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1.
Vascular ; : 17085381241273293, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158503

RESUMO

OBJECTIVE: The survey aimed to evaluate the precise roles and importance of carotid plaque thickness and carotid intima-media thickness measured in plaque-free areas (PF CC-IMTmean) in future cardiovascular risk prediction. MATERIAL AND METHODS: 188 respondents between the age of 46 and 87 divided into two groups (I group - 94 respondents without plaques with CIMT measurement and II Group 94 respondents with carotid plaques; 118 men and 70 women; mean age ± SD, 61.80 ± 5.49) were prospectively examined by the carotid ultrasound Doppler (carotid measurements included plaque thickness PT - nonstenotic plaques (carotid stenosis <50%) and stenotic culprit plaques (carotid stenosis ≥50%), mean CIMT and maximum CIMT). Subjects were followed for 36 months from the inclusion in the study (regular control examinations). Data were recorded on new cases of mortality (CV mortality) and adverse CV events (myocardial infarction - -MI, surgical or endovascular revascularization - coronary or stroke). RESULTS: In this study, CIMT values vary between 0.62 and 1.43 mm (mean CIMT = 1.21 ± 0.2 mm) while 52 subjects had nonstenotic plaques (14 respondents plaque ulceration, 22 type 2 diabetes mellitus, 38 arterial hypertension) and 38 subjects had stenotic culprit plaques (17 respondents plaque ulceration, 20 type 2 diabetes mellitus, 31 arterial hypertension). After 36 months of follow-up, 76 vascular events were noted (MI, transient ischaemic attack - TIA, stroke and cardiovascular angioplasty or surgery) in this period. CONCLUSION: Respondents with carotid plaques had higher cardiovascular events occurrence (p < .01, high statistical difference). Carotid plaques as a parameter have higher predictive vascular event value importance than CIMT. Of note, stenotic plaques, the presence of ulceration on the free surface of the plaque, type 2 diabetes mellitus and hypertension were connected with the highest events occurrence.

2.
Acta Chir Belg ; : 1-5, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38842285

RESUMO

Pleuropulmonary blastoma (PPB) is a very rare tumor of the chest seen predominantly in young children with great heterogeneity and clinical, biochemical, and biological complexity and recognized, described, and classified as distinct from the pulmonary blastoma typically encountered in adults. Unfortunately, it has a poor and dismal prognosis and is mainly classified as cystic (type 1), mixed type (type 2), and solid (type 3). Herein, we present one case of PPB type 2 presenting clinically with a right pulmonary abscess, a rare clinical presentation of PPB, which was initially treated with surgery, and after approximately 1 year of follow-up, pulmonary rest-recurrence and central nervous system secondary deposits were detected. When a large pleural-based mass is identified in a young child, PPB should also be considered, especially in a patient with a positive oncological family history. Suggestive findings include the absence of chest wall invasion, presence of pleural fluid, right-sided location, and heterogeneous native (NECT) low attenuation with variable postcontrast enhancement. The authors believe that a modern therapeutic approach should consider these results for a better understanding of the genetic nature and complex mechanism and process of PPB disease development (both clinical and preclinical data concerning PPB pathophysiology are still lacking and are not completely understood) so that it would be possible to establish new possible therapeutic options (i.e. nuclear medicine theranostics in PPB treatment, developments and innovation in FLASH radiotherapy and proton therapy) and approaches, and so that, given the severity of the disease, it would be possible to indicate the importance of genetic testing and counseling of close relatives. In line with the previous, the rapid development of artificial intelligence could potentially bring the development of a novel fusion of radio mics and semantic features and MRI-based machine learning in distinguishing PPB from similar pathology.

