Biomedical subjects
E R Smith
Publications and source records attributed to E R Smith.
Reflections on the state of our health care system.
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Structure, sequence, and promoter analysis of human disabled-2 gene (DAB2).
Disabled-2 (DAB2 for human and Dab2 for other species) is one of two mammalian orthologues of Drosophila Disabled. DAB2 exhibits properties of a tumor suppressor gene: the expression of DAB2 is eliminated in 85-95% of breast and ovarian tumors; homozygous deletions of the gene have been found in some of these tumors; and reintroduction of DAB2 expression suppresses tumorigenicity of carcinoma cells. To study the mechanisms of loss of expression and to detect possible mutations in tumors, we have investigated the genomic structure of the DAB2 gene. The complete DAB2 gene was identified and sequenced from four overlapping BAC clones found to contain the gene. Complement factor 9 (C9) gene was localized next to the DAB2 gene at the 3'-end of the BAC DNA fragments. The human DAB2 gene is about 35 kb in size and consists of 15 exons and 14 introns, producing an approximately 4-kb message. A spliced variant corresponding to mouse Dab2 p93 and a 3'-end spliced variant were also identified. The translation initiation site resides in the second exon, and the noncoding first exon is separated from the second exon by a 14-kb intron. The 420-bp sequence 5' of exon 1 contains a CpG island (39 CpG sites). This 420-bp putative promoter was found to contain the site for transcription initiation, identified by RNase protection assay, and is sufficient for active transcription in epithelial cells. The information about the gene structure of DAB2 will enable us to analyze possible mutations and the mechanisms of loss of DAB2 expression in tumors.
A new human member of the MYST family of histone acetyl transferases with high sequence similarity to Drosophila MOF.
We have identified a novel human gene product, hMOF, which exhibits significant similarity to the Drosophila dosage compensation regulator, MOF. A recombinant C-terminal portion of hMOF has histone acetyltransferase activity directed toward histones H3, H2A and H4, a specificity characteristic of other MYST family histone acetyltransferases. Based on hMOF's chromodomain, we discuss possible interactions with other proteins.
Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics.
The Frank-Starling Law accounts for many changes in cardiac performance previously attributed to changes in contractility in that changes in contractility might have been incorrectly inferred from changing ventricular function curves (i.e. systolic performance plotted against filling pressure) if diastolic compliance also changed. To apply the Frank-Starling Law in the presence of changing diastolic compliance, it is necessary to measure end-diastolic volume directly or to calculate end-diastolic transmural pressure, which requires that pericardial pressure be known. Under most normal circumstances, increased intrathoracic pressure (and other interventions, such as vasodilators or lower-body negative pressure, that decrease central blood volume) decreases the transmural end-diastolic pressures of both ventricles, their end-diastolic volumes and stroke work. However, when ventricular interaction is significant, the effects of these interventions might be quite different; this may be important in patients with heart-failure. Although these interventions decrease RV transmural pressure, they may increase LV transmural pressure, end-diastolic volume, and thus stroke work by the Frank-Starling mechanism.
Effects of sphingosine and other sphingolipids on protein kinase C.
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The impact of structured student debates on critical thinking and informatics skills of second-year medical students.
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The drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin modification linked to dosage compensation.
In Drosophila, dosage compensation-the equalization of most X-linked gene products in males and females-is achieved by a twofold enhancement of the level of transcription of the X chromosome in males relative to each X chromosome in females. A complex consisting of at least five gene products preferentially binds the X chromosome at numerous sites in males and results in a significant increase in the presence of a specific histone isoform, histone 4 acetylated at lysine 16. Recently, RNA transcripts (roX1 and roX2) encoded by two different genes have also been found associated with the X chromosome in males. We have partially purified a complex containing MSL1, -2, and -3, MOF, MLE, and roX2 RNA and demonstrated that it exclusively acetylates H4 at lysine 16 on nucleosomal substrates. These results demonstrate that the MSL complex is responsible for the specific chromatin modification characteristic of the X chromosome in Drosophila males.
Oncolytic viruses as novel anticancer agents: turning one scourge against another.
Although the use of viruses as oncolytic agents is an historic concept, the use of genetically modified viruses to selectively target tumour cells is relatively novel and recent. The ability of viruses to efficiently infect and lyse cells, combined with the potential augmentation of this effect by progeny viruses throughout the tumour provide justification for exploitation of these agents in cancer therapy. Before application to humans, though, issues related to tumour cell selectivity, lack of toxicity to normal tissues and the effect of the antiviral immune response, will have to be clarified. The more commonly used oncolytic viruses are based on mutant strains of herpes simplex virus, adenovirus and reovirus. The tumour selectivity of each of these strains is discussed, particularly the complementation of the viral defect by cellular pathways involved in tumourigenesis. The combination of oncolytic viruses with radiation, chemotherapy and gene therapy is also reviewed. Further study of the interaction of viral proteins with cellular pathways involved in cell cycle control will provide the rationale for viral mutants with increased selectivity for tumour cells.
