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1.
Nat Neurosci ; 22(12): 1961-1965, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31768057

RESUMO

The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivated a combined analysis across ASD and ADHD, identifying microtubule-associated protein 1A (MAP1A) as a new exome-wide significant gene conferring risk for childhood psychiatric disorders.

2.
Proc Natl Acad Sci U S A ; 115(52): 13347-13352, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30530686

RESUMO

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.


Assuntos
Imunidade Inata/fisiologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Fatores Etários , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Carbono/metabolismo , Feminino , Imunidade Celular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Biogênese de Organelas , Respiração , Linfócitos T/metabolismo
3.
Nat Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478444

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

4.
Am J Hum Genet ; 102(6): 1204-1211, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861106

RESUMO

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

5.
Cell Rep ; 22(8): 1945-1955, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29466723

RESUMO

Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen.

6.
Mol Cell ; 63(6): 1006-20, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27635760

RESUMO

While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Leucemia Mieloide Aguda/metabolismo , Prolina/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/química , Acetil-CoA Carboxilase/genética , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Hidroxilação , Prolina Dioxigenases do Fator Induzível por Hipóxia/química , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos NOD , Modelos Moleculares , Transplante de Neoplasias , Oxirredução , Prolina/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Homologia Estrutural de Proteína , Análise de Sobrevida
7.
Cell Metab ; 24(1): 104-17, 2016 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-27411012

RESUMO

Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T cell activation and survival.


Assuntos
Carbono/metabolismo , Ativação Linfocitária/imunologia , Biogênese de Organelas , Proteoma/metabolismo , Linfócitos T/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular , Metabolismo Energético , Epitopos , Redes e Vias Metabólicas , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteômica , Pirimidinas/biossíntese
8.
Aging Cell ; 14(5): 818-25, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26109058

RESUMO

The mitochondrial deacetylase SIRT3 regulates several important metabolic processes. SIRT3 is transcriptionally upregulated in multiple tissues during nutrient stresses such as dietary restriction and fasting, but the molecular mechanism of this induction is unclear. We conducted a bioinformatic study to identify transcription factor(s) involved in SIRT3 induction. Our analysis identified an enrichment of binding sites for nuclear respiratory factor 2 (NRF-2), a transcription factor known to play a role in the expression of mitochondrial genes, in the DNA sequences of SIRT3 and genes with closely correlated expression patterns. In vitro, knockdown or overexpression of NRF-2 modulated SIRT3 levels, and the NRF-2α subunit directly bound to the SIRT3 promoter. Our results suggest that NRF-2 is a regulator of SIRT3 expression and may shed light on how SIRT3 is upregulated during nutrient stress.


Assuntos
Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Sirtuína 3/genética , Animais , Sítios de Ligação , Células Cultivadas , Biologia Computacional , Indução Enzimática/genética , Fator de Transcrição de Proteínas de Ligação GA/deficiência , Células HEK293 , Humanos , Regiões Promotoras Genéticas/genética , Sirtuína 3/biossíntese
9.
Methods Enzymol ; 543: 141-63, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24924131

RESUMO

Sirtuin 3 (SIRT3) is a major regulator of oncometabolism. Indeed, the activity of SIRT3 significantly affects the response to oxidative stress, glycolytic proficiency, and tumorigenic potential of malignant cells. Thus, a system to accurately measure the transcriptional activity of the SIRT3 promoter could facilitate the identification of novel antineoplastic agents or have diagnostic applications. Here, we describe all the steps involved in the development of a luciferase-based reporter system to measure the activation of the human SIRT3 promoter, encompassing the design of appropriate primers, the cloning of the promoter fragment, and its site-directed mutagenesis. We validated this system in human embryonic kidney 293T cells, taking advantage of the renowned ability of the transcription factor estrogen-related receptor α to transactivate SIRT3. Moreover, here we demonstrate that SIRT3 expression is responsive to rapamycin, a small inhibitor of mammalian target of rapamycin that has been extensively employed as a caloric restriction mimetic. Finally, we provide an overview of the complementary molecular biology techniques that might be employed to further verify the reliability of this system.