3.
Medicina (Kaunas) ; 60(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38929539

RESUMO

Background and Objectives: Human papillomavirus (HPV) infection and its etiological role in the development of cervical cancer are well established. The cervical cancer mortality rate in Serbia is one of the highest among European countries, and this cancer is the second-leading cause of death in Serbian women aged from 15 to 44. Materials and Methods: This retrospective study was conducted at the Institute of Public Health of Vojvodina. A total of 10,062 cervical specimens from Serbian women were collected and HPV tested in ten years. The study patients were divided into five age groups. HPV genotype testing was performed using a commercial kit to detect 14 high-risk (HR) HPV genotypes. Additionally, cervix cytology data have been available for patients tested in 2022 and 2023. Results: An overall positive rate was found in 43.3% of patients (4356/10,062). A single HPV infection (62.1%) was the main infection pattern. The most frequent HR HPV genotypes were HPV 16, 31, 52, 56, 39, and 51, comprising 62.3% of the detected genotypes, including multiple infections. A significant difference was noted in the HPV prevalence across the different age groups, with a bimodal distribution of HPV infection. The highest prevalence was recorded in the age group ≤ 30 and those after 61 years. Women diagnosed with high-grade squamous intraepithelial lesions (HSIL) were significantly older compared to others. HR HPV is the most prevalent in patients with HSIL cytological findings (76.5%). The most common type, according to age-specific distribution and cytological findings, was HR HPV 16. Conclusions: This study provides comprehensive data on HR HPV distribution among Serbian women, which can serve as a basis for subsequent monitoring of genotypic distribution. It is particularly significant considering they are missing in the updated ICO/IARC Report for Serbia, and the cervical cancer mortality rate in Serbia is one of the highest among European countries.


Assuntos
Genótipo , Papillomaviridae , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Sérvia/epidemiologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Adulto , Estudos Retrospectivos , Prevalência , Pessoa de Meia-Idade , Adolescente , Papillomaviridae/genética , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/epidemiologia , Adulto Jovem , Idoso
4.
Nephrol Dial Transplant ; 39(1): 122-132, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-37381173

RESUMO

BACKGROUND: Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function [e.g. glomerular filtration rate (GFR)], those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared with plasma. We explored the urine-to-plasma ratio of urea concentrations (U/P urea ratio) as a marker of tubular functions. METHODS: We evaluated the relationship of the U/P urea ratio with eGFR at baseline in 1043 participants (48 ± 17 years) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P urea ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K and uric acid for comparison. RESULTS: In a transversal study at baseline, estimated GFR (eGFR) was positively associated with U/P-urea ratio [ßscaled = 0.08, 95% CI (0.04; 0.13)] but not with the U/P ratio of osmolarity. Considering separately participants with renal function >90 or ≤90 mL/min × 1.73 m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2 mL/min per year. A significant association was observed between baseline U/P urea ratio and eGFR decline [ßscaled = 0.08, 95% CI (0.01; 0.15)]. A lower baseline U/P urea ratio was associated with a greater eGFR decline. CONCLUSION: This study provides evidence that the U/P urea ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P urea ratio could become an easily available tubular marker for evaluating renal function decline.


Assuntos
Insuficiência Renal Crônica , Ureia , Adulto , Humanos , Estudos Longitudinais , Rim , Taxa de Filtração Glomerular , Testes de Função Renal , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco
5.
Proc Natl Acad Sci U S A ; 117(10): 5310-5318, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32079722

RESUMO

The ubiquity of phospho-ligands suggests that phosphate binding emerged at the earliest stage of protein evolution. To evaluate this hypothesis and unravel its details, we identified all phosphate-binding protein lineages in the Evolutionary Classification of Protein Domains database. We found at least 250 independent evolutionary lineages that bind small molecule cofactors and metabolites with phosphate moieties. For many lineages, phosphate binding emerged later as a niche functionality, but for the oldest protein lineages, phosphate binding was the founding function. Across some 4 billion y of protein evolution, side-chain binding, in which the phosphate moiety does not interact with the backbone at all, emerged most frequently. However, in the oldest lineages, and most characteristically in αßα sandwich enzyme domains, N-helix binding sites dominate, where the phosphate moiety sits atop the N terminus of an α-helix. This discrepancy is explained by the observation that N-helix binding is uniquely realized by short, contiguous sequences with reduced amino acid diversity, foremost Gly, Ser, and Thr. The latter two amino acids preferentially interact with both the backbone amide and the side-chain hydroxyl (bidentate interaction) to promote binding by short sequences. We conclude that the first αßα sandwich domains emerged from shorter and simpler polypeptides that bound phospho-ligands via N-helix sites.


