Biomedical subjects

Nicola Smart

Publications and source records attributed to Nicola Smart.

9 recordsLinked to original sources

PubMed2006

Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization.

Cardiac failure has a principal underlying aetiology of ischaemic damage arising from vascular insufficiency. Molecules that regulate collateral growth in the ischaemic heart also regulate coronary vasculature formation during embryogenesis. Here we identify thymosin beta4 (Tbeta4) as essential for all aspects of coronary vessel development in mice, and demonstrate that Tbeta4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. Tbeta4 knockdown in the heart is accompanied by significant reduction in the pro-angiogenic cleavage product N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). Although injection of AcSDKP was unable to rescue Tbeta4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies Tbeta4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals Tbeta4-induced adult epicardial cells as a viable source of vascular progenitors for continued renewal of regressed vessels at low basal level or sustained neovascularization following cardiac injury.

Animals↗

PubMed2006

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart.

The precise origins of myocardial progenitors and their subsequent contribution to the developing heart has been an area of considerable activity within the field of cardiovascular biology. How these progenitors are regulated and what signals are responsible for their development are, however, much less well understood. Clearly, not only is there a need to identify factors that regulate the transition from proliferation of cardioblasts to differentiation of cardiac muscle, but it is also necessary to identify factors that maintain an adequate pool of undifferentiated myocyte precursors as a prerequisite to preventing organ hypoplasia and congenital heart disease. Here, we report how upregulation of the basic helix-loop-helix (bHLH) transcription factor Hand1, restricted exclusively to Hand1-expressing cells, brings about a significant extension of the heart tube and extraneous looping caused by the elevated proliferation of cardioblasts in the distal outflow tract. This activity is independent of the further recruitment of extracardiac cells from the secondary heart field and permissive for the continued differentiation of adjacent myocardium. Culture studies using embryonic stem (ES) cell-derived cardiomyocytes revealed that, in a Hand1-null background, there is significantly elevated cardiomyocyte differentiation, with an apparent default mesoderm pathway to a cardiomyocyte fate. However, Hand1 gain of function maintains proliferating precursors resulting in delayed and significantly reduced cardiomyocyte differentiation that is mediated by the prevention of cell-cycle exit, by G1 progression and by increased cell division. Thus, this work identifies Hand1 as a crucial cardiac regulatory protein that controls the balance between proliferation and differentiation in the developing heart, and fills a significant gap in our understanding of how the myocardium of the embryonic heart is established.

Animals↗

PubMed2005

IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes.

OBJECTIVE: Interleukin-6 (IL-6) is a pro-inflammatory cytokine which is a prognostic marker associated with left ventricular contractile dysfunction and heart failure. On the other hand, IL-6 activates signalling pathways which mediate delayed ischemic preconditioning. We have therefore studied the cellular mechanisms of IL-6-induced cardioprotection. METHODS: Inducible nitric oxide synthase (iNOS) expression, cardiomyocyte calcium handling, mitochondrial energetics, and the activation of protective signalling pathways in response to IL-6 were studied in a model of simulated ischemia/reperfusion (sI/R) in isolated neonatal rat ventricular cardiomyocytes. RESULTS: Reperfusion after sI/R induced a rise in cytosolic [Ca2+], a loss of cell morphology and integrity, and a transient increase in mitochondrial potential (Deltapsi m), followed by mitochondrial swelling and collapse of Deltapsi m. Pre-treatment of cardiomyocytes with 10 ng/ml IL-6 for 6 h, 24 h prior to sI/R prevented the secondary rise in cytosolic [Ca2+] and induced expression of iNOS and NO-dependent protection against sI/R injury. The protection against sI/R was concomitant with a NO-dependent reduction in the amplitude of cytosolic Ca2+ transients. IL-6 induced an increase in inner mitochondrial membrane polarisation and increased mitochondrial Ca2+ loading (rhod-2 fluorescence) at baseline, but prevented the reperfusion-induced changes in mitochondrial function. IL-6 pre-treatment also resulted in activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and both iNOS induction and IL-6-dependent protection were blocked by the PI 3-kinase inhibitor wortmannin. CONCLUSION: IL-6 induces a PI 3-kinase and NO-dependent protection of cardiomyocytes, which is associated with alterations in mitochondrial Ca2+ handling, inhibition of reperfusion-induced mitochondrial depolarisation, swelling and loss of structural integrity, and suppression of cytosolic Ca2+ transients.

