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Find video protocols related to scientific articles indexed in Pubmed.
An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.
PLoS ONE
PUBLISHED: 08-11-2014
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Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFN?, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFN?, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.
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Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus.
Semin Immunopathol
PUBLISHED: 08-08-2014
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Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.
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Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery.
J. Cardiovasc. Pharmacol.
PUBLISHED: 05-03-2014
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With the perspective of functional myocardial regeneration, we investigated small cardiomyocytes bordering on microdomains of fibrosis, where they are dedifferentiated re-expressing fetal genes, and determined: (1) whether they are atrophied segments of the myofiber syncytium, (2) their redox state, (3) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and redifferentiation, (4) the relevance of proteolytic ligases of the ubiquitin-proteasome system as a mechanistic link to their size, and (5) whether they could be rescued from their dedifferentiated phenotype. Chronic aldosterone/salt treatment (ALDOST) was invoked, where hypertensive heart disease with attendant myocardial fibrosis creates the fibrillar collagen substrate for myocyte sequestration, with propensity for disuse atrophy, activated myoFb, and oxidative stress. To address phenotype rescue, 4 weeks of ALDOST was terminated followed by 4 weeks of neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4, and nebivolol (assisted recovery). Compared with controls, at 4 weeks of ALDOST, we found small myocytes to be: (1) sequestered by collagen fibrils emanating from microdomains of fibrosis and representing atrophic segments of the myofiber syncytia, (2) dedifferentiated re-expressing fetal genes (?-myosin heavy chain and atrial natriuretic peptide), (3) proximal to activated myoFb expressing ?-smooth muscle actin microfilaments and angiotensin-converting enzyme, (4) expressing reactive oxygen species and nitric oxide with increased tissue 8-isoprostane, coupled to ventricular diastolic and systolic dysfunction, and (5) associated with upregulated redox-sensitive proteolytic ligases MuRF1 and atrogin-1. In a separate study, we did not find evidence of myocyte replication (BrdU labeling) or expression of stem cell antigen (c-Kit) at weeks 1-4 ALDOST. Assisted recovery caused complete disappearance of myoFb from sites of fibrosis with redifferentiation of these myocytes, loss of oxidative stress, and ubiquitin-proteasome system activation, with restoration of nitric oxide and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can re-differentiate and represent a potential source of autologous cells for functional myocardial regeneration.
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The role of antigen specificity in the binding of murine monoclonal anti-DNA antibodies to microparticles from apoptotic cells.
Clin. Immunol.
PUBLISHED: 04-22-2014
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Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus and markers of underlying immune system disturbances. These antibodies bind to both single-stranded and double-stranded DNA, mediating pathogenesis by forming immune complexes. As shown recently, DNA in blood exists in both free and particulate forms, with DNA representing an important component of microparticles. Microparticles are membrane-bound vesicles containing nuclear molecules, released by membrane blebbing during cell death and activation. A panel of monoclonal NZB/NZW F1 anti-DNA antibodies was tested for binding to microparticles generated from apoptotic THP-1 and Jurkat cells. These studies showed that only certain anti-DNA antibodies in the panel, specific for double-stranded DNA, bound to microparticles. Binding to particles was reduced by soluble DNA or DNase treatment. Together, these results indicate that particle binding is a feature of only certain anti-DNA antibodies, reflecting immunochemical properties of the antibodies and the nature of the exposed DNA antigens.
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Atrophic cardiomyocyte signaling in hypertensive heart disease.
J. Cardiovasc. Pharmacol.
PUBLISHED: 10-03-2013
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: Cardinal pathological features of hypertensive heart disease (HHD) include not only hypertrophied cardiomyocytes and foci of scattered microscopic scarring, a footprint of prior necrosis, but also small myocytes ensnared by fibrillar collagen where disuse atrophy with protein degradation would be predicted. Whether atrophic signaling is concordant with the appearance of HHD and involves oxidative and endoplasmic reticulum (ER) stress remains unexplored. Herein, we examine these possibilities focusing on the left ventricle and cardiomyocytes harvested from hypertensive rats receiving 4 weeks aldosterone/salt treatment (ALDOST) alone or together with ZnSO4, a nonvasoactive antioxidant, with the potential to attenuate atrophy and optimize hypertrophy. Compared with untreated age-/sex-/strain-matched controls, ALDOST was accompanied by (1) left ventricle hypertrophy with preserved systolic function; (2) concordant cardiomyocyte atrophy (<1000 ?m) found at sites bordering on fibrosis where they were reexpressing ?-myosin heavy chain; and (3) upregulation of ubiquitin ligases, muscle RING-finger protein-1 and atrogin-1, and elevated 8-isoprostane and unfolded protein ER response with messenger RNA upregulation of stress markers. ZnSO4 cotreatment reduced lipid peroxidation, fibrosis, and the number of atrophic myocytes, together with a further increase in cell area and width of atrophied and hypertrophied myocytes, and improved systolic function but did not attenuate elevated blood pressure. We conclude that atrophic signaling, concordant with hypertrophy, occurs in the presence of a reparative fibrosis and induction of oxidative and ER stress at sites of scarring where myocytes are atrophied. ZnSO4 cotreatment in HHD with ALDOST attenuates the number of atrophic myocytes, optimizes size of atrophied and hypertrophied myocytes, and improves systolic function.
