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3.
Artigo em Inglês | MEDLINE | ID: mdl-31898076

RESUMO

Numerous studies have shown that more visual features can be stored in visual short-term memory (VSTM) when they are encoded from fewer objects (Luck & Vogel, 1997, Nature, 390, 279-281; Olson & Jiang, 2002, Perception & Psychophysics, 64[7], 1055-1067). This finding has been consistent for simple objects with one surface and one boundary contour, but very few experiments have shown a clear performance benefit when features are organized as multipart objects versus spatially dispersed single-feature objects. Some researchers have suggested multipart object integration is not mandatory because of the potential ambiguity of the display (Balaban & Luria, 2015, Cortex, 26(5), 2093-2104; Luria & Vogel, 2014, Journal of Cognitive Neuroscience, 26[8], 1819-1828). For example, a white bar across the middle of a red circle could be interpreted as two objects, a white bar occluding a red circle, or as a single two-colored object. We explore whether an object benefit can be found by disambiguating the figure-ground organization of multipart objects using a luminance gradient and linear perspective to create the appearance of a unified surface. Also, we investigated memory for objects with a visual feature indicated by a hole, rather than an additional surface on the object. Results indicate the organization of multipart objects can influence VSTM performance, but the effect is driven by how the specific organization allows for use of global ensemble statistics of the memory array rather than a memory benefit for local object representations.

4.
BMC Genomics ; 21(1): 17, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906859

RESUMO

BACKGROUND: Daphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders. RESULTS: In this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes. CONCLUSIONS: The epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.

5.
Med Educ ; 54(1): 4-6, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31849097
6.
Artigo em Inglês | MEDLINE | ID: mdl-31822607

RESUMO

The life histories of animals reflect the allocation of metabolic energy to traits that determine fitness and the pace of living. Here, we extend metabolic theories to address how demography and mass-energy balance constrain allocation of biomass to survival, growth, and reproduction over a life cycle of one generation. We first present data for diverse kinds of animals showing empirical patterns of variation in life-history traits. These patterns are predicted by theory that highlights the effects of 2 fundamental biophysical constraints: demography on number and mortality of offspring; and mass-energy balance on allocation of energy to growth and reproduction. These constraints impose 2 fundamental trade-offs on allocation of assimilated biomass energy to production: between number and size of offspring, and between parental investment and offspring growth. Evolution has generated enormous diversity of body sizes, morphologies, physiologies, ecologies, and life histories across the millions of animal, plant, and microbe species, yet simple rules specified by general equations highlight the underlying unity of life.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31818823

RESUMO

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12h [q12h], 1,000 mg q12h, and 1,000 mg every 8h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA) and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the 750-mg q12h group, 89% for the gepotidacin 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 µg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N,both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial.

8.
Chem Res Toxicol ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31802667

RESUMO

Here we review recent studies which illustrate three areas where the microbiome directly impacts drug development: 1) microbial effects on drug safety and efficacy; 2) the effects of drugs on causing collateral restructuring of microbiome communities and 3) the potential side-effects of novel therapies targeting the microbiome. Based on the findings of these and other studies, we advocate the systematic incorporation of microbiome analyses in early to late stage clinical trials as a strategy to increase the overall success rate of the drug discovery and development process.

9.
Nat Commun ; 10(1): 5711, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836714

RESUMO

In order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.

10.
Nat Commun ; 10(1): 5662, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827096

RESUMO

Single-molecule assays have, by definition, the ultimate sensitivity and represent the next frontier in biological analysis and diagnostics. However, many of these powerful technologies require dedicated laboratories and trained personnel and have therefore remained research tools for specialists. Here, we present a single-molecule confocal system built from a 3D-printed scaffold, resulting in a compact, plug and play device called the AttoBright. This device performs single photon counting and fluorescence correlation spectroscopy (FCS) in a simple format and is widely applicable to the detection of single fluorophores, proteins, liposomes or bacteria. The power of single-molecule detection is demonstrated by detecting single α-synuclein amyloid fibrils, that are currently evaluated as biomarkers for Parkinson's disease, with an improved sensitivity of >100,000-fold over bulk measurements.

