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1.
Cardiovasc Res ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165538

RESUMO

The ability to generate multi-omics data coupled with deeply characterizing the clinical phenotype of individual patients promises to improve understanding of complex cardiovascular pathobiology. There remains an important disconnection between the magnitude and granularity of these data and our ability to improve phenotype-genotype correlations for complex cardiovascular diseases. This shortcoming may be due to limitations associated with traditional reductionist analytical methods, which tend to emphasize a single molecular event in the pathogenesis of diseases more aptly characterized by crosstalk between overlapping molecular pathways. Network medicine is a rapidly growing discipline that considers diseases as the consequences of perturbed interactions between multiple interconnected biological components. This powerful integrative approach has enabled a number of important discoveries in complex disease mechanisms. In this review, we introduce the basic concepts of network medicine and highlight specific examples by which this approach has accelerated cardiovascular research. We also review how network medicine is well-positioned to promote rational drug design for patients with cardiovascular diseases, with particular emphasis on advancing precision medicine.

2.
Sci Rep ; 10(1): 17029, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046794

RESUMO

Several studies have linked maternal asthma, excess BMI, and low vitamin D status with increased risk of Preeclampsia (PE) development. Given prior evidence in the literature and our observations from the subjects in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we hypothesized that PE, maternal asthma, vitamin D insufficiency, and excess body mass index (BMI) might share both peripheral blood and placental gene signatures that link these conditions together. We used samples collected in the VDAART to investigate relationships between these four conditions and gene expression patterns in peripheral blood obtained at early pregnancy. We identified a core set of differentially expressed genes in all comparisons between women with and without these four conditions and confirmed them in two separate sets of samples. We confirmed the differential expression of the shared gene signatures in the placenta from an independent study of preeclampsia cases and controls and constructed the preeclampsia module using protein-protein interaction networks. CXC chemokine genes showed the highest degrees of connectivity and betweenness centrality in the peripheral blood and placental modules. The shared gene signatures demonstrate the biological pathways involved in preeclampsia at the pre-clinical stage and may be used for the prediction of preeclampsia.

3.
BMC Biol ; 18(1): 138, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33050894

RESUMO

BACKGROUND: Growing evidence shows that scientific collaboration plays a crucial role in transformative innovation in the life sciences. For example, contemporary drug discovery and development reflects the work of teams of individuals from academic centers, the pharmaceutical industry, the regulatory science community, health care providers, and patients. However, public understanding of how collaborations between academia and industry catalyze novel target identification and first-in-class drug discovery is limited. RESULTS: We perform a comprehensive network analysis on a large scientific corpus of collaboration and citations (97,688 papers with 1,862,500 citations from 170 million scientific records) to quantify the success trajectory of innovative drug development. By focusing on four types of cardiovascular drugs, we demonstrate how knowledge flows between institutions to highlight the underlying contributions of many different institutions in the development of a new drug. We highlight how such network analysis could help to increase industrial and governmental support, and improve the efficiency or accelerate decision-making in drug discovery and development. CONCLUSION: We demonstrate that network analysis of large public databases can identify and quantify investigator and institutional relationships in drug discovery and development. If broadly applied, this type of network analysis may help to enhance public understanding of and support for biomedical research, and could identify factors that facilitate decision-making in first-in-class drug discovery among academia, the pharmaceutical industry, and healthcare systems.

6.
Circulation ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32965135
7.
Am J Clin Nutr ; 112(3): 721-769, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32687145

RESUMO

BACKGROUND: The US faces remarkable food and nutrition challenges. A new federal effort to strengthen and coordinate nutrition research could rapidly generate the evidence base needed to address these multiple national challenges. However, the relevant characteristics of such an effort have been uncertain. OBJECTIVES: Our aim was to provide an objective, informative summary of 1) the mounting diet-related health burdens facing our nation and corresponding economic, health equity, national security, and sustainability implications; 2) the current federal nutrition research landscape and existing mechanisms for its coordination; 3) the opportunities for and potential impact of new fundamental, clinical, public health, food and agricultural, and translational scientific discoveries; and 4) the various options for further strengthening and coordinating federal nutrition research, including corresponding advantages, disadvantages, and potential executive and legislative considerations. METHODS: We reviewed government and other published documents on federal nutrition research; held various discussions with expert groups, advocacy organizations, and scientific societies; and held in-person or phone meetings with >50 federal staff in executive and legislative roles, as well as with a variety of other stakeholders in academic, industry, and nongovernment organizations. RESULTS: Stark national nutrition challenges were identified. More Americans are sick than are healthy, largely from rising diet-related illnesses. These conditions create tremendous strains on productivity, health care costs, health disparities, government budgets, US economic competitiveness, and military readiness. The coronavirus disease 2019 (COVID-19) outbreak has further laid bare these strains, including food insecurity, major diet-related comorbidities for poor outcomes from COVID-19 such as diabetes, hypertension, and obesity, and insufficient surveillance on and coordination of our food system. More than 10 federal departments and agencies currently invest in critical nutrition research, yet with relatively flat investments over several decades. Coordination also remains suboptimal, documented by multiple governmental reports over 50 years. Greater harmonization and expansion of federal investment in nutrition science, not a silo-ing or rearrangement of existing investments, has tremendous potential to generate new discoveries to improve and sustain the health of all Americans. Two identified key strategies to achieve this were as follows: 1) a new authority for robust cross-governmental coordination of nutrition research and other nutrition-related policy and 2) strengthened authority, investment, and coordination for nutrition research within the NIH. These strategies were found to be complementary, together catalyzing important new science, partnerships, coordination, and returns on investment. Additional complementary actions to accelerate federal nutrition research were identified at the USDA. CONCLUSIONS: The need and opportunities for strengthened federal nutrition research are clear, with specific identified options to help create the new leadership, strategic planning, coordination, and investment the nation requires to address the multiple nutrition-related challenges and grasp the opportunities before us.