Assuntos
Genes Reporter , Luciferases/genética , Regiões Promotoras Genéticas , Sirtuína 3/genética , Transcrição Genética , Sequência de Bases , Western Blotting , Primers do DNA , Células HEK293 , Humanos , Reação em Cadeia da Polimerase
10.
J Biol Chem ; 287(51): 42444-52, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23086954

RESUMO

Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD(+)-dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.


Assuntos
Doença , Sirtuínas/metabolismo , Envelhecimento/metabolismo , Encéfalo/metabolismo , Humanos , Metabolismo
11.
Risk Anal ; 32(3): 374-80, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22023503

RESUMO

Current governmental practices often use a method called weight of evidence (WoE) to integrate and weigh different sources of information in the process of reaching a decision. Recent advances in cognitive neuroscience have identified WoE-like processes in the brain, and we believe that these advances have the potential to improve current decision-making practices. In this article, we describe five specific areas where knowledge emerging from cognitive neuroscience may be applied to the challenges confronting decisionmakers who manage risks: (1) quantifying evidence, (2) comparing the value of different sources of evidence, (3) reaching a decision, (4) illuminating the role of subjectivity, and (5) adapting to new information. We believe that the brain is an appropriate model for structuring decision-making processes because the brain's network is designed for complex, flexible decision making, and because policy decisions that must ultimately depend on human judgment will be best served by methods that complement human abilities. Future discoveries in cognitive neuroscience will likely bring further applications to decision practice.


Assuntos
Tomada de Decisões , Política Pública , Encéfalo/fisiologia , Cognição , Política Ambiental , Humanos , Neurociências , Medição de Risco
12.
J Nanopart Res ; 11(3): 513-527, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19655050

RESUMO

Nanomaterials and their associated technologies hold promising opportunities for the development of new materials and applications in a wide variety of disciplines, including medicine, environmental remediation, waste treatment, and energy conservation. However, current information regarding the environmental effects and health risks associated with nanomaterials is limited and sometimes contradictory. This article summarizes the conclusions of a 2008 NATO workshop designed to evaluate the wide-scale implications (e.g., benefits, risks, and costs) of the use of nanomaterials on human health and the environment. A unique feature of this workshop was its interdisciplinary nature and focus on the practical needs of policy decision makers. Workshop presentations and discussion panels were structured along four main themes: technology and benefits, human health risk, environmental risk, and policy implications. Four corresponding working groups (WGs) were formed to develop detailed summaries of the state-of-the-science in their respective areas and to discuss emerging gaps and research needs. The WGs identified gaps between the rapid advances in the types and applications of nanomaterials and the slower pace of human health and environmental risk science, along with strategies to reduce the uncertainties associated with calculating these risks.

13.
Sci Total Environ ; 407(19): 5199-205, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19619890

RESUMO

Assessments of human health and ecological risk draw upon multiple types and sources of information, requiring the integration of multiple lines of evidence before conclusions may be reached. Risk assessors often make use of weight-of-evidence (WOE) approaches to perform the integration, whether integrating evidence concerning potential carcinogenicity, toxicity, and exposure from chemicals at a contaminated site, or evaluating processes concerned with habitat loss or modification when managing a natural resource. Historically, assessors have relied upon qualitative WOE approaches, such as professional judgment, or limited quantitative methods, such as direct scoring, to develop conclusions from multiple lines of evidence. Current practice often lacks transparency resulting in risk estimates lacking quantified uncertainty. This paper reviews recent applications of weight of evidence used in human health and ecological risk assessment. Applications are sorted based on whether the approach relies on qualitative and quantitative methods in order to reveal trends in the use of the term weight of evidence, especially as a means to facilitate structured and transparent development of risk conclusions from multiple lines of evidence.