11.
Can J Urol ; 26(6): 10054-10060, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860423

RESUMO

INTRODUCTION: Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins involved in tissue mechanical stability and matrix organization. Initial work has demonstrated that alpha-DG expression is decreased in many types of adenocarcinoma, including prostate, and potentially associated with the development of metastatic disease. However, the consistency between prostate and lymph node alpha-DG staining has not been previously reported. In addition, identification of an immunohistochemical marker associated with prostate cancer grade, stage, need for adjuvant or salvage therapy and mortality would have potential clinical value. MATERIALS AND METHODS: Node positive, margin negative radical prostatectomy specimens at a single institution from 1982 to 2012 were reviewed and identified 35 prostate specimens, including 26 patients with available tissue from both the primary prostatectomy and lymph node specimens. The expression levels of the alpha-DG subunit were analyzed using immunohistochemistry and graded from 0 to 4. Survival was compared in different staining pattern groups. RESULTS: Strength of alpha-DG staining was found to be consistent between prostate and lymph node specimens (p < 0.004). The median overall survival was shorter in those without alpha-DG staining in the prostate compared to those with positive staining, but this difference was not statistically significant (13.2 years versus 19.4 years, p = 0.21). In addition, negative staining was associated with higher mean PSA, pathologic T stage, Gleason grade and the need for adjuvant or salvage therapy compared to positive group but none reached statistical significance (16.06 ng/mL versus 11.67 ng/mL, p = 0.79; 89% versus 68%, p = 0.38; 33.3% versus 23.1%, p = 0.66; 88.9% versus 76.9%, p = 0.44). CONCLUSIONS: DG expression by immunohistochemistry staining was consistent between prostate and metastatic lymph node specimens. In a small cohort of prostate cancer patients with margin negative but node positive disease, DG staining was not associated with Gleason grade or with overall mortality.

12.
Sci Rep ; 9(1): 16595, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719551

RESUMO

Using two advanced sequencing approaches, Illumina and PacBio, we derive the entire Dscam gene from an M2 assembly of the complete Penaeus monodon genome. The P. monodon Dscam (PmDscam) gene is ~266 kbp, with a total of 44 exons, 5 of which are subject to alternative splicing. PmDscam has a conserved architectural structure consisting of an extracellular region with hypervariable Ig domains, a transmembrane domain, and a cytoplasmic tail. We show that, contrary to a previous report, there are in fact 26, 81 and 26 alternative exons in N-terminal Ig2, N-terminal Ig3 and the entirety of Ig7, respectively. We also identified two alternatively spliced exons in the cytoplasmic tail, with transmembrane domains in exon variants 32.1 and 32.2, and stop codons in exon variants 44.1 and 44.2. This means that alternative splicing is involved in the selection of the stop codon. There are also 7 non-constitutive cytoplasmic tail exons that can either be included or skipped. Alternative splicing and the non-constitutive exons together produce more than 21 million isoform combinations from one PmDscam locus in the P. monodon gene. A public-facing database that allows BLAST searches of all 175 exons in the PmDscam gene has been established at http://pmdscam.dbbs.ncku.edu.tw/ .

13.
Sci Rep ; 9(1): 17618, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772306

RESUMO

The cricetine rodents Peromyscus leucopus and P. maniculatus are key reservoirs for several zoonotic diseases in North America. We determined the complete circular mitochondrial genome sequences of representatives of 3 different stock colonies of P. leucopus, one stock colony of P. maniculatus and two wild populations of P. leucopus. The genomes were syntenic with that of the murids Mus musculus and Rattus norvegicus. Phylogenetic analysis confirmed that these two Peromyscus species are sister taxa in a clade with P. polionotus and also uncovered a distinction between P. leucopus populations in the eastern and the central United States. In one P. leucopus lineage four extended regions of mitochondrial pseudogenes were identified in the nuclear genome. RNA-seq analysis revealed transcription of the entire genome and differences from controls in the expression profiles of mitochondrial genes in the blood, but not in liver or brain, of animals infected with the zoonotic pathogen Borrelia hermsii. PCR and sequencing of the D-loop of the mitochondrion identified 32 different haplotypes among 118 wild P. leucopus at a Connecticut field site. These findings help to further establish P. leucopus as a model organism for studies of emerging infectious diseases, ecology, and in other disciplines.