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Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity.
Semin Immunopathol
PUBLISHED: 01-09-2013
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Autoantibodies to DNA and histones (chromatin) are the defining antigen specificity in systemic lupus erythematosus (SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remain mysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) were discovered and observed to play a conserved role in innate immune responses to a broad variety of microbial pathogens. At the center of an infectious process, neutrophils exert various antimicrobial defenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, a complex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrade microbial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies as a source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin forms an essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and other autoimmune immune complex diseases.
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The Yaa locus and IFN-? fine-tune germinal center B cell selection in murine systemic lupus erythematosus.
J. Immunol.
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Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-? to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-? relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.
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Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response.
Am. J. Clin. Nutr.
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African Americans with genotype 1 chronic hepatitis C attain a sustained virologic response (SVR) at only approximately one-half the rate of whites after peginterferon and ribavirin treatment. The serum concentration of 25-hydroxyvitamin D [25(OH)D] has recently been established as a predictor of treatment response. Therefore, the low serum concentrations of 25(OH)D found among African Americans may contribute to the low response rate; however, to our knowledge, none of the studies of vitamin D in chronic hepatitis C treatment have included a significant number of black patients.
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The Chlamydia trachomatis CT149 protein exhibits esterase activity in vitro and catalyzes cholesteryl ester hydrolysis when expressed in HeLa cells.
Microbes Infect.
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Chlamydia, like other intracellular bacteria, are auxotrophic for a variety of essential metabolites and obtain cholesterol and fatty acids from their eukaryotic host cell, however not many Chlamydia-specific enzymes have been identified that are involved in lipid metabolism. In silico analysis of one candidate Chlamydia trachomatis enzyme, annotated as a conserved putative hydrolase (CT149), identified two lipase/esterase GXSXG motifs, and a potential cholesterol recognition/interaction amino acid consensus (CRAC) sequence. His-tag purified recombinant CT149 exhibited ester hydrolysis activity in a nitrophenyl acetate-based cell-free assay system. When cholesteryl linoleate was used as substrate, ester hydrolysis occurred and production of cholesterol was detected by high performance liquid chromatography. Exogenous expression of transfected CT149 in HeLa cells resulted in a significant decrease of cytoplasmic cholesteryl esters within 48 h. These results demonstrate that CT149 has cholesterol esterase activity and is likely to contribute to the hydrolysis of eukaryotic cholesteryl esters during intracellular chlamydial growth.
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Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice.
Kidney Int.
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The strongest serological correlate for lupus nephritis is antibody to double-stranded DNA, although the mechanism by which anti-DNA antibodies initiate lupus nephritis is unresolved. Most recent reports indicate that anti-DNA must bind chromatin in the glomerular basement membrane or mesangial matrix to form glomerular deposits. Here we determined whether direct binding of anti-DNA antibody to glomerular basement membrane is critical to initiate glomerular binding of anti-DNA in experimental lupus nephritis. Mice were co-injected with IgG monoclonal antibodies or hybridomas with similar specificity for DNA and chromatin but different IgG subclass and different relative affinity for basement membrane. Only anti-DNA antibodies that bound basement membrane bound to glomeruli, activated complement, and induced proteinuria whether injected alone or co-injected with a non-basement-membrane-binding anti-DNA antibody. Basement membrane-binding anti-DNA antibodies co-localized with heparan sulfate proteoglycan in glomerular basement membrane and mesangial matrix but not with chromatin. Thus, direct binding of anti-DNA antibody to antigens in the glomerular basement membrane or mesangial matrix may be critical to initiate glomerular inflammation. This may accelerate and exacerbate glomerular immune complex formation in human and murine lupus nephritis.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.