Assuntos
Enzimas/química , Enzimas/classificação , Evolução Molecular , Proteínas de Ligação a Fosfato/química , Proteínas de Ligação a Fosfato/classificação , Sequência de Aminoácidos , Sítios de Ligação , Bases de Dados de Proteínas , Ligantes , Ligação Proteica , Domínios Proteicos
6.
J Chem Inf Model ; 62(12): 2999-3007, 2022 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-35699524

RESUMO

Peptides are an important modality in drug discovery. While current peptide optimization focuses predominantly on the small number of natural and commercially available non-natural amino acids, the chemical spaces available for small molecule drug discovery are in the billions of molecules. In the present study, we describe the development of a large virtual library of readily synthesizable non-natural amino acids that can power the virtual screening protocols and aid in peptide optimization. To that end, we enumerated nearly 380 thousand amino acids and demonstrated their vast chemical diversity compared to the 20 natural and commercial residues. Furthermore, we selected a diverse ten thousand amino acid subset to validate our virtual screening workflow on the Keap1-Neh2 complex model system. Through in silico mutations of Neh2 peptide residues to those from the virtual library, our docking-based protocol identified a number of possible solutions with a significantly higher predicted affinity toward the Keap1 protein. This protocol demonstrates that the non-natural amino acid chemical space can be massively extended and virtually screened with a reasonable computational cost.


Assuntos
Aminoácidos , Fator 2 Relacionado a NF-E2 , Aminoácidos/química , Descoberta de Drogas/métodos , Proteína 1 Associada a ECH Semelhante a Kelch , Simulação de Acoplamento Molecular , Peptídeos/química
7.
J Chem Inf Model ; 62(16): 3832-3843, 2022 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-35920716

RESUMO

ROS1 rearrangements account for 1-2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 1015 synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 1010 subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Computação em Nuvem , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Estudos Prospectivos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases
8.
Eur J Epidemiol ; 37(6): 629-640, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35595947

RESUMO

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.


Assuntos
Neoplasias Pulmonares , Fumar , Carcinogênese , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Humanos , Pulmão , Neoplasias Pulmonares/genética , Fumar/efeitos adversos
9.
Scand J Public Health ; 50(1): 124-135, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34664529

RESUMO

Aims: To assess SARS-CoV-2 seroprevalence over the first epidemic wave in the canton of Geneva, Switzerland, as well as risk factors for infection and symptoms associated with IgG seropositivity. Methods: Between April and June 2020, former participants of a representative survey of the 20-74-year-old population of canton Geneva were invited to participate in the study, along with household members aged over 5 years. Blood samples were tested for anti-SARS-CoV-2 immunoglobulin G. Questionnaires were self-administered. We estimated seroprevalence with a Bayesian model accounting for test performance and sampling design. Results: We included 8344 participants, with an overall adjusted seroprevalence of 7.8% (95% credible interval 6.8-8.9). Seroprevalence was highest among 18-49 year-olds (9.5%), and lowest in 5-9-year-old children (4.3%) and individuals >65 years (4.7-5.4%). Odds of seropositivity were significantly reduced for female retirees and unemployed men compared to employed individuals, and smokers compared to non-smokers. We found no significant association between occupation, level of education, neighborhood income and the risk of being seropositive. The symptom most strongly associated with seropositivity was anosmia/dysgeusia. Conclusions: Anti-SARS-CoV-2 population seroprevalence remained low after the first wave in Geneva. Socioeconomic factors were not associated with seropositivity in this sample. The elderly, young children and smokers were less frequently seropositive, although it is not clear how biology and behaviours shape these differences.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Idoso , Teorema de Bayes , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estudos Soroepidemiológicos , Suíça/epidemiologia , Adulto Jovem
10.
Chimia (Aarau) ; 76(12): 1052-1062, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38069802

RESUMO

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes.

