Scoring functions are essential for modern in silico drug discovery. However, the accurate prediction of binding affinity by scoring functions remains a challenging task. The performance of scoring ...functions is very heterogeneous across different target classes. Scoring functions based on precise physics-based descriptors better representing protein-ligand recognition process are strongly needed. We developed a set of new empirical scoring functions, named DockTScore, by explicitly accounting for physics-based terms combined with machine learning. Target-specific scoring functions were developed for two important drug targets, proteases and protein-protein interactions, representing an original class of molecules for drug discovery. Multiple linear regression (MLR), support vector machine and random forest algorithms were employed to derive general and target-specific scoring functions involving optimized MMFF94S force-field terms, solvation and lipophilic interactions terms, and an improved term accounting for ligand torsional entropy contribution to ligand binding. DockTScore scoring functions demonstrated to be competitive with the current best-evaluated scoring functions in terms of binding energy prediction and ranking on four DUD-E datasets and will be useful for in silico drug design for diverse proteins as well as for specific targets such as proteases and protein-protein interactions. Currently, the MLR DockTScore is available at www.dockthor.lncc.br .
Chronic diseases are a global problem, yet information on their determinants is generally scant in low- and middle-income countries. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) ...aims to contribute relevant information regarding the development and progression of clinical and subclinical chronic diseases, particularly cardiovascular diseases and diabetes, in one such setting. At Visit 1, we enrolled 15 105 civil servants from predefined universities or research institutes. Baseline assessment (2008-10) included detailed interviews and measurements to assess social and biological determinants of health, as well as various clinical and subclinical conditions related to diabetes, cardiovascular diseases and mental health. A second visit of interviews and examinations is under way (2012-14) to enrich the assessment of cohort exposures and to detect initial incident events. Annual surveillance has been conducted since 2009 for the ascertainment of incident events. Biological samples (sera, plasma, urine and DNA) obtained at both visits have been placed in long-term storage. Baseline data are available for analyses, and collaboration via specific research proposals directed to study investigators is welcome.
To investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer (CAC).
C57BL/6 mice received an intraperitoneal injection of ...azoxymethane (10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water (5% w/v). Probiotic group received daily a mixture of
,
and
. Microbiota composition was assessed by 16S rRNA Illumina HiSeq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR (Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two-sided. The level of significance was set at
< 0.05. Graphs were generated and statistical analysis performed using the software GraphPad Prism 5.0. The project was approved by the institutional review board committee.
At day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size (< 2 mm) (
< 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera
,
,
,
XI and
XVIII increased in the probiotic group (
< 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p-IKK and TNF-α and increased IL-10 expression in the colon.
Our results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC.
Abortion, particularly when illegal, highlights inequities in different populations. Although abortion-related mortality is lower compared to other obstetric causes, abortion complications tend to be ...more lethal. Delays in seeking and obtaining care are determinants of negative outcomes. This study, nested within the GravSus-NE, analyzed healthcare delays and their association with abortion-related complications in three cities of northeastern Brazil (Salvador, Recife and São Luís). Nineteen public maternity hospitals were involved. All eligible women ≥18 years old hospitalized between August and December 2010 were evaluated. Descriptive, stratified and multivariate analyses were performed. Youden's index was used to determine delay. One model was created with all the women and another with those admitted in good clinical conditions, thus determining complications that occurred during hospitalization and their associated factors. Of 2,371 women, most (62.3%) were ≤30 years old (median 27 years) and 89.6% reported being black or brown-skinned. Most (90.5%) were admitted in good condition, 4.0% in fair condition and 5.5% in poor/very poor condition. Median time between admission and uterine evacuation was 7.9 hours. After a cut-off time of 10 hours, the development of complications increased considerably. Black women and those admitted during nightshifts were more likely to experience a wait time ≥10 hours. Delays were associated with severe complications (OR 1.97; 95%CI: 1.55-2.51), including in the women admitted in good condition (OR 2,56; 95%CI: 1.85-3.55), and even following adjustment for gestational age and reported abortion type (spontaneous/induced). These findings corroborate the literature, highlighting the social vulnerability of women hospitalized within Brazil's public healthcare system in a situation of abortion. The study strongpoints include having objectively measured the time between admission and uterine evacuation and having established a cut-off time defining delay based on conceptual and epidemiological criteria. Further studies should evaluate other settings and new measurement tools for effectively preventing life-threatening complications.
