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1.
J Med Primatol ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31709573

RESUMO

INTRODUCTION: The baboon is a well-characterized model of human early stage atherosclerosis. However, histological and morphological changes involved in atherogenesis in baboons are not known. Previously, we challenged baboons with a high-cholesterol, high-fat diet for two years and observed fatty streak and plaque lesions in iliac arteries (RCIA). METHODS: We evaluated histological and morphological changes of baboon arterial lesions and control arteries. In addition, we evaluated the vascular expression of CD68 and SMαA markers with progression of atherosclerosis. RESULTS: We observed changes that correlated with extent of atherosclerosis, including increased maximum intimal thickness. We demonstrated at molecular level the infiltration of smooth muscle cells and macrophages into the intimal layer. Further, we observed histological and morphological discordancy between the affected and adjacent areas of the same RCIA. CONCLUSION: Atherogenesis in baboons is accompanied by histological, morphological, and molecular changes, as in humans, providing insights to evaluate the mechanisms underlying early stage atherosclerosis in target tissues.

2.
Physiol Behav ; 211: 112659, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465782

RESUMO

Social behavior is critical for relationship formation and is influenced by myriad environmental and individual factors. Basic and preclinical research typically relies on rodent models to identify the mechanisms that underlie behavior; however, it is important to use non-rodent models as well. A major objective of the present study was to test the hypothesis that biological sex and social experience modulate the expression of social behavior in the adult gray short-tailed opossum (Monodelphis domestica), a non-traditional model. We also investigated the non-associative learning abilities of these animals. Following a period of social isolation, animals of both sexes were paired with a non-familiar, same-sex partner for 10 min on three different occasions, with 24-hour inter-trial intervals. We are the first research group to find significant sex differences in submissive and nonsocial behaviors in Monodelphis. Females displayed significantly higher durations of nonsocial behavior that increased over trials. Males were more aggressive; their latencies to the first attack and submissive behavior decreased over trials whereas these latencies increased for females; males' duration of submissive behavior increased over trials whereas it decreased for females. A different group of subjects habituated in response to repeated presentations to neutral odors and dishabituated in response to novel odors. In addition, both males and females demonstrated the ability to form social memories in a standard individual (social) recognition test. Our results contribute to the characterization of this marsupial species, an important first step in developing it as a model of complex social behaviors.

3.
J Lipid Res ; 60(9): 1630-1639, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227640

RESUMO

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

4.
Nature ; 571(7766): 505-509, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243369

RESUMO

The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Transcriptoma/genética , Animais , Evolução Biológica , Galinhas/genética , Feminino , Humanos , Macaca mulatta/genética , Masculino , Camundongos , Gambás/genética , Coelhos , Ratos
5.
PLoS One ; 14(4): e0214487, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30951537

RESUMO

Atherosclerotic plaques are characterized by an accumulation of macrophages, lipids, smooth muscle cells, and fibroblasts, and, in advanced stages, necrotic debris within the arterial walls. Dietary habits such as high fat and high cholesterol (HFHC) consumption are known risk factors for atherosclerosis. However, the key metabolic contributors to diet-induced atherosclerosis are far from established. Herein, we investigate the role of a 2-year HFHC diet challenge in the metabolic changes of development and progression of atherosclerosis. We used a non-human primate (NHP) model (baboons, n = 60) fed a HFHC diet for two years and compared metabolomic profiles in serum from animals on baseline chow with serum collected after the challenge diet using two-dimensional gas chromatography time-of-flight mass-spectrometry (2D GC-ToF-MS) for untargeted metabolomic analysis, to quantify metabolites that contribute to atherosclerotic lesion formation. Further, clinical biomarkers associated with atherosclerosis, lipoprotein measures, fat indices, and arterial plaque formation (lesions) were quantified. Using two chemical derivatization (i.e., silylation) approaches, we quantified 321 metabolites belonging to 66 different metabolic pathways, which revealed significantly different metabolic profiles of HFHC diet and chow diet fed baboon sera. We found heritability of two important metabolites, lactic acid and asparagine, in the context of diet-induced metabolic changes. In addition, abundance of cholesterol, lactic acid, and asparagine were sex-dependent. Finally, 35 metabolites correlated (R2, 0.068-0.271, P < 0.05) with total lesion burden assessed in three arteries (aortic arch, common iliac artery, and descending aorta) which could serve as potential biomarkers pending further validation. This study demonstrates the feasibility of detecting sex-specific and heritable metabolites in NHPs with diet-induced atherosclerosis using untargeted metabolomics allowing understanding of atherosclerotic disease progression in humans.