11.
Lancet ; 396(10247): 313-319, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534626

RESUMO

BACKGROUND: Assessing the burden of COVID-19 on the basis of medically attended case numbers is suboptimal given its reliance on testing strategy, changing case definitions, and disease presentation. Population-based serosurveys measuring anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies provide one method for estimating infection rates and monitoring the progression of the epidemic. Here, we estimate weekly seroprevalence of anti-SARS-CoV-2 antibodies in the population of Geneva, Switzerland, during the epidemic. METHODS: The SEROCoV-POP study is a population-based study of former participants of the Bus Santé study and their household members. We planned a series of 12 consecutive weekly serosurveys among randomly selected participants from a previous population-representative survey, and their household members aged 5 years and older. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA. We estimated seroprevalence using a Bayesian logistic regression model taking into account test performance and adjusting for the age and sex of Geneva's population. Here we present results from the first 5 weeks of the study. FINDINGS: Between April 6 and May 9, 2020, we enrolled 2766 participants from 1339 households, with a demographic distribution similar to that of the canton of Geneva. In the first week, we estimated a seroprevalence of 4·8% (95% CI 2·4-8·0, n=341). The estimate increased to 8·5% (5·9-11·4, n=469) in the second week, to 10·9% (7·9-14·4, n=577) in the third week, 6·6% (4·3-9·4, n=604) in the fourth week, and 10·8% (8·2-13·9, n=775) in the fifth week. Individuals aged 5-9 years (relative risk [RR] 0·32 [95% CI 0·11-0·63]) and those older than 65 years (RR 0·50 [0·28-0·78]) had a significantly lower risk of being seropositive than those aged 20-49 years. After accounting for the time to seroconversion, we estimated that for every reported confirmed case, there were 11·6 infections in the community. INTERPRETATION: These results suggest that most of the population of Geneva remained uninfected during this wave of the pandemic, despite the high prevalence of COVID-19 in the region (5000 reported clinical cases over <2·5 months in the population of half a million people). Assuming that the presence of IgG antibodies is associated with immunity, these results highlight that the epidemic is far from coming to an end by means of fewer susceptible people in the population. Further, a significantly lower seroprevalence was observed for children aged 5-9 years and adults older than 65 years, compared with those aged 10-64 years. These results will inform countries considering the easing of restrictions aimed at curbing transmission. FUNDING: Swiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), Fondation de Bienfaisance du Groupe Pictet, Fondation Ancrage, Fondation Privée des Hôpitaux Universitaires de Genève, and Center for Emerging Viral Diseases.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Imunoglobulina G/sangue , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Adolescente , Adulto , Distribuição por Idade , Idoso , COVID-19 , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , SARS-CoV-2 , Estudos Soroepidemiológicos , Distribuição por Sexo , Suíça/epidemiologia , Adulto Jovem
12.
Blood Press ; 30(1): 67-74, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33073631

RESUMO

PURPOSE: Sodium and water handling by the kidney and the sympathetic nervous system have been implicated in the development of obesity-related hypertension and kidney disease. They have seldom been studied together during stress conditions. The objective of this study was to compare the systemic, renal and hormonal responses to lower body negative pressure (LBNP) in adult healthy participants (H), obese normotensive (OBN) and obese hypertensive patients (OBH). MATERIALS AND METHODS: This was a prospective case-control study. Participants from the three groups were exposed to one hour of LBNP. Systemic and renal haemodynamics, sodium and water excretion and hormones were measured before and after LBNP. Intergroup LBNP responses were tested using a Student t-test or a Wilcoxon rank-sum test. An extension of the Wilcoxon rank-sum test was used to test for a trend across the three groups. RESULTS: The study included 54 participants (H: 25, OBN: 16, OBH: 13). LBNP induced a stepwise increase in systolic blood pressure (+2.7 ± 4.7 mmHg (H) vs. +4.7 ± 8.8 mmHg (OBN) vs. +8.0 ± 8.6 mmHg (OBH, p = .028)) and heart rate (-1.3 ± 4.9 bpm (H) vs. 2.2 ± 6.1 bpm (OBN) vs. 1.9 ± 4.1 bpm (OBH, p = .041). Urinary output (-2.8 ± 2.1 ml/min vs. -1.4 ± 1.7 ml/min, p = .028) and free water clearance (-1.9 ± 1.7 mOsm/kg vs. -0.7 ± 1.3 mOsm/kg, p = .016) responses were more marked in OBN compared to H. CONCLUSIONS: These results show that the systemic and the renal response to LBNP differ according to weight and to BP categories. Systolic BP and heart show a progressive increased response form healthy volunteers to OBN and then to obese hypertensive participants while urinary output and free water clearance responses are increased in OBN only, suggesting that the occurrence of hypertension in obese individuals modifies the early kidney responses to stress. CLINICALTRIAL.GOV IDENTIFIER: NCT01734096.