14.
Eur J Sport Sci ; : 1-12, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31665980

RESUMO

Rugby Sevens ('Sevens') is one of the fastest growing sports in the world. This growth was marked by the inclusion of the sport in the Olympic Games in 2016. The most frequently occurring contact events in Sevens are the tackle and ruck. Performing specific techniques during these contact events can reduce the risk of injury and increase the likelihood of success. Therefore, the purpose of this study was to identify the technical determinants associated with tackle and ruck performance outcomes in Sevens. A total of 4799 tackles and 1405 rucks from the 2014/2015 HSBC Sevens World Series were coded for contact, post-contact, ruck, match contextual variables and outcomes. Relative risk ratio (RR), the ratio of the probability of an outcome occurring when a variable was observed, was determined using multinomial logistic regression. A moderate ball-carrier leg drive reduced the probability of losing possession by 25% (RR 0.75, 95% CI, 0.58-0.97, p < .05). Conversely, ball-carriers had a 53% higher likelihood of losing possession when the tackler executed a moderate leg drive (RR 1.53, 95% CI, 1.09-2.14, p ≤ .05). Maintaining possession at the ruck was more likely to occur when committing one attacker compared to two (RR 0.31, 95% CI, 0.19-0.49, p < .001). Active ball-carrier placement also increased the likelihood of maintaining possession at the ruck (RR 14.67, 95% CI, 9.55-22.56, p < .001). Sevens coaches and trainers can now positively design evidence-based technical training programmes and emphasise specific tackle techniques in training using data from Sevens video analysis. Also, given that this is the first study to relate tackle technical determinants to an outcome (i.e. the first 'how' study) in Sevens, this work provides the foundation for similar Sevens video analysis studies in the future.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31705174

RESUMO

PURPOSE: The novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS. METHODS: Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion. RESULTS: The optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values. CONCLUSIONS: This first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.

16.
BMJ Open Respir Res ; 6(1): e000395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673360

RESUMO

Introduction: People living with HIV (PLWH) are more likely to smoke than the general population and are at greater risk of smoking-related illness. Healthcare services need to address this burden of preventable disease. Methods: We evaluated the impact of a brief intervention that asked service users about smoking when they attended for ambulatory HIV care in London, UK, and offered referral to smoking cessation. Results: Overall, 1548 HIV-positive individuals were asked about their smoking status over a 12-month period. Of this group, 385 (25%) reported that they were current smokers, 372 (97%) were offered referral to smoking cessation services and 154 (40%) accepted this. We established an outcome of referral for 114 (74%) individuals. A total of 36 (10% of smokers) attended stop smoking clinics and 16 (4%) individuals were recorded as having quit smoking. Discussion: The simple intervention of asking PLWH about tobacco smoking and offering referral to smoking cessation services rapidly identified current smokers, 40% of whom accepted referral to smoking cessation services. This highlights the importance of promoting behaviour and lifestyle changes with every contact with health services. However, a large proportion of those referred were either not seen in local services or the outcome of referral could not be ascertained. If the risk of smoking-related morbidity among PLWH is to be reduced, more sustainable referral pathways and ways of improving uptake of smoking cessation services must be developed.

17.
Aust J Gen Pract ; 48(11): 773-778, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31722464

RESUMO

BACKGROUND AND OBJECTIVES: The transfer of general practice training in Australia to the two general practice colleges is an opportunity for change in the model of training. The dialectical theory of institutional change suggests that change occurs where organisational structures of training are in tension with the needs of those delivering training, and effective change arises from innovation within these tension points. These tensions have also been faced by general practice training organisations internationally, where solutions have also been crafted. By exploring training tensions and responses to these, the aim of this study was to inform the remodelling of general practice training in Australia. METHOD: Senior educators and stakeholder representatives in Australia and internationally were interviewed to identify tensions in training delivery and innovative responses to these. An interpretative qualitative analysis was undertaken. RESULTS: Eight key tensions and associated innovative responses were identified. DISCUSSION: Drawing from the findings, this article provides recommendations for remodelling general practice training in Australia.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31591712

RESUMO

BACKGROUND: Maternal obesity is a key risk factor for morbidity in pregnancy. Accurate data on trends in obesity are required in high-risk populations such as in western Sydney to implement effective policy. AIMS: This study examines multi-site public hospital data on maternal ethnicity, body mass index (BMI), gestational diabetes mellitus (GDM) and hypertension across 20 years in Western Sydney Local Health District (WSLHD). MATERIALS AND METHODS: This is a retrospective cohort study of all women who delivered a live birth beyond 20 weeks at Westmead, Blacktown and Auburn Hospitals (WSLHD) between 1 January 1997 and 31 December 2016. RESULTS: There were 112 308 pregnant women included. Between 1997 and 2006, mean booking-in BMI climbed from 24.9 (median 23.9) to peak at 26.2 (24.9). It then fell to 25.3 (24.1) in 2012 before rising to 25.6 (24.4) in 2016. Rates of hypertensive disorders changed little over the period, with a small fall in pre-eclampsia. In contrast, there was a progressive upward trend in the prevalence of GDM, accelerating considerably after 2010. These trends were associated with a shifting ethnic profile with proportions of Australia/New Zealand-born women falling from 56.9% to 36.8%, while those from South Asia increased from 4.5% to 26.3%. CONCLUSIONS: Western Sydney booking-in BMI fluctuated between 1997 and 2016, reaching its peak in 2006. Despite this, rates of GDM progressively rose, with one in six mothers in western Sydney now diagnosed with some form of the condition. Both patterns are associated with a notable shift in the ethnic profile of patients booking-in to antenatal care in the region.