6.
PLoS One ; 14(3): e0213494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30875406

RESUMO

RATIONALE: Plasma low-density lipoprotein cholesterol (plasma LDL-C), vascular endothelial cells and peripheral blood mononuclear cells (PBMCs), particularly monocytes, play key roles in initiating atherosclerosis, the primary cause of cardiovascular disease (CVD). Although the mechanisms underlying development of atherosclerosis are not well understood, LDL-C is known to influence expression of endothelial microRNAs (miRNAs) and gene-targets of miRNAs to promote cell senescence. However, the impact of LDL-C on expression of PBMC miRNAs and miRNA targeted genes in response to an atherogenic diet is not known. In this study, we used unbiased methods to identify coordinately responsive PBMC miRNA- gene networks that differ between low and high LDL-C baboons when fed a high-cholesterol, high-fat (HCHF) diet. METHODS AND RESULTS: Using RNA Seq, we quantified PBMC mRNAs and miRNAs from half-sib baboons discordant for LDL-C plasma concentrations (low LDL-C, n = 3; high LDL-C, n = 3) before and after a 7-week HCHF diet challenge. For low LDL-C baboons, 626 genes exhibited significant change in expression (255 down-regulated, 371 up-regulated) in response to the HCHF diet, and for high LDL-C baboons 379 genes exhibited significant change in expression (162 down-regulated, 217 up-regulated) in response to the HCHF diet. We identified 494 miRNAs identical to human miRNAs and 47 novel miRNAs. Fifty miRNAs were differentially expressed in low LDL-C baboons (21 up- and 29 down-regulated) and 20 in high LDL-C baboons (11 up- and 9 down-regulated) in response to the HCHF diet. Among the differentially expressed miRNAs were miR-221/222 and miR-34a-3p, which were down-regulated, and miR-148a/b-5p, which was up-regulated. In addition, gene-targets of these miRNAs, VEGFA, MAML3, SPARC, and DMGDH, were inversely expressed and are central hub genes in networks and signaling pathways that differ between low and high LDL-C baboon HCHF diet response. CONCLUSIONS: We have identified coordinately regulated HCHF diet-responsive PBMC miRNA-gene networks that differ between baboons discordant for LDL-C concentrations. Our findings provide potential insights into molecular mechanisms underlying initiation of atherosclerosis where LDL-C concentrations influence expression of specific miRNAs, which in turn regulate expression of genes that play roles in initiation of lesions.

7.
Neuropsychopharmacology ; 43(13): 2556-2563, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30082891

RESUMO

Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = -0.64, p = 1.24 × 10-04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10-04; ßsuicide = -0.70, se = 0.25, p = 8.90 × 10-03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (ßsuicide-efflux = -0.45, p = 0.039; ßefflux-cholexterol = -0.34, p < 0.0001; ßindirect = -0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.

8.
Hum Genet ; 137(1): 45-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29181734

RESUMO

Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h 2) and genetic correlations (r g) between 15 anthropometric and 9 CMS traits. Anthropometric traits were adjusted by body mass index (BMI) to determine whether the observed genetic correlation was independent of obesity. After adjustment for multiple testing, all CMS and anthropometric traits were significantly heritable (h 2 range 0.18-0.57). We identified 50 significant genetic correlations (r g range: - 0.37 to 0.75) between CMS and anthropometric traits. Five genetic correlations remained significant after adjustment for BMI [high density lipoprotein cholesterol (HDL-C) and waist-hip ratio; triglycerides and waist-hip ratio; triglycerides and waist-height ratio; non-HDL-C and waist-height ratio; insulin and iliac skinfold thickness]. This study provides evidence for the presence of potentially pleiotropic genes that affect both anthropometric and CMS traits, independently of obesity.

9.
J Med Primatol ; 47(1): 3-17, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28620920

RESUMO

BACKGROUND: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model. METHODS: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. RESULTS: We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. CONCLUSIONS: Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans.