Assuntos
Hemodinâmica , Hipertensão/complicações , Rim/fisiopatologia , Obesidade/complicações , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Pressão Negativa da Região Corporal Inferior , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , Estudos Prospectivos , Adulto Jovem
13.
J Sleep Res ; 28(5): e12799, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30474290

RESUMO

Sleep-disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep-disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle-related behaviours such as smoking and alcohol use, may also be risk factors for sleep-disordered breathing. Here, we investigate the associations between socioeconomic status and sleep-disordered breathing, as measured by sleep apnea-hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle-related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population-based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep-disordered breathing was assessed through polysomnography and measured using the apnea-hypopnea index (AHI: number of apnea/hypopnea events/hr: ≥15/≥30 events), and the ≥3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: ≥15/≥30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population-based study, we found that low socioeconomic status is a risk factor for sleep-disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep-disordered breathing and may help implement policies for identifying high-risk profiles for this disorder.


Assuntos
Polissonografia/métodos , Síndromes da Apneia do Sono/complicações , Idoso , Feminino , Humanos , Masculino , Fatores de Risco , Mudança Social
14.
Appl Microbiol Biotechnol ; 103(12): 4801-4812, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993383

RESUMO

Poly(ethylene terephthalate) (PET) is one of the most widely applied synthetic polymers, but its hydrophobicity is challenging for many industrial applications. Biotechnological modification of PET surface can be achieved by PET hydrolyzing cutinases. In order to increase the adsorption towards their unnatural substrate, the enzymes are fused to carbohydrate-binding modules (CBMs) leading to enhanced activity. In this study, we identified novel PET binding CBMs and characterized the CBM-PET interplay. We developed a semi-quantitative method to detect CBMs bound to PET films. Screening of eight CBMs from diverse families for PET binding revealed one CBM that possesses a high affinity towards PET. Molecular dynamics (MD) simulations of the CBM-PET interface revealed tryptophan residues forming an aromatic triad on the peptide surface. Their interaction with phenyl rings of PET is stabilized by additional hydrogen bonds formed between amino acids close to the aromatic triad. Furthermore, the ratio of hydrophobic to polar contacts at the interface was identified as an important feature determining the strength of PET binding of CBMs. The interaction of CBM tryptophan residues with PET was confirmed experimentally by tryptophan quenching measurements after addition of PET nanoparticles to CBM. Our findings are useful for engineering PET hydrolyzing enzymes and may also find applications in functionalization of PET.


Assuntos
Metabolismo dos Carboidratos , Carboidratos/química , Interações Hidrofóbicas e Hidrofílicas , Polietilenotereftalatos/metabolismo , Triptofano/metabolismo , Sítios de Ligação , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Ligação Proteica
15.
Biophys J ; 114(7): 1614-1623, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29642031

RESUMO

Intrinsically disordered proteins dynamically sample a wide conformational space and therefore do not adopt a stable and defined three-dimensional conformation. The structural heterogeneity is related to their proper functioning in physiological processes. Knowledge of the conformational ensemble is crucial for a complete comprehension of this kind of proteins. We here present an approach that utilizes dynamic nuclear polarization-enhanced solid-state NMR spectroscopy of sparsely isotope-labeled proteins in frozen solution to take snapshots of the complete structural ensembles by exploiting the inhomogeneously broadened line-shapes. We investigated the intrinsically disordered protein α-synuclein (α-syn), which plays a key role in the etiology of Parkinson's disease, in three different physiologically relevant states. For the free monomer in frozen solution we could see that the so-called "random coil conformation" consists of α-helical and ß-sheet-like conformations, and that secondary chemical shifts of neighboring amino acids tend to be correlated, indicative of frequent formation of secondary structure elements. Based on these results, we could estimate the number of disordered regions in fibrillar α-syn as well as in α-syn bound to membranes in different protein-to-lipid ratios. Our approach thus provides quantitative information on the propensity to sample transient secondary structures in different functional states. Molecular dynamics simulations rationalize the results.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , alfa-Sinucleína/química , Sequência de Aminoácidos , Simulação de Dinâmica Molecular , Conformação Proteica , Temperatura
16.
Proteins ; 86(9): 935-944, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29790608