Assuntos
Infecções por Coronavirus/complicações , Transtornos Nutricionais/complicações , Fenômenos Fisiológicos da Nutrição , Pneumonia Viral/complicações , Pesquisa/normas , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde , Disparidades em Assistência à Saúde/economia , Humanos , Militares , National Institutes of Health (U.S.)/economia , Transtornos Nutricionais/economia , Transtornos Nutricionais/epidemiologia , Pandemias , Estados Unidos/epidemiologia , United States Department of Agriculture/economia , United States Dept. of Health and Human Services/economia
8.
FASEB J ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32638415

RESUMO

Ectopic cardiovascular calcification is a highly prevalent pathology for which there are no effective novel or repurposed pharmacotherapeutics to prevent disease progression. We created a human calcification endophenotype module (ie, the "calcificasome") by mapping vascular calcification genes (proteins) to the human vascular smooth muscle-specific protein-protein interactome (218 nodes and 632 edges, P < 10-5 ). Network proximity analysis was used to demonstrate that the calcificasome overlapped significantly with endophenotype modules governing inflammation, thrombosis, and fibrosis in the human interactome (P < 0.001). A network-based drug repurposing analysis further revealed that everolimus, temsirolimus, and pomalidomide are predicted to target the calcificasome. The efficacy of these agents in limiting calcification was confirmed experimentally by treating human coronary artery smooth muscle cells in an in vitro calcification assay. Each of the drugs affected expression or activity of their predicted target in the network, and decreased calcification significantly (P < 0.009). An integrated network analytical approach identified novel mediators of ectopic cardiovascular calcification and biologically plausible candidate drugs that could be repurposed to target calcification. This methodological framework for drug repurposing has broad applicability to other diseases.

12.
Blood ; 136(5): 553-571, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32396938

RESUMO

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial respiration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.

13.
Wiley Interdiscip Rev Syst Biol Med ; 12(6): e1489, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32307915

RESUMO

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein-protein interaction networks, correlation-based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseases. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Translational, Genomic, and Systems Medicine > Translational Medicine Analytical and Computational Methods > Analytical Methods Analytical and Computational Methods > Computational Methods.

16.
Dev Cell ; 53(2): 240-252.e7, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197067

RESUMO

Understanding of NAD+ metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD+ metabolism in live cells and in vivo remains difficult. Here, we present ratiometric, highly responsive genetically encoded fluorescent indicators, FiNad, for monitoring NAD+ dynamics in living cells and animals. FiNad sensors cover physiologically relevant NAD+ concentrations and sensitively respond to increases and decreases in NAD+. Utilizing FiNad, we performed a head-to-head comparison study of common NAD+ precursors in various organisms and mapped their biochemical roles in enhancing NAD+ levels. Moreover, we showed that increased NAD+ synthesis controls morphofunctional changes of activated macrophages, and directly imaged NAD+ declines during aging in situ. The broad utility of the FiNad sensors will expand our mechanistic understanding of numerous NAD+-associated physiological and pathological processes and facilitate screening for drug or gene candidates that affect uptake, efflux, and metabolism of this important cofactor.

18.
J Clin Invest ; 130(1): 29-38, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31895052

RESUMO

Advanced phenotyping of cardiovascular diseases has evolved with the application of high-resolution omics screening to populations enrolled in large-scale observational and clinical trials. This strategy has revealed that considerable heterogeneity exists at the genotype, endophenotype, and clinical phenotype levels in cardiovascular diseases, a feature of the most common diseases that has not been elucidated by conventional reductionism. In this discussion, we address genomic context and (endo)phenotypic heterogeneity, and examine commonly encountered cardiovascular diseases to illustrate the genotypic underpinnings of (endo)phenotypic diversity. We highlight the existing challenges in cardiovascular disease genotyping and phenotyping that can be addressed by the integration of big data and interpreted using novel analytical methodologies (network analysis). Precision cardiovascular medicine will only be broadly applied to cardiovascular patients once this comprehensive data set is subjected to unique, integrative analytical strategies that accommodate molecular and clinical heterogeneity rather than ignore or reduce it.


Assuntos
Big Data , Doenças Cardiovasculares/genética , Medicina de Precisão , Ensaios Clínicos como Assunto , Registros Eletrônicos de Saúde , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
20.
Antioxid Redox Signal ; 32(18): 1330-1347, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31218894

RESUMO

Significance: Reducing equivalents (NAD(P)H and glutathione [GSH]) are essential for maintaining cellular redox homeostasis and for modulating cellular metabolism. Reductive stress induced by excessive levels of reduced NAD+ (NADH), reduced NADP+ (NADPH), and GSH is as harmful as oxidative stress and is implicated in many pathological processes. Recent Advances: Reductive stress broadens our view of the importance of cellular redox homeostasis and the influences of an imbalanced redox niche on biological functions, including cell metabolism. Critical Issues: The distribution of cellular NAD(H), NADP(H), and GSH/GSH disulfide is highly compartmentalized. Understanding how cells coordinate different pools of redox couples under unstressed and stressed conditions is critical for a comprehensive view of redox homeostasis and stress. It is also critical to explore the underlying mechanisms of reductive stress and its biological consequences, including effects on energy metabolism. Future Directions: Future studies are needed to investigate how reductive stress affects cell metabolism and how cells adapt their metabolism to reductive stress. Whether or not NADH shuttles and mitochondrial nicotinamide nucleotide transhydrogenase enzyme can regulate hypoxia-induced reductive stress is also a worthy pursuit. Developing strategies (e.g., antireductant approaches) to counteract reductive stress and its related adverse biological consequences also requires extensive future efforts.

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