Androstadienes↗

PubMed2005

A rapid and sensitive assay for quantification of siRNA efficiency and specificity.

RNA Interference has rapidly emerged as an efficient procedure for knocking down gene expression in model systems. However, cross-reactivity, whereby multiple genes may be simultaneously targeted by a single short interfering RNA (siRNA), can potentially jeopardize correct interpretation of gene function. As such, it is essential to test the specificity of a siRNA prior to a full phenotypic analysis. To this end, we have adapted a reporter-based assay harnessing the sensitivity of luciferase activity to provide a quantitative readout of relative RNAi efficacy and specificity. We have tested different siRNAs directed against Thymosin beta4 (Tbeta4); determined their effectiveness at silencing Tbeta4 and have both excluded off-target silencing of the Tbeta4 homologue Thymosin beta10 (Tbeta10) and demonstrated partial knockdown of Tbeta10 despite significant (12/23; 52%) sequence mismatch. This assay system is applicable to any RNAi study where there is a risk of targeting homologous genes and to the monitoring of off-target effects at the genome level following microarray expression profiling.

Journal Article↗

PubMed2003

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Animals↗

PubMed2003

Long-term treatment and management of violent tendencies of men with intellectual disabilities convicted of assault.

Success of anger management treatment with individuals who have intellectual disabilities convicted of assault-related offenses has not been verified. We employed a single case design with repeated measures with 6 such men. Recidivism is reported at least 4.5 years and up to 10 years. Modified anger management training incorporating cognitive restructuring and arousal reduction was employed. Participants showed no uniform reductions in emotional or behavioral systems of anger and aggression. Although several retained significant anger feelings, there were reductions in the extent to which they would act in an aggressive fashion. Five have not re-offended; 1 re-offended within 6 months but not in the subsequent 4 years. Anger management treatment seems effective for men with intellectual disabilities in the community who have committed socially and legally unacceptable acts.

Activities of Daily Living↗

PubMed2002

A differential screen for putative targets of the bHLH transcription factor Hand1 in cardiac morphogenesis.

The bHLH transcription factor, Hand1 has been implicated in cardiac looping in the mouse, however its function in the developing heart remains unknown. To investigate the mechanism(s) through which Hand1 might function, we screened for potential downstream target genes using representational difference analysis. Thymosin beta4 was found to be down-regulated whereas cystatin C and alphaCA were up-regulated in Hand1-null embryoid bodies. Whole-mount in situ hybridisation on wild type embryos (E8.0-E10.5) and Hand1 homozygous-mutant embryos (E8.0) confirmed co-expression of the putative targets with Hand1 in the heart and their aberrant expression in a Hand1-null background.

Basic Helix-Loop-Helix Proteins↗

PubMed2002

A differential screen for putative targets of the bHLH transcription factor Hand1 in cardiac morphogenesis.

Animals↗

PubMedDate not supplied

NMAP: UK's nursing Internet gateway.

This article describes the development of NMAP, the UK academic gateway to high-quality Internet resources for Nurses, Midwives and Allied health Professionals. The service is described and the rationale for NMAP summarized, focusing on the increasing use of Internet resources in nursing education and practice. International concerns over the quality of health information available on the Internet are considered, and the approach adopted by NMAP to quality filtering described. The usage data and results of evaluation studies show the need for this type of Internet gateway, and some of the lessons may be relevant to others involved in developing national high-quality Internet gateways for nurses.

Attitude of Health Personnel↗