G-Protein coupled receptors (GPCRs) are involved in a myriad of pathways key for human physiology through the formation of complexes with intracellular partners such as G-proteins and arrestins ...(Arrs). However, the structural and dynamical determinants of these complexes are still largely unknown. Herein, we developed a computational big-data pipeline that enables the structural characterization of GPCR complexes with no available structure. This pipeline was used to study a well-known group of catecholamine receptors, the human dopamine receptor (DXR) family and its complexes, producing novel insights into the physiological properties of these important drug targets. A detailed description of the protein interfaces of all members of the DXR family (D1R, D2R, D3R, D4R, and D5R) and the corresponding protein interfaces of their binding partners (Arrs: Arr2 and Arr3; G-proteins: Gi1, Gi2, Gi3, Go, Gob, Gq, Gslo, Gssh, Gt2, and Gz) was generated. To produce reliable structures of the DXR family in complex with either G-proteins or Arrs, we performed homology modeling using as templates the structures of the β2-adrenergic receptor (β2AR) bound to Gs, the rhodopsin bound to Gi, and the recently acquired neurotensin receptor-1 (NTSR1) and muscarinic 2 receptor (M2R) bound to arrestin (Arr). Among others, the work demonstrated that the three partner groups, Arrs and Gs- and Gi-proteins, are all structurally and dynamically distinct. Additionally, it was revealed the involvement of different structural motifs in G-protein selective coupling between D1- and D2-like receptors. Having constructed and analyzed 50 models involving DXR, this work represents an unprecedented large-scale analysis of GPCR-intracellular partner interface determinants. All data is available at www.moreiralab.com/resources/dxr.
Previous analyses of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) identified four main dietary patterns (DP). The aim of this study was to explore the association between the ...previously defined DP and renal function (RF). A cross-sectional study using the ELSA-Brasil baseline data was carried out. DP ("traditional", "fruits and vegetables", "bakery", and "low sugar/low fat), metabolic syndrome (MS) using the Joint Interim Statement criteria, microalbuminuria (MA), and glomerular filtration rate (eGFR) through the CKD-EPI equation were evaluated. Abnormal RF was defined as eGFR<60 mL·min-1·(1.73 m2)-1 and MA≥3.0 mg/dL. Factors associated with RF were determined and mediation analysis was performed to investigate the association between DP, MS, and RF. A total of 15,105 participants were recruited, with a mean age of 52±9 years; 8,134 participants (54%) were females. The mediation analysis identified indirect associations between "bakery" and "fruits and vegetables", and both were associated with decreased eGFR and albuminuria in both genders, compared with "traditional" and "low sugar/low fat" patterns in the general population. There was a direct association of the "bakery" pattern with MA in men (OR: 1.17, 95%CI: 1.92-1.48). The "fruits and vegetables" pattern also showed a direct association with reduced eGFR in women (OR: 1.65, 95%CI: 1.28-2.12), although there was no significance after adjustment. The "fruits and vegetables" and "bakery" DPs were associated with renal dysfunction. The only independent, direct association was between "bakery" DP and MA in men, raising concerns about DP and renal damage in men.
Although the genus
includes only two taxonomically accepted species, the published literature is unanimous about the invasive nature of this genus in different regions of the globe, and about the ...availability of large amounts of biomass for which it is important to find a commercial application. This review shows that extracts from
species have already been evaluated for antioxidant, antibacterial, antifungal, antiviral, antifouling, cytotoxic, antimethanogenic and enzyme-inhibitory activity. However, the tables presented herein show, with few exceptions, that the activity level displayed is generally low when compared with positive controls. Studies involving pure compounds being identified in
species are rare. The chemical compositions of most of the evaluated extracts are unknown. At best, the families of the compounds present are suggested. This review also shows that the volatile halogenated compounds, fatty acids and sterols that are biosynthesized by the
species are relatively well known. Many other non-volatile metabolites (halogen compounds, flavonoids, other phenolic compounds) seem to be produced by these species, but their chemical structures and properties haven'been investigated. This shows how much remains to be investigated regarding the secondary-metabolite composition of these species, suggesting further studies following more targeted methodologies.