19.
Langmuir ; 35(45): 14670-14680, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31630525

RESUMO

A variety of natural surfaces exhibit antibacterial properties; as a result, significant efforts in the past decade have been dedicated toward fabrication of biomimetic surfaces that can help control biofilm growth. Examples of such surfaces include rose petals, which possess hierarchical structures like the micropapillae measuring tens of microns and nanofolds that range in the size of 700 ± 100 nm. We duplicated the natural structures on rose petal surfaces via a simple UV-curable nanocasting technique and tested the efficacy of these artificial surfaces in preventing biofilm growth using clinically relevant bacteria strains. The rose petal-structured surfaces exhibited hydrophobicity (contact angle (CA) ≈ 130.8° ± 4.3°) and high CA hysteresis (∼91.0° ± 4.9°). Water droplets on rose petal replicas evaporated following the constant contact line mode, indicating the likely coexistence of both Cassie and Wenzel states (Cassie-Baxter impregnating the wetting state). Fluorescence microscopy and image analysis revealed the significantly lower attachment of Staphylococcus epidermidis (86.1 ± 6.2% less) and Pseudomonas aeruginosa (85.9 ± 3.2% less) on the rose petal-structured surfaces, compared with flat surfaces over a period of 2 h. An extensive biofilm matrix was observed in biofilms formed by both species on flat surfaces after prolonged growth (several days), but was less apparent on rose petal-biomimetic surfaces. In addition, the biomass of S. epidermidis (63.2 ± 9.4% less) and P. aeruginosa (76.0 ± 10.0% less) biofilms were significantly reduced on the rose petal-structured surfaces, in comparison to the flat surfaces. By comparing P. aeruginosa growth on representative unitary nanopillars, we demonstrated that hierarchical structures are more effective in delaying biofilm growth. The mechanisms are two-fold: (1) the nanofolds across the hemispherical micropapillae restrict initial attachment of bacterial cells and delay the direct contact of cells via cell alignment and (2) the hemispherical micropapillae arrays isolate bacterial clusters and inhibit the formation of a fibrous network. The hierarchical features on rose petal surfaces may be useful for developing strategies to control biofilm formation in medical and industrial contexts.

20.
Plant Methods ; 15: 108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31548848

RESUMO

Background: The growing field of plant molecular farming relies on expression vectors that allow high yields of recombinant proteins to be produced through transient gene expression. While numerous expression vectors currently exist for this purpose, there are very few examples of systematic efforts to improve upon these. Moreover, the current generation of expression systems makes use of naturally-occurring regulatory elements, typically selected from plant viruses, to maximise yields. This study aims to use rational design to generate synthetic sequences that can rival existing ones. Results: In this work, we present the rational design of novel synthetic 5' and 3' untranslated regions (UTRs) which can be used in various combinations to modulate accumulation levels of transiently-expressed recombinant proteins. Using the pEAQ-HT expression vector as a point of comparison, we show that pre-existing expression systems can be improved by the deployment of rationally designed synthetic UTRs. Notably, we show that a suite of short, synthetic 5'UTRs behave as expression enhancers that outperform the HT 5'UTR present in the CPMV-HT expression system. Furthermore, we confirm the critical role played by the 3'UTR of cowpea mosaic virus RNA-2 in the performance of the CPMV-HT system. Finally, we use the knowledge obtained from these results to develop novel expression vectors (named pHRE and pHREAC) that equal or outperform pEAQ-HT in terms of recombinant protein yield. These new vectors are also domesticated for the use of certain Type IIS restriction enzymes, which allows for quicker cloning and straightforward assessment of different combinations of UTRs. Conclusions: We have shown that it is possible to rationally design a suite of expression modulators in the form of synthetic UTRs. We have created novel expression vectors that allow very high levels of recombinant protein expression in a transient expression context. This will have important consequences for future efforts to develop ever-better plant transient overexpression vectors for research or industrial applications.

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