RESUMO

Although the protein backbone is the most fundamental part of the structure, the fine-tuning of side-chain conformations is important for protein function, for example, in protein-protein and protein-ligand interactions, and also in enzyme catalysis. While several benchmarks testing the performance of protein force fields for side chain properties have already been published, they often considered only a few force fields and were not tested against the same experimental observables; hence, they are not directly comparable. In this work, we explore the ability of twelve force fields, which are different flavors of AMBER, CHARMM, OPLS, or GROMOS, to reproduce average rotamer angles and rotamer populations obtained from extensive NMR studies of the 3 J and residual dipolar coupling constants for two small proteins: ubiquitin and GB3. Based on a total of 196 µs sampling time, our results reveal that all force fields identify the correct side chain angles, while the AMBER and CHARMM force fields clearly outperform the OPLS and GROMOS force fields in estimating rotamer populations. The three best force fields for representing the protein side chain dynamics are AMBER 14SB, AMBER 99SB*-ILDN, and CHARMM36. Furthermore, we observe that the side chain ensembles of buried amino acid residues are generally more accurately represented than those of the surface exposed residues.


Assuntos
Antígenos Glicosídicos Associados a Tumores/química , Ubiquitina/química , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Teoria Quântica
17.
J Am Chem Soc ; 140(46): 15889-15903, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30362343

RESUMO

Conformational changes are crucial for the catalytic action of many enzymes. A prototypical and well-studied example is loop opening and closure in triosephosphate isomerase (TIM), which is thought to determine the rate of catalytic turnover in many circumstances. Specifically, TIM loop 6 "grips" the phosphodianion of the substrate and, together with a change in loop 7, sets up the TIM active site for efficient catalysis. Crystal structures of TIM typically show an open or a closed conformation of loop 6, with the tip of the loop moving ∼7 Šbetween conformations. Many studies have interpreted this motion as a two-state, rigid-body transition. Here, we use extensive molecular dynamics simulations, with both conventional and enhanced sampling techniques, to analyze loop motion in apo and substrate-bound TIM in detail, using five crystal structures of the dimeric TIM from Saccharomyces cerevisiae. We find that loop 6 is highly flexible and samples multiple conformational states. Empirical valence bond simulations of the first reaction step show that slight displacements away from the fully closed-loop conformation can be sufficient to abolish most of the catalytic activity; full closure is required for efficient reaction. The conformational change of the loops in TIM is thus not a simple "open and shut" case and is crucial for its catalytic action. Our detailed analysis of loop motion in a highly efficient enzyme highlights the complexity of loop conformational changes and their role in biological catalysis.


Assuntos
Saccharomyces cerevisiae/enzimologia , Triose-Fosfato Isomerase/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Triose-Fosfato Isomerase/metabolismo
18.
Prev Med ; 113: 15-31, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29752959

RESUMO

Unhealthy behaviors and their social patterning have been frequently proposed as factors mediating socioeconomic differences in health. However, a clear quantification of the contribution of health behaviors to the socioeconomic gradient in health is lacking. This study systematically reviews the role of health behaviors in explaining socioeconomic inequalities in health. Published studies were identified by a systematic review of PubMed, Embase and Web-of-Science. Four health behaviors were considered: smoking, alcohol consumption, physical activity and diet. We restricted health outcomes to cardiometabolic disorders and mortality. To allow comparison between studies, the contribution of health behaviors, or the part of the socioeconomic gradient in health that is explained by health behaviors, was recalculated in all studies according to the absolute scale difference method. We identified 114 articles on socioeconomic position, health behaviors and cardiometabolic disorders or mortality from electronic databases and articles reference lists. Lower socioeconomic position was associated with an increased risk of all-cause mortality and cardiometabolic disorders, this gradient was explained by health behaviors to varying degrees (minimum contribution -43%; maximum contribution 261%). Health behaviors explained a larger proportion of the SEP-health gradient in studies conducted in North America and Northern Europe, in studies examining all-cause mortality and cardiovascular disease, among men, in younger individuals, and in longitudinal studies, when compared to other settings. Of the four behaviors examined, smoking contributed the most to social inequalities in health, with a median contribution of 19%. Health behaviors contribute to the socioeconomic gradient in cardiometabolic disease and mortality, but this contribution varies according to population and study characteristics. Nevertheless, our results should encourage the implementation of interventions targeting health behaviors, as they may reduce socioeconomic inequalities in health and increase population health.