Assuntos
Ecotoxicologia , Medicina Ambiental/métodos , Técnicas de Apoio para a Decisão , Nível de Saúde , Humanos , Medição de Risco/métodos
14.
Nanomedicine ; 4(2): 167-71, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18329962

RESUMO

Current nanomaterial research is focused on the medical applications of nanotechnology, whereas side effects associated with nanotechnology use, especially the environmental impacts, are not taken into consideration during the engineering process. Nanomedical users and developers are faced with the challenge of balancing the medical and societal benefits and risks associated with nanotechnology. The adequacy of available tools, such as physiologically-based pharmacokinetic modeling or predictive structure-activity relationships, in assessing the toxicity and risk associated with specific nanomaterials is unknown. Successful development of future nanomedical devices and pharmaceuticals thus requires a consolidated information base to select the optimal nanomaterial in a given situation--understanding the toxicology and potential side effects associated with candidate materials for medical applications, understanding product life cycle, and communicating effectively with personnel, stakeholders, and regulators. This can be achieved through an innovative combination of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (MCDA).


Assuntos
Tomada de Decisões , Nanomedicina/tendências , Nanoestruturas/efeitos adversos , Medição de Risco/métodos , Avaliação da Tecnologia Biomédica , Toxicologia/tendências , Estados Unidos
15.
Integr Environ Assess Manag ; 3(3): 310-21, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17695104

RESUMO

An intensification of interest in environmental assessment during the last 2 decades has driven corporate efforts to better document environmental goals, improve environmental management systems, and increase awareness of the environmental and ecological effects of business operations. This trend has been motivated partly by regulatory requirements (such as the Toxics Release Inventory in the United States) and partly by the inclination of some large manufacturing firms to embrace a broader social and environmental mission characterized as "sustainability" or "ecoefficiency." Moreover, the importance of measurable objectives in the US government has been recognized at least since the Government Performance Results Act of 1993, which was intended to both improve the efficiency of government and the confidence of the American public in government managers. However, in management of environmental crises - such as catastrophic oil or chemical spills - development of measurable performance standards has lagged. Consequently, government spill managers are unable to define success in terms that are easily communicated to public and other stakeholder groups, and they could be disadvantaged in their efforts to deploy response resources with maximum efficiency. In this paper, we present a typological review of environmental assessment measures and summarize some of the current practices and strategic goals among federal agencies with regard to oil and chemical spills. A general approach to organizing metrics for oil spill response, restoration, and recovery is also presented. The results could improve planning efforts and communication among different federal, state, and local agencies and public or stakeholder groups involved in spill management.


Assuntos
Acidentes , Meio Ambiente , Petróleo , Planejamento em Desastres , Governo Federal , Indústrias
16.
Integr Environ Assess Manag ; 3(2): 223-33, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17477290

RESUMO

Environmental decision making is becoming increasingly more information intensive and complex. Our previous work shows that multicriteria decision analysis (MCDA) tools offer a scientifically sound decision analytical framework for environmental management, in general, and specifically for selecting optimal sediment management alternatives. Integration of MCDA into risk assessment and sediment management may require linkage of different models and software platforms whose results may lead to somewhat different conclusions. This paper illustrates the application of 3 different MCDA methods in 2 case studies involving contaminated sediment management. These case studies are based on real sediment management problems experienced by the US Army Corps of Engineers and other stakeholders in New York/New Jersey Harbor, USA, and the Cocheco River Superfund Site in New Hampshire, USA. Our analysis shows that application of 3 different MCDA tools points to similar management solutions no matter which tool is applied. MCDA tools and approaches were constructively used to elicit the strengths and weaknesses of each method when solving the problem.


Assuntos
Técnicas de Apoio para a Decisão , Poluição Ambiental , Sedimentos Geológicos/análise , Substâncias Perigosas/toxicidade , Gerenciamento de Resíduos/métodos , Abastecimento de Água/análise , Poluição Ambiental/efeitos adversos , Poluição Ambiental/análise , New Hampshire , New Jersey , New York , Formulação de Políticas , Medição de Risco , Estados Unidos , United States Environmental Protection Agency , Serviço Veterinário Militar , Gerenciamento de Resíduos/economia
17.
Wound Repair Regen ; 14(4): 398-404, 2006 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16939566