10.
Genome Res ; 27(12): 1961-1973, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29079676

RESUMO

Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes. In mouse, but not opossum and chicken, sex bias is coordinated across tissues such that autosomal testis-biased miRNAs tend to be somatically male-biased, whereas autosomal ovary-biased miRNAs are female-biased, possibly due to broad hormonal control. In chicken, which has a Z/W sex chromosome system, expression output of genes on the Z Chromosome is expected to be male-biased, since there is no global dosage compensation mechanism that restores expression in ZW females after almost all genes on the W Chromosome decayed. Nevertheless, we found that the dominant liver miRNA, miR-122-5p, is Z-linked but expressed in an unbiased manner, due to the unusual retention of a W-linked copy. Another Z-linked miRNA, the male-biased miR-2954-3p, shows conserved preference for dosage-sensitive genes on the Z Chromosome, based on computational and experimental data from chicken and zebra finch, and acts to equalize male-to-female expression ratios of its targets. Unexpectedly, our findings thus establish miRNA regulation as a novel gene-specific dosage compensation mechanism.


Assuntos
Galinhas/genética , Compensação de Dosagem (Genética)/genética , MicroRNAs/genética , Monodelphis/genética , Caracteres Sexuais , Animais , Conjuntos de Dados como Assunto , Feminino , Tentilhões/genética , Perfilação da Expressão Gênica , Masculino , Camundongos , MicroRNAs/biossíntese , Proteínas/genética , Sequências Reguladoras de Ácido Nucleico
11.
ILAR J ; 58(2): 235-250, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28985395

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Human epidemiological studies provide challenges for understanding mechanisms that regulate initiation and progression of CVD due to variation in lifestyle, diet, and other environmental factors. Studies describing metabolic and physiologic aspects of CVD, and those investigating genetic and epigenetic mechanisms influencing CVD initiation and progression, have been conducted in multiple Old World nonhuman primate (NHP) species. Major advantages of NHPs as models for understanding CVD are their genetic, metabolic, and physiologic similarities with humans, and the ability to control diet, environment, and breeding. These NHP species are also genetically and phenotypically heterogeneous, providing opportunities to study gene by environment interactions that are not feasible in inbred animal models. Each Old World NHP species included in this review brings unique strengths as models to better understand human CVD. All develop CVD without genetic manipulation providing multiple models to discover genetic variants that influence CVD risk. In addition, as each of these NHP species age, their age-related comorbidities such as dyslipidemia and diabetes are accelerated proportionally 3 to 4 times faster than in humans.In this review, we discuss current CVD-related research in NHPs focusing on selected aspects of CVD for which nonprimate model organism studies have left gaps in our understanding of human disease. We include studies on current knowledge of genetics, epigenetics, calorie restriction, maternal calorie restriction and offspring health, maternal obesity and offspring health, nonalcoholic steatohepatitis and steatosis, Chagas disease, microbiome, stem cells, and prevention of CVD.


Assuntos
Doenças Cardiovasculares/genética , Pesquisa Médica Translacional/métodos , Animais , Restrição Calórica , Doença de Chagas/genética , Humanos , Primatas
12.
J Am Assoc Lab Anim Sci ; 56(1): 57-62, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28905716

RESUMO

The protozoan parasite Trypanosoma cruzi causes Chagas disease, uses kissing bugs as a vector, and is maintained in nature by a variety of wildlife reservoirs. Many natural cases of Chagas disease have been reported in NHP at facilities across the southern United States, where infected vectors and wildlife occur. Infection of NHP with T. cruzi can diminish their value as research models and lead to health problems and death. Identifying the modes of transmission and role of wildlife reservoirs in these facilities is therefore critical to guide interventions to reduce transmission. Here we investigated the role of roof rats (Rattus rattus), the most abundant nuisance species at a primate facility in San Antonio, in the maintenance and transmission of T. cruzi. The hearts and blood from the carcasses of the 145 rats collected underwent 2 independent PCR assays for detection of T. cruzi and other trypanosomes. The 145 hearts and 61 blood samples were all negative for T. cruzi. This population sample of 145 subjects would allow the detection of disease prevalence of 0.020 with a confidence level of 95%. The limited active vector surveillance efforts by our team combined with passive surveillance by facility personnel yielded no kissing bugs during the study period. Our results suggest that roof rats are unlikely to be important local reservoirs of T. cruzi at this facility. Further investigation of transmission dynamics across multiple years and more comprehensive vector surveillance is warranted.