Assuntos
Doenças Cardiovasculares/epidemiologia , Comportamentos Relacionados com a Saúde , Disparidades nos Níveis de Saúde , Fumar/epidemiologia , Fatores Socioeconômicos , Doenças Cardiovasculares/mortalidade , Saúde Global , Humanos , Fatores Sexuais
19.
J Chem Inf Model ; 58(4): 848-858, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29522682

RESUMO

Engineering high chemo-, regio-, and stereoselectivity is a prerequisite for enzyme usage in organic synthesis. Cytochromes P450 can oxidize a broad range of substrates, including macrocycles, which are becoming popular scaffolds for therapeutic agents. However, a large conformational space explored by macrocycles not only reduces the selectivity of oxidation but also impairs computational enzyme design strategies based on docking and molecular dynamics (MD) simulations. We present a novel design workflow that uses enhanced-sampling Hamiltonian replica exchange (HREX) MD and focuses on quantifying the substrate binding for suggesting the mutations to be made. This computational approach is applied to P450 BM3 with the aim to shift regioselectively toward one of the numerous possible positions during ß-cembrenediol oxidation. The predictions are experimentally tested and the resulting product distributions validate our design strategy, as single mutations led up to 5-fold regioselectivity increases. We thus conclude that the HREX-MD-based workflow is a promising tool for the identification of positions for mutagenesis aiming at P450 enzymes with improved regioselectivity.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Engenharia de Proteínas , Domínio Catalítico , Sistema Enzimático do Citocromo P-450/química , Mutagênese , Mutação , Oxirredução , Estereoisomerismo , Especificidade por Substrato , Termodinâmica
20.
J Am Chem Soc ; 139(30): 10514-10525, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28683550

RESUMO

Triosephosphate isomerase (TIM) is a proficient catalyst of the reversible isomerization of dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde phosphate (GAP), via general base catalysis by E165. Historically, this enzyme has been an extremely important model system for understanding the fundamentals of biological catalysis. TIM is activated through an energetically demanding conformational change, which helps position the side chains of two key hydrophobic residues (I170 and L230), over the carboxylate side chain of E165. This is critical both for creating a hydrophobic pocket for the catalytic base and for maintaining correct active site architecture. Truncation of these residues to alanine causes significant falloffs in TIM's catalytic activity, but experiments have failed to provide a full description of the action of this clamp in promoting substrate deprotonation. We perform here detailed empirical valence bond calculations of the TIM-catalyzed deprotonation of DHAP and GAP by both wild-type TIM and its I170A, L230A, and I170A/L230A mutants, obtaining exceptional quantitative agreement with experiment. Our calculations provide a linear free energy relationship, with slope 0.8, between the activation barriers and Gibbs free energies for these TIM-catalyzed reactions. We conclude that these clamping side chains minimize the Gibbs free energy for substrate deprotonation, and that the effects on reaction driving force are largely expressed at the transition state for proton transfer. Our combined analysis of previous experimental and current computational results allows us to provide an overview of the breakdown of ground-state and transition state effects in enzyme catalysis in unprecedented detail, providing a molecular description of the operation of a hydrophobic clamp in triosephosphate isomerase.


Assuntos
Fosfato de Di-Hidroxiacetona/metabolismo , Gliceraldeído 3-Fosfato/metabolismo , Simulação de Dinâmica Molecular , Triose-Fosfato Isomerase/metabolismo , Biocatálise , Fosfato de Di-Hidroxiacetona/química , Gliceraldeído 3-Fosfato/química , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Saccharomyces cerevisiae/enzimologia , Termodinâmica , Triose-Fosfato Isomerase/química , Triose-Fosfato Isomerase/genética
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