Biomedical subjects
V Ramakrishnan
Publications and source records attributed to V Ramakrishnan.
Ribosomal protein structures: insights into the architecture, machinery and evolution of the ribosome.
Models of the bacterial ribosome based on recent structural analyses are beginning to provide new insights into the protein synthetic machinery. Central to evolving models are the high-resolution structures of individual ribosomal proteins, which represent detailed probes of their local RNA and protein environments. Ribosomal proteins are extremely ancient molecules; the structures therefore also provide a unique window into early protein evolution. Many of the proteins contain domains that are present in more recently evolved families of RNA- and DNA-binding proteins. Such structural homology can be used