To investigate sex-specific associations of birth weight with body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) in mid-to-late adulthood.
ELSA-Brasil is a multicenter ...cohort study of adults aged 35-74 years affiliated with universities or research institutions of six capital cities in Brazil. After exclusions, we investigated 11 636 participants. Socio-demographic factors and birth weight were obtained by interview. All anthropometry was directly measured at baseline. We categorized birth weight as low (⩽2.5 kg); normal (2.5-4 kg) and high (⩾4 kg). We performed analysis of covariance (ANCOVA) for continuous outcomes and ordinal logistic regression for categorical adiposity outcomes. We examined interaction on the multiplicative scale by sex and by race.
High birth weight uniformly predicted greater overall and central obesity in men and women. However, low (vs normal) birth weight, in ANCOVA models adjusted for participant age, family income, race, education, maternal education, and maternal and paternal history of diabetes, was associated with lower BMI, WC and WHR means for men, but not for women (Pinteraction=0.01, <0.0001 and <0.0001, respectively). In similarly adjusted ordinal logistic regression models, odds of obesity (odds ratio (OR)=0.65, 0.46-0.90) and of being in the high (vs low) tertile of WC (OR=0.66, 0.50-0.87) and of WHR (OR=0.79, 0.60-1.03) were lower for low (vs normal) birth weight men, but trended higher (BMI: OR=1.18, 0.92-1.51; WC: OR=1.21, 0.97-1.53; WHR: OR=1.44, 1.15-1.82) for low (vs normal) birth weight women.
In this Brazilian sample of middle-aged and elderly adults who have lived through a rapid nutritional transition, low birth weight was associated with adult adiposity in a sex-specific manner. In men, low birth weight was associated with lower overall and central adult adiposity, while in women low birth weight was generally associated with greater central adiposity.
Although low- and middle-income countries still bear the burden of major infectious diseases, chronic noncommunicable diseases are becoming increasingly common due to rapid demographic, ...epidemiologic, and nutritional transitions. However, information is generally scant in these countries regarding chronic disease incidence, social determinants, and risk factors. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) aims to contribute relevant information with respect to the development and progression of clinical and subclinical chronic diseases, particularly cardiovascular diseases and diabetes. In this report, the authors delineate the study's objectives, principal methodological features, and timeline. At baseline, ELSA-Brasil enrolled 15,105 civil servants from 5 universities and 1 research institute. The baseline examination (2008-2010) included detailed interviews, clinical and anthropometric examinations, an oral glucose tolerance test, overnight urine collection, a 12-lead resting electrocardiogram, measurement of carotid intima-media thickness, echocardiography, measurement of pulse wave velocity, hepatic ultrasonography, retinal fundus photography, and an analysis of heart rate variability. Long-term biologic sample storage will allow investigation of biomarkers that may predict cardiovascular diseases and diabetes. Annual telephone surveillance, initiated in 2009, will continue for the duration of the study. A follow-up examination is scheduled for 2012-2013.
Recent evidence suggests that glaucoma and Alzheimer's disease are neurodegenerative diseases sharing common pathophysiological and etiological features, although findings are inconclusive. We sought ...to investigate whether self-reported glaucoma patients without dementia present poorer cognitive performance, an issue that has been less investigated. We employed cross-sectional data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) and included participants ≥50 years of age without a known diagnosis of dementia and a self-reported glaucoma diagnosis. We excluded those with previous stroke, other eye conditions, and using drugs that could impair cognition. We evaluated cognition using delayed word recall, phonemic verbal fluency, and trail making (version B) tests. We used multinomial linear regression models to investigate associations between self-reported glaucoma with cognition, adjusted by several sociodemographic and clinical variables. Out of 4,331 participants, 139 reported glaucoma. Fully-adjusted models showed that self-reported glaucoma patients presented poorer performance in the verbal fluency test (β=-0.39, 95%CI=-0.64 to -0.14, P=0.002), but not in the other cognitive assessments. Thus, our results support the hypothesis that self-reported glaucoma is associated with poor cognitive performance; however, longitudinal data are necessary to corroborate our findings.
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