RESUMO

Regeneration of mammalian digit tips is well described; however, associated cellular or molecular events have not been studied in humans. We describe an in vitro human fetal model of response to digit tip amputation, and report expression of the transcription repressor Msx1 in the developing and regrowing human digit tip. Human fetal digits from specimens ranging from 53 to 117 days' estimated gestational age (EGA) were cultured in a defined serum-free medium with supplemented oxygen for time periods from 4 days to 4 weeks. Histology and immunohistochemistry were performed on paired control and tip-amputated digits. Regrowing tissue covered the cut end of the distal phalanx in digits up to 80 days' EGA. Msx1 expression was detected beneath the nail field in control digits to at least 70 days' EGA and at the regrowing tip of 57-day digits at 4 and 7 days post-amputation. Our results show that human fetal digits regrow tissue in vitro in response to tip amputation. This process appears spatially associated with Msx1 expression. Msx1 expression appears increased at the regrowing tip of 57-day digits by 4 days after amputation.


Assuntos
Amputação Traumática/metabolismo , Amputação Traumática/fisiopatologia , Dedos/fisiopatologia , Fator de Transcrição MSX1/metabolismo , Regeneração/fisiologia , Feto , Dedos/embriologia , Idade Gestacional , Humanos , Fatores de Tempo , Técnicas de Cultura de Tecidos , Cicatrização/fisiologia
19.
Integr Environ Assess Manag ; 2(1): 92-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16640324

RESUMO

Current uncertainties in our understanding of ecosystems require shifting from optimization-based management to an adaptive management paradigm. Risk managers routinely make suboptimal decisions because they are forced to predict environmental response to different management policies in the face of complex environmental challenges, changing environmental conditions, and even changing social priorities. Rather than force risk managers to make single suboptimal management choices, adaptive management explicitly acknowledges the uncertainties at the time of the decision, providing mechanisms to design and institute a set of more flexible alternatives that can be monitored to gain information and reduce the uncertainties associated with future management decisions. Although adaptive management concepts were introduced more than 20 y ago, their implementation has often been limited or piecemeal, especially in remedial decision making. We believe that viable tools exist for using adaptive management more fully. In this commentary, we propose that an adaptive management approach combined with multicriteria decision analysis techniques would result in a more efficient management decision-making process as well as more effective environmental management strategies. A preliminary framework combining the 2 concepts is proposed for future testing and discussion.


Assuntos
Conservação dos Recursos Naturais , Tomada de Decisões , Meio Ambiente , Poluição Ambiental/prevenção & controle , Ecossistema , Humanos , Formulação de Políticas , Reprodutibilidade dos Testes , Medição de Risco
20.
Environ Sci Technol ; 39(18): 6917-22, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16201611

RESUMO

The assessment of human health and ecological risks at chemically contaminated sites often includesthe use of models to assess chemical transport, fate, and exposure/toxicity. These models require input data on a variety of physical and chemical properties for each compound of concern. Small changes in some of these parameters may result in significant differences in estimated human health or ecological risks and in the extent of required remediation efforts. The octanol-water partition coefficient (Kow) for hydrophobic organic compounds is one such parameter, particularly because it is often used to estimate additional partitioning and bioaccumulation parameters. Unfortunately, there is considerable variability among tabulated Kow values for many compounds of concern. This paper assesses the implications of using various values of Kow to calculate health-protective polychlorinated biphenyl (PCB) sediment quality objectives (SQOs) in a case study using a simplified food chain model and the range of Kow values available from or recommended by the U. S. EPA. For the site and Kow values considered in this study, which are a snapshot of values available in the spring of 2004, the SQOs differ by as much as a factor of 5. This range of SQOs is estimated to correspond to a difference in remediation costs of $48 million.


Assuntos
Monitoramento Ambiental/métodos , Octanóis/análise , Medição de Risco/métodos , Poluentes da Água/análise , Água/análise , Animais , Ecossistema , Poluentes Ambientais , Peixes , Cadeia Alimentar , Sedimentos Geológicos/análise , Humanos , Cinética , Modelos Teóricos , Compostos Orgânicos , Reprodutibilidade dos Testes , Solo/análise , Estados Unidos , Washington , Poluentes Químicos da Água
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