Assuntos
Doença de Chagas/veterinária , Primatas/parasitologia , Doenças dos Roedores/parasitologia , Trypanosoma cruzi , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Habitação , Reação em Cadeia da Polimerase , Prevalência , Ratos , Doenças dos Roedores/epidemiologia , Texas/epidemiologia , Trypanosoma cruzi/genética
13.
J Appl Physiol (1985) ; 123(3): 513-525, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28522766

RESUMO

Terrestrial opossums use their semiprehensile tail for grasping nesting materials as opposed to arboreal maneuvering. We relate the development of this adaptive behavior with ontogenetic changes in myosin heavy chain (MHC) isoform expression from 21 days to adulthood. Monodelphis domestica is expected to demonstrate a progressive ability to flex the distal tail up to age 7 mo, when it should exhibit routine nest construction. We hypothesize that juvenile stages (3-7 mo) will be characterized by retention of the neonatal isoform (MHC-Neo), along with predominant expression of fast MHC-2X and -2B, which will transition into greater MHC-1ß and -2A isoform content as development progresses. This hypothesis was tested using Q-PCR to quantify and compare gene expression of each isoform with its protein content determined by gel electrophoresis and densitometry. These data were correlated with nesting activity in an age-matched sample of each age group studied. Shifts in regulation of MHC gene transcripts matched well with isoform expression. Notably, mRNA for MHC-Neo and -2B decrease, resulting in little-to-no isoform translation after age 7 mo, whereas mRNA for MHC-1ß and -2A increase, and this corresponds with subtle increases in content for these isoforms into late adulthood. Despite the tail remaining intrinsically fast-contracting, a critical growth period for isoform transition is observed between 7 and 13 mo, correlating primarily with use of the tail during nesting activities. Functional transitions in MHC isoforms and fiber type properties may be associated with muscle "tuning" repetitive nest remodeling tasks requiring sustained contractions of the caudal flexors.NEW & NOTEWORTHY Little is understood about skeletal muscle development as it pertains to tail prehensility in mammals. This study uses an integrative approach of relating both MHC gene and protein expression with behavioral and morphometric changes to reveal a predominant fast MHC expression with subtle isoform transitions in caudal muscle across ontogeny. The functional shifts observed are most notably correlated with increased tail grasping for nesting activities.


Assuntos
Força da Mão/fisiologia , Monodelphis/fisiologia , Cadeias Pesadas de Miosina/biossíntese , Cadeias Pesadas de Miosina/genética , Cauda/fisiologia , Animais , Feminino , Expressão Gênica , Masculino , Miosinas/biossíntese , Miosinas/genética , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética
14.
Sci Rep ; 7: 46719, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28429755

RESUMO

APOBEC3s (A3s) are single-stranded DNA cytosine deaminases that provide innate immune defences against retroviruses and mobile elements. A3s are specific to eutherian mammals because no direct homologs exist at the syntenic genomic locus in metatherian (marsupial) or prototherian (monotreme) mammals. However, the A3s in these species have the likely evolutionary precursors, the antibody gene deaminase AID and the RNA/DNA editing enzyme APOBEC1 (A1). Here, we used cell culture-based assays to determine whether opossum A1 restricts the infectivity of retroviruses including human immunodeficiency virus type 1 (HIV-1) and the mobility of LTR/non-LTR retrotransposons. Opossum A1 partially inhibited HIV-1, as well as simian immunodeficiency virus (SIV), murine leukemia virus (MLV), and the retrotransposon MusD. The mechanism of inhibition required catalytic activity, except for human LINE1 (L1) restriction, which was deamination-independent. These results indicate that opossum A1 functions as an innate barrier to infection by retroviruses such as HIV-1, and controls LTR/non-LTR retrotransposition in marsupials.