Adipocyte metabolism in adipocyte fatty acid binding protein knockout mice (aP2-/-) after short-term high-fat feeding: functional compensation by the keratinocyte [correction of keritinocyte] fatty acid binding protein.
Mice null for adipocyte fatty acid binding protein (AFABP) compensate by increasing expression of keratinocyte fatty acid binding protein (KFABP) (Hotamisligil et al. Science 274:1377-1379, 1996). In the present study, AFABP knockout (KO) and wild-type (WT) mice became equally obese on a high-fat diet, as judged by fat pad weights, adipocyte size, and body composition analysis. High-fat feeding led to moderate insulin resistance in both WT and AFABP knockout mice, as indicated by an approximately 2-fold increase in plasma insulin. However, in the high fat-fed mice, plasma glucose levels were approximately 15% lower in the AFABP-KO mice. Adipocytes isolated from AFABP-KO and WT mice fed high- or low-fat diets exhibited similar rates of basal and norepinephrine-stimulated lipolysis and insulin-stimulated rates of glucose conversion to fatty acids and glyceride-glycerol. However, basal glucose conversion to fatty acids was higher in adipocytes of AFABP-KO mice. Adipocyte tumor necrosis factor-alpha release was similarly increased by high-fat diet-induced obesity in both WT and AFABP-KO mice. As assessed by Western blot analysis, the level of KFABP protein in AFABP-KOs was approximately 40% of the level of AFABP in WT controls. The binding affinities of KFABP for long-chain fatty acids were 2- to 4-fold higher than those of AFABP, but the relative affinities for different fatty acids were similar. As for AFABP, the rate of fatty acid transfer from KFABP to model phospholipid vesicles was increased with acceptor membrane concentration and by inclusion of acidic phospholipids, indicating a similar mechanism of transfer. We conclude KFABP can functionally compensate for the absence of AFABP, resulting in no major alterations in adipocyte metabolism or fat accumulation in response to short-term feeding of high-fat diets that result in moderate hyperinsulinemia.
Cardiovascular disease and the global village.
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Medicine and the media.
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Pericardial pressure in experimental chronic heart failure.
BACKGROUND: In the normal heart, pericardial pressure is greater than previously believed. OBJECTIVES: To explore the contribution of pericardial constraint to the elevated left ventricular (LV) end-diastolic pressure in chronic heart failure (CHF). ANIMALS AND METHODS: Pericardial pressure was measured directly in 11 dogs with CHF. Seven dogs were instrumented with LV and right ventricular micromanometers and epicardial pacing leads, and paced at 240 to 260 beats/min for four to seven weeks. After the development of CHF, a left thoracotomy was performed and a flat pericardial balloon was positioned over the LV free wall through a slit in the pericardium. RESULTS: LV end-diastolic pressure was 31+/-9 mmHg, and pericardial pressure only 7+/-2 mmHg. Nitroglycerin in six dogs decreased LV end-diastolic pressure from 33+/-8 to 28+/-7 and pericardial pressure from 7+/-2 to 6+/-3 mmHg (both P<0.05). Calculated transmural LV end-diastolic pressure also decreased (26+/-8 to 22+/-7 mmHg, P<0.05). Volume loading in five dogs increased LV end-diastolic pressure from 29+/-8 to 42+/-10 mmHg (P<0.05), pericardial pressure from 6+/-3 to 12+/-6 mmHg (not significant) and transmural LV end-diastolic pressure from 23+/-7 to 30+/-7 mmHg (not significant). When the pericardium was opened in three dogs, the LV end-diastolic pressure decreased by 5 mmHg. Four previously uninstrumented dogs were studied to exclude the effects of epicardial scarring; LV end-diastolic pressure was 42+/-6 mmHg and pericardial pressure was 10+/-6 mmHg. CONCLUSION: Pericardial constraint, a prerequisite for pericardially mediated ventricular interaction, was not present to the same extent in this model of CHF as in acute models, probably reflecting the importance of pericardial remodelling.
Integrity of the peer review process.
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Celebrating our heroes.
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Intergroup emotions: explaining offensive action tendencies in an intergroup context.
Three studies tested the idea that when social identity is salient, group-based appraisals elicit specific emotions and action tendencies toward out-groups. Participants' group memberships were made salient and the collective support apparently enjoyed by the in-group was measured or manipulated. The authors then measured anger and fear (Studies 1 and 2) and anger and contempt (Study 3), as well as the desire to move against or away from the out-group. Intergroup anger was distinct from intergroup fear, and the inclination to act against the out-group was distinct from the tendency to move away from it. Participants who perceived the in-group as strong were more likely to experience anger toward the out-group and to desire to take action against it. The effects of perceived in-group strength on offensive action tendencies were mediated by anger.