characteristics, we further develop a self-similar hierarchical model that can spontaneously capture the power-law characteristics of creep compliance over time and complex modulus over frequency. The present model suggests that mechanical responses of cells may depend primarily on their generic architectural mechanism, rather than specific molecular properties.


Assuntos
Citoplasma/fisiologia , Citoesqueleto/fisiologia , Modelos Estruturais , Reologia , Membrana Celular , Modelos Teóricos
5.
Soft Matter ; 17(38): 8585-8589, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34553206

RESUMO

Chemical and shape recognition are the main assembling mechanisms of complex bio-structures. A refined assessment of relevant thermodynamic parameters includes the consideration of a variety of contributions from different molecular motions and electronic interactions. An additional refinement includes the analysis of recognition involving multiple distant partners. This perspective note highlights some of the above issues in the cases of fibrillogenesis, and enzyme-substrate and antigen-antibody associations. Translational motions are found to be particularly relevant to the fibrillogenesis process. The assembly of enzyme-substrate complexes is discussed in terms of a dynamic equilibrium process.


Assuntos
Enzimas , Modelos Moleculares , Modelos Estruturais , Eletrônica , Enzimas/metabolismo , Conformação Molecular
7.
Health Place ; 71: 102665, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34564025

RESUMO

This study tested the relationship of neighborhood crime as a driver of pediatric asthma diagnoses via the mechanism of toxic stress utilizing data from a police department, and pediatric clinic in a large urban city in the southwestern United States. Using structural equation modeling, a full mediation model of neighborhood crime as a driver of toxic stress resulting in increased asthma diagnoses fit the data well (Χ2 = 14.0, p =.371; df = 13; RMSEA = .028 [90% CI: 0.00, 0.102]; CFI: 0.995; SRMR = .053). Advocates should explore ways to reduce neighborhood crime to address toxic stress and asthma.


Assuntos
Asma , Características de Residência , Asma/epidemiologia , Asma/etiologia , Criança , Crime , Humanos , Modelos Estruturais , Polícia
8.
J Biol Chem ; 297(3): 101071, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400168

RESUMO

VhCBP is a periplasmic chitooligosaccharide-binding protein mainly responsible for translocation of the chitooligosaccharide (GlcNAc)2 across the double membranes of marine bacteria. However, structural and thermodynamic understanding of the sugar-binding/-release processes of VhCBP is relatively less. VhCBP displayed the greatest affinity toward (GlcNAc)2, with lower affinity for longer-chain chitooligosaccharides [(GlcNAc)3-4]. (GlcNAc)4 partially occupied the closed sugar-binding groove, with two reducing-end GlcNAc units extending beyond the sugar-binding groove and barely characterized by weak electron density. Mutation of three conserved residues (Trp363, Asp365, and Trp513) to Ala resulted in drastic decreases in the binding affinity toward the preferred substrate (GlcNAc)2, indicating their significant contributions to sugar binding. The structure of the W513A-(GlcNAc)2 complex in a 'half-open' conformation unveiled the intermediary step of the (GlcNAc)2 translocation from the soluble CBP in the periplasm to the inner membrane-transporting components. Isothermal calorimetry data suggested that VhCBP adopts the high-affinity conformation to bind (GlcNAc)2, while its low-affinity conformation facilitated sugar release. Thus, chitooligosaccharide translocation, conferred by periplasmic VhCBP, is a crucial step in the chitin catabolic pathway, allowing Vibrio bacteria to thrive in oceans where chitin is their major source of nutrients.


Assuntos
Quitina/metabolismo , Dissacarídeos/metabolismo , Vibrio/metabolismo , Carboidratos , Quitinases/metabolismo , Quitosana/metabolismo , Cristalografia por Raios X/métodos , Dissacarídeos/fisiologia , Modelos Estruturais , Oligossacarídeos/metabolismo , Periplasma/metabolismo , Proteínas Periplásmicas de Ligação/metabolismo , Relação Estrutura-Atividade
9.
Ann Epidemiol ; 63: 22-28, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34289408

RESUMO

BACKGROUND: In the presence of non-adherence and lost to follow up, results of an Intention to Treat (ITT) analysis may be biased as it is measuring the effect of assignment rather than the effect of treatment. Given that Marginal Structural Models (MSMs) adjust for such issues, this study examines the use of MSMs to assess the validity of ITT analyses in the presence of non-adherence and lost to follow up in an existing randomized clinical trial on asthma treatment. METHODS: Inverse probability weights were obtained from a pooled logistic regression assessing the probability of staying on assigned treatment (adherence) and of remaining uncensored (censored) for subjects at each visit by treatment arm. Weights were then pooled into a MSM analysis using a Poisson generalized estimating equation with an independent correlation matrix. RESULTS: Out of 488 participants, 174 (36%) did not adhere to the baseline assignment and 85 (17%) were lost to follow up by the end of the study. The adjusted relative risks (RR), and 95% confidence intervals (CI), obtained from the MSMs (theophylline vs. montelukast; RR=1.24; 95% CI: 0.83,1.84; theophylline vs. placebo: RR=1.01; 95% CI: 0.70,1.48; and montelukast vs. placebo: RR=0.83; 95% CI: 0.57,1.19) were nearly identical to that of the ITT analysis (theophylline vs. montelukast: RR=1.22; 95% CI: 0.82,1.86; theophylline vs. placebo: RR=0.99; 95% CI: 0.67,1.50; and montelukast vs. placebo: RR=0.82; 95% CI: 0.55,1.21). CONCLUSION: Concordance between the results of ITT and MSMs indicate adherence and censoring may not invalidate ITT analysis. However, no adherence or censorship thresholds currently exist to assist researchers in determining when MSMs may be superior to ITT in the analysis of clinical trials with non-adherence or censorship issues, and therefore, MSMs should be conducted as a sensitivity analysis to the ITT approach in clinical trials.


Assuntos
Modelos Estruturais , Cooperação do Paciente , Humanos , Análise de Intenção de Tratamento , Perda de Seguimento , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Artigo em Inglês | MEDLINE | ID: mdl-34281043

RESUMO

Structural models of psychopathology have emerged as an alternative to traditional categorical approaches. The bifactor model, which incorporates a general p-factor, has become the preferred structure. The p-factor is claimed to represent a substantive construct or property of the system; however, recent evidence suggests that it may be without substantive meaning. If a universal substantive p, and associated specific factors, is to be developed they not only must be applicable and consistent between populations but also must be applicable and consistent within subgroups of a population. This consistency needs to include not only factor loadings but also factor correlates. We used a simulated data approach to explore the applicability and consistency of four popular models of psychopathology to a range of heterogeneous subgroups and examined the consistency of their neurocognitive correlates. We found that only eight out of sixty-three subgroups fitted any of the models with all significant loadings, no negative loadings, no non-positive-definite identification issues, and no negative variance. All eight of these subgroups fit the correlated factors model, none fit the original bifactor model, four subgroups fit the revised bifactor model, and one subgroup fit the single-factor model. Correlates of the factors also varied substantially between the subgroups fitted to the same model. We discuss the implications of the findings, including the implications for the development of universal substantive factors of psychopathology.


Assuntos
Transtornos Mentais , Humanos , Transtornos Mentais/epidemiologia , Modelos Estruturais , Psicopatologia , Convulsões
11.
J Environ Manage ; 297: 113282, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34314965

RESUMO

Green technology innovation is an important driving force for high-quality development in China. Recently, much attention has focused on the connotation, influencing factors and mode selection of green technology innovation, yet few studies have systematically tested the transmission paths between green technology innovation and economic performance. Green technology innovation can be divided into green process innovation and green product innovation, both of which can improve the environmental and economic performance of enterprises. Drawing on previous research, this study constructs a model of economic performance transmission for green technology innovation and upgrading, and conducts an empirical analysis based on data from 642 industrial enterprises in China. The results show that green process innovation and green product innovation can effectively improve the economic performance of enterprises. The environmental performance and market competitiveness of enterprises are important mediating variables in the paths of economic performance improvement. An enterprise's green process innovation can positively promote green product innovation, and there is also room for technological innovation upgrading. There are two main differences in the transmission paths for different types of green technology innovation: (1) Green process innovation can improve economic performance directly, whereas green product innovation can only do this indirectly; (2) In most cases, the path from green product innovation to economic performance is more important than that from green process innovation to economic performance. This study deepens understanding of the green technology innovation process and has implications for optimizing policy design for green development.


Assuntos
Desenvolvimento Econômico , Invenções , China , Indústrias , Modelos Estruturais , Tecnologia
12.
PLoS One ; 16(7): e0254694, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270630

RESUMO

PURPOSE: Decision Making Trial and Evaluation Laboratory (DEMATEL) and Interpretive Structural Modeling (ISM) are commonly used separately, but also may be combined per their common characteristics to identify causal relationships and hierarchical structure among factors in complex systems with a relatively small computational burden. The purpose of this study is to establish an improved DEMATEL-ISM integration approach to remedy the disadvantages of the traditional DEMATEL-ISM integration method. A case study was conducted to compare the proposed improved integration approach against the traditional integration method, and to validate its feasibility and effectiveness. METHODS: The proposed improved DEMATEL-ISM integration approach has two main parts: a threshold determination via maximum mean de-entropy (MMDE) method and an additional transitivity check process. The factors influencing China's rural-urban floating population's willingness to participate in social insurance was analyzed as a case study. RESULTS: The traditional and improved methods show notable differences in the hierarchical factor structure and the inner influence relationship among factors that they respectively reveal. The traditional integration approach results in some irrationality, while the improved approach does not. ORIGINALITY: This study confirms the importance of proper threshold determination and reachability matrix transitivity checking during DEMATEL-ISM integration. The improved approach includes a scientific threshold determination method based on the MMDE method, plus a transitivity check of the reachability matrix with necessary corrections to ensure its soundness. It can be straightforwardly operated at a relatively low computational burden while providing accurate analysis results.


Assuntos
Tomada de Decisões Gerenciais , Técnicas de Apoio para a Decisão , Modelos Estruturais , Estudos de Viabilidade , Marketing/métodos , Incerteza
13.
mBio ; 12(3): e0080021, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34061603

RESUMO

Capsular polysaccharides (CPSs) are major virulence factors that decorate the surfaces of many human bacterial pathogens. In their pure form or as glycoconjugate vaccines, CPSs are extensively used in vaccines deployed in clinical practice worldwide. However, our understanding of the structural requirements for interactions between CPSs and antibodies is limited. A longstanding model based on comprehensive observations of antibody repertoires binding to CPSs is that antibodies expressing heavy chain variable gene family 3 (VH3) predominate in these binding interactions in humans and VH3 homologs in mice. Toward understanding this highly conserved interaction, we generated a panel of mouse monoclonal antibodies (MAb) against Streptococcus pneumoniae serotype 3 CPS, determined an X-ray crystal structure of a protective MAb in complex with a hexasaccharide derived from enzymatic hydrolysis of the polysaccharide, and elucidated the structural requirements for this binding interaction. The crystal structure revealed a binding pocket containing aromatic side chains, suggesting the importance of hydrophobicity in the interaction. Through mutational analysis, we determined the amino acids that are critical in carbohydrate binding. Through elucidating the structural and functional properties of a panel of murine MAbs, we offer an explanation for the predominant use of the human VH3 gene family in antibodies against CPSs with implications in knowledge-based vaccine design. IMPORTANCE Infectious diseases caused by pathogenic bacteria are a major threat to human health. Capsular polysaccharides (CPSs) of many pathogenic bacteria have been used as the main components of glycoconjugate vaccines against bacterial diseases in clinical practice worldwide, with various degrees of success. Immunization with a glycoconjugate vaccine elicits T cell help for B cells that produce IgG antibodies to the CPS. Thus, it is important to develop an in-depth understanding of the interactions of carbohydrate epitopes with the antibodies. Structural characterization of the ligand binding of polysaccharide-specific antibodies laid out in this study may have fundamental biological implications for our comprehension of how the humoral immune system recognizes polysaccharide antigens, and in future knowledge-based vaccine design.


Assuntos
Anticorpos Antibacterianos/imunologia , Cápsulas Bacterianas/química , Polissacarídeos Bacterianos/imunologia , Polissacarídeos Bacterianos/metabolismo , Streptococcus pneumoniae/química , Streptococcus pneumoniae/imunologia , Animais , Anticorpos Monoclonais , Cápsulas Bacterianas/classificação , Cápsulas Bacterianas/imunologia , Cristalização , Feminino , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Modelos Estruturais , Polissacarídeos Bacterianos/química , Sorogrupo , Streptococcus pneumoniae/classificação , Streptococcus pneumoniae/patogenicidade , Vacinação
14.
Artigo em Inglês | MEDLINE | ID: mdl-34073657

RESUMO

The aim of this study to discover the relationship between psychological well-being, emotional intelligence, willpower, and job-efficacy. The data were collected from 26 May to 30 May 2020 by distributing a questionnaire to 317 clinical nurses with six months of experience in a general hospital located in Seoul. Three hundred copies were collected and used for final data analysis. The results of the study verified that the direct factors of psychological well-being, emotional intelligence, and willpower affect the job-efficacy of clinical nurses and confirmed that emotional intelligence is a mediating factor between psychological well-being and job-efficacy. This study is meaningful in that it proves the necessity of establishing various curriculums focusing on these factors so that nursing students can best perform their duties as professional nurses. In particular, it is suggested that an educational program and curriculum be established that can strengthen the psychological well-being and enhance the emotional intelligence of nursing students. It is expected that such training will equip professional clinical nurses to effectively handle future work in their stress-filled field.


Assuntos
Enfermeiras e Enfermeiros , Estudantes de Enfermagem , Inteligência Emocional , Humanos , Modelos Estruturais , Seul , Inquéritos e Questionários
15.
Acta Crystallogr D Struct Biol ; 77(Pt 6): 727-745, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34076588

RESUMO

Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB). Not only will this facilitate the remediation of existing models, but also, more importantly, it will inform and thus improve the quality of future linkages. By considering linkages of known type in the CCP4 Monomer Library (CCP4-ML), failure to model a covalent linkage is identified to result in inaccurate (systematically longer) interatomic distances. Scanning the PDB for proximal atom pairs that do not have a corresponding type in the CCP4-ML reveals a large number of commonly occurring types of unannotated potential linkages; in general, these may or may not be covalently linked. Manual consideration of the most commonly occurring cases identifies a number of genuine classes of covalent linkages. The recent expansion of the CCP4-ML is discussed, which has involved the addition of over 16 000 and the replacement of over 11 000 component dictionaries using AceDRG. As part of this effort, the CCP4-ML has also been extended using AceDRG link dictionaries for the aforementioned linkage types identified in this analysis. This will facilitate the identification of such linkage types in future modelling efforts, whilst concurrently easing the process involved in their application. The need for a universal standard for maintaining link records corresponding to covalent linkages, and references to the associated dictionaries used during modelling and refinement, following deposition to the PDB is emphasized. The importance of correctly modelling covalent linkages is demonstrated using a case study, which involves the covalent linkage of an inhibitor to the main protease in various viral species, including SARS-CoV-2. This example demonstrates the importance of properly modelling covalent linkages using a comprehensive restraint dictionary, as opposed to just using a single interatomic distance restraint or failing to model the covalent linkage at all.


Assuntos
Modelos Estruturais , Cristalografia por Raios X , Bases de Dados de Proteínas , Ligantes , SARS-CoV-2/química , Proteínas Virais/química
16.
Stat Med ; 40(23): 4996-5005, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34184763

RESUMO

Methods for estimating optimal treatment strategies typically assume unlimited access to resources. However, when a health system has resource constraints, such as limited funds, access to medication, or monitoring capabilities, medical decisions must account for competition between individuals in resource usage. The problem of incorporating resource constraints into optimal treatment strategies has been solved for point exposures (1), that is, treatment strategies entailing a decision at just one time point. However, attempts to directly generalize the point exposure solution to dynamic time-varying treatment strategies run into complications. We sidestep these complications by targeting the optimal strategy within a clinically defined subclass. Our approach is to employ dynamic marginal structural models to estimate (counterfactual) resource usage under the class of candidate treatment strategies and solve a constrained optimization problem to choose the optimal strategy for which expected resource usage is within acceptable limits. We apply this method to determine the optimal dynamic monitoring strategy for people living with HIV when resource limits on monitoring exist using observational data from the HIV-CAUSAL Collaboration.


Assuntos
Projetos de Pesquisa , Humanos , Modelos Estruturais
17.
Biom J ; 63(7): 1526-1541, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33983641

RESUMO

Observational longitudinal data on treatments and covariates are increasingly used to investigate treatment effects, but are often subject to time-dependent confounding. Marginal structural models (MSMs), estimated using inverse probability of treatment weighting or the g-formula, are popular for handling this problem. With increasing development of advanced causal inference methods, it is important to be able to assess their performance in different scenarios to guide their application. Simulation studies are a key tool for this, but their use to evaluate causal inference methods has been limited. This paper focuses on the use of simulations for evaluations involving MSMs in studies with a time-to-event outcome. In a simulation, it is important to be able to generate the data in such a way that the correct forms of any models to be fitted to those data are known. However, this is not straightforward in the longitudinal setting because it is natural for data to be generated in a sequential conditional manner, whereas MSMs involve fitting marginal rather than conditional hazard models. We provide general results that enable the form of the correctly specified MSM to be derived based on a conditional data generating procedure, and show how the results can be applied when the conditional hazard model is an Aalen additive hazard or Cox model. Using conditional additive hazard models is advantageous because they imply additive MSMs that can be fitted using standard software. We describe and illustrate a simulation algorithm. Our results will help researchers to effectively evaluate causal inference methods via simulation.


Assuntos
Modelos Estatísticos , Simulação por Computador , Modelos Estruturais , Modelos de Riscos Proporcionais
18.
J Bacteriol ; 203(15): e0008221, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-33972353

RESUMO

Treponema pallidum, an obligate human pathogen, has an outer membrane (OM) whose physical properties, ultrastructure, and composition differ markedly from those of phylogenetically distant Gram-negative bacteria. We developed structural models for the outer membrane protein (OMP) repertoire (OMPeome) of T. pallidum Nichols using solved Gram-negative structures, computational tools, and small-angle X-ray scattering (SAXS) of selected recombinant periplasmic domains. The T. pallidum "OMPeome" harbors two "stand-alone" proteins (BamA and LptD) involved in OM biogenesis and four paralogous families involved in the influx/efflux of small molecules: 8-stranded ß-barrels, long-chain-fatty-acid transporters (FadLs), OM factors (OMFs) for efflux pumps, and T. pallidum repeat proteins (Tprs). BamA (TP0326), the central component of a ß-barrel assembly machine (BAM)/translocation and assembly module (TAM) hybrid, possesses a highly flexible polypeptide-transport-associated (POTRA) 1-5 arm predicted to interact with TamB (TP0325). TP0515, an LptD ortholog, contains a novel, unstructured C-terminal domain that models inside the ß-barrel. T. pallidum has four 8-stranded ß-barrels, each containing positively charged extracellular loops that could contribute to pathogenesis. Three of five FadL-like orthologs have a novel α-helical, presumptively periplasmic C-terminal extension. SAXS and structural modeling further supported the bipartite membrane topology and tridomain architecture of full-length members of the Tpr family. T. pallidum's two efflux pumps presumably extrude noxious small molecules via four coexpressed OMFs with variably charged tunnels. For BamA, LptD, and OMFs, we modeled the molecular machines that deliver their substrates into the OM or external milieu. The spirochete's extended families of OM transporters collectively confer a broad capacity for nutrient uptake. The models also furnish a structural road map for vaccine development. IMPORTANCE The unusual outer membrane (OM) of T. pallidum, the syphilis spirochete, is the ultrastructural basis for its well-recognized capacity for invasiveness, immune evasion, and persistence. In recent years, we have made considerable progress in identifying T. pallidum's repertoire of OMPs. Here, we developed three-dimensional (3D) models for the T. pallidum Nichols OMPeome using structural modeling, bioinformatics, and solution scattering. The OM contains three families of OMP transporters, an OMP family involved in the extrusion of noxious molecules, and two "stand-alone" proteins involved in OM biogenesis. This work represents a major advance toward elucidating host-pathogen interactions during syphilis; understanding how T. pallidum, an extreme auxotroph, obtains a wide array of biomolecules from its obligate human host; and developing a vaccine with global efficacy.


Assuntos
Membrana Externa Bacteriana/química , Vacinas Bacterianas/química , Sífilis/prevenção & controle , Treponema pallidum/imunologia , Membrana Externa Bacteriana/imunologia , Vacinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Humanos , Modelos Estruturais , Conformação Proteica , Sífilis/microbiologia , Treponema pallidum/química , Treponema pallidum/genética , Difração de Raios X
19.
J Chem Inf Model ; 61(4): 1875-1888, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33792302

RESUMO

Leucine-zipper transcription regulator 1 (LZTR1) is a highly mutated tumor suppressor gene, involved in the pathogenesis of several cancer types and developmental disorders. In proteasomal degradation, it acts as an adaptor protein responsible for the recognition and recruitment of substrates to be ubiquitinated in Cullin3-RING ligase E3 (CRL3) machinery. LZTR1 belongs to the BTB-Kelch family, a multi-domain protein where the Kelch propeller plays as the substrate recognition region and for which no experimental structure has been solved. Recently, large effort mutational analyses pointed to the role of disease-associated LZTR1 mutations in the RAS/MAPK signaling pathway and RIT1, a small Ras-related GTPase protein, has been identified by mass spectroscopy to interact with LZTR1. Hence, a better understanding of native structure, molecular mechanism, and substrate specificity would help clarifying the role of LZTR1 in pathological diseases, thus promoting advancement in the development of novel therapeutic strategies. Here, we address the interaction model between adaptor LZTR1 and substrate RIT1 by applying an integrated computational approach, including molecular modeling and docking techniques. We observe that the interaction model LZTR1-RIT1 is stabilized by an electrostatic bond network established between the two protein surfaces, which is reminiscent of homologous ubiquitin ligases complexes. Then, running MD simulations, we characterize differential conformational dynamics of the multi-domain LZTR1, offering interesting implications on the mechanistic role of specific point mutations. We identify G248R and R283Q as damaging mutations involved in the recognition process of the substrate RIT1 and R412C as a possible allosteric mutation from the Kelch to the C-term BTB-domain. Our findings provide important structural insights on targeting CRL3s for drug discovery.


Assuntos
Fatores de Transcrição , Ubiquitina-Proteína Ligases , Modelos Estruturais , Transdução de Sinais , Ubiquitina , Ubiquitina-Proteína Ligases/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-33808864

RESUMO

PURPOSE: This study developed and examined a structural model and influencing factors of suicidal ideation by path analysis of family violence exposure, school violence exposure, anger, aggression, depression, hopelessness, and ego resilience among adolescents. METHODS: A hypothetical model was constructed on the basis of general strain theory developed by Agnew, as well as a review of studies in the literature related to suicidal ideation in adolescents in terms of violence exposure. The subjects were 1150 middle school students located in P city and K province. The model included 8 concepts and 24 paths. Data were collected using self-report questionnaires from September 2 to 20, 2013, and analyzed using the IBM SPSS and AMOS 21.0 programs. RESULTS: Family violence exposure, school violence exposure, anger, depression, hopelessness, and ego resilience showed a direct effect, while aggression showed an indirect effect on suicidal ideation in adolescents. These factors accounted for 45% of the variance of suicidal ideation in middle school students in terms of violence exposure. CONCLUSIONS: The results suggest that suicidal ideation of adolescents who are exposed to violence could be decreased by increasing ego resilience and reducing family violence exposure. It is necessary to develop an intervention strategy to prevent suicidal ideation.


Assuntos
Comportamento do Adolescente , Exposição à Violência , Adolescente , Agressão , Depressão/epidemiologia , Humanos , Modelos Estruturais , Fatores de Risco , Ideação Suicida
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