15.
PLoS Negl Trop Dis ; 11(2): e0005233, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28225764

RESUMO

BACKGROUND: Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease. METHODS AND FINDINGS: In this cross-sectional study design, flow cytometry and systems biology approaches were used to characterize the ex vivo and in vitro T. cruzi-specific functional cytokine signature of circulating leukocytes from TcI-T. cruzi naturally infected cynomolgus macaques (CH). Results showed that CH presented an overall CD4+-derived IFN-γ pattern regulated by IL-10-derived from CD4+ T-cells and B-cells, contrasting with the baseline profile observed in non-infected hosts (NI). Homologous TcI-T. cruzi-antigen recall in vitro induced a broad pro-inflammatory cytokine response in CH, mediated by TNF from innate/adaptive cells, counterbalanced by monocyte/B-cell-derived IL-10. TcIV-antigen triggered a more selective cytokine signature mediated by NK and T-cell-derived IFN-γ with modest regulation by IL-10 from T-cells. While NI presented a cytokine network comprised of small number of neighborhood connections, CH displayed a complex cross-talk amongst network elements. Noteworthy, was the ability of TcI-antigen to drive a complex global pro-inflammatory network mediated by TNF and IFN-γ from NK-cells, CD4+ and CD8+ T-cells, regulated by IL-10+CD8+ T-cells, in contrast to the TcIV-antigens that trigger a modest network, with moderate connecting edges. CONCLUSIONS: Altogether, our findings demonstrated that CH present a pro-inflammatory/regulatory cytokine signature similar to that observed in human Chagas disease. These data bring additional insights that further validate these non-human primates as experimental models for Chagas disease.


Assuntos
Doença de Chagas/imunologia , Mediadores da Inflamação/imunologia , Macaca fascicularis , Trypanosoma cruzi/fisiologia , Animais , Linfócitos B/imunologia , Doença de Chagas/genética , Doença de Chagas/parasitologia , Estudos Transversais , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Trypanosoma cruzi/imunologia
16.
Genetics ; 204(4): 1601-1612, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27784721

RESUMO

Evolutionary studies have long emphasized that the genetic architecture of traits holds important microevolutionary consequences. Yet, studies comparing the genetic architecture of traits across species are rare, and discussions of the evolution of genetic systems are made on theoretical arguments rather than on empirical evidence. Here, we compared the genetic architecture of cranial traits in two different mammalian model organisms: the gray short-tailed opossum, Monodelphis domestica, and the laboratory mouse, Mus musculus We show that both organisms share a highly polygenic genetic architecture for craniofacial traits, with many loci of small effect. However, these two model species differ significantly in the overall degree of pleiotropy, N, of the genotype-to-phenotype map, with opossums presenting a higher average N They also diverge in their degree of genetic modularity, with opossums presenting less modular patterns of genetic association among traits. We argue that such differences highlight the context dependency of gene effects, with developmental systems shaping the variational properties of genetic systems. Finally, we also demonstrate based on the opossum data that current measurements for the relationship between the mutational effect size and N need to be re-evaluated in relation to the importance of the cost of pleiotropy for mammals.


Assuntos
Evolução Molecular , Pleiotropia Genética , Genótipo , Animais , Camundongos , Modelos Genéticos , Monodelphis/genética
17.
Oncotarget ; 7(10): 10857-69, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26908459

RESUMO

Endometriosis is a chronic estrogen-dependent disease that occurs in approximately 10% of reproductive age women. Baboons offer a clear benefit for studying the initiation and progression of endometriosis since baboon is very close to humans phylogenetically. Progestins are used in the treatment of endometriosis. The therapeutic window of progestins depends on the ratio of its affinity towards progesterone receptor agonism verses antagonism. The present study is to determine the role of pure antiprogestin in baboon endometriosis. We hypothesize that pure antiprogestin will induce unopposed estrogenicity and spontaneous endometriosis in baboons. The rate of endometrial invasion and attachment through modeled peritoneum in the presence and absence of progesterone and antiprogestin was evaluated in this study. A baboon model of endometriosis induced by unopposed estrogenicity using progesterone receptor antagonist (EC304) was used in this study. We observed EC304 has induced unopposed estrogenicity that deregulated proteins involved in attachment, invasion, cell growth, and steroid hormone receptors in this model. Our data suggest that depleting progesterone levels in the endometrium will increase estrogen hyper-responsiveness that leads to increased endometriotic lesion progression in the baboon (Papio anubis) model. This study reports a refined model of human endometriosis in baboons that could potentially be used to develop new diagnostic and therapeutic strategies for the benefit of women suffering from endometriosis.


Assuntos
Modelos Animais de Doenças , Endometriose/induzido quimicamente , Endométrio/efeitos dos fármacos , Receptores de Progesterona/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Estrogênios/metabolismo , Feminino , Humanos , Papio
18.
PLoS Negl Trop Dis ; 10(1): e0004302, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26808481

RESUMO

BACKGROUND: Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations. METHODS AND FINDINGS: Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications. CONCLUSIONS: Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.


Assuntos
Doença de Chagas/imunologia , Modelos Animais de Doenças , Leucócitos/imunologia , Macaca fascicularis , Trypanosoma cruzi/fisiologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/parasitologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Macaca fascicularis/imunologia , Macaca fascicularis/parasitologia , Masculino , Monócitos/imunologia
19.
Am J Stem Cells ; 4(1): 32-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25973329

RESUMO

Traditionally, CD34 positive cells are predominantly found in the umbilical cord and bone marrow, thus are considered as hematopoietic progenitors. Increasing evidence has suggested that the CD34+ cells represent a distinct subset of cells with enhanced progenitor activity; CD34 is a general marker of progenitor cells in a variety of cell types. Because the CD34 protein shows expression early on in hematopoietic and vascular-associated tissues, CD34+ cells have enormous potential as cellular agents for research and for clinical cell transplantation. Directed differentiation of embryonic stem cells will give rise to an inexhaustible supply of CD34+ cells, creating an exciting approach for biomedical research and for regenerative medicine. Here, we review the main methods that have been published for the derivation of CD34+ cells from embryonic stem cells; specifically those approaches the human and nonhuman primate stem cells. We summarize current status of this field, compare the methods used, and evaluate the issues in translating the bench science to bedside therapy.

20.
PLoS Negl Trop Dis ; 9(5): e0003765, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25993316

RESUMO

BACKGROUND: Trypanosoma cruzi has been classified into six Discrete Typing Units (DTUs), designated as TcI-TcVI. In order to effectively use this standardized nomenclature, a reproducible genotyping strategy is imperative. Several typing schemes have been developed with variable levels of complexity, selectivity and analytical sensitivity. Most of them can be only applied to cultured stocks. In this context, we aimed to develop a multiplex Real-Time PCR method to identify the six T. cruzi DTUs using TaqMan probes (MTq-PCR). METHODS/PRINCIPAL FINDINGS: The MTq-PCR has been evaluated in 39 cultured stocks and 307 biological samples from vectors, reservoirs and patients from different geographical regions and transmission cycles in comparison with a multi-locus conventional PCR algorithm. The MTq-PCR was inclusive for laboratory stocks and natural isolates and sensitive for direct typing of different biological samples from vectors, reservoirs and patients with acute, congenital infection or Chagas reactivation. The first round SL-IR MTq-PCR detected 1 fg DNA/reaction tube of TcI, TcII and TcIII and 1 pg DNA/reaction tube of TcIV, TcV and TcVI reference strains. The MTq-PCR was able to characterize DTUs in 83% of triatomine and 96% of reservoir samples that had been typed by conventional PCR methods. Regarding clinical samples, 100% of those derived from acute infected patients, 62.5% from congenitally infected children and 50% from patients with clinical reactivation could be genotyped. Sensitivity for direct typing of blood samples from chronic Chagas disease patients (32.8% from asymptomatic and 22.2% from symptomatic patients) and mixed infections was lower than that of the conventional PCR algorithm. CONCLUSIONS/SIGNIFICANCE: Typing is resolved after a single or a second round of Real-Time PCR, depending on the DTU. This format reduces carryover contamination and is amenable to quantification, automation and kit production.


Assuntos
Doença de Chagas/diagnóstico , Tipagem Molecular/métodos , Trypanosoma cruzi/classificação , Trypanosoma cruzi/genética , Adolescente , Adulto , Bioensaio/métodos , Doença de Chagas/genética , Doença de Chagas/parasitologia , Criança , Pré-Escolar , Coinfecção , Feminino , Variação Genética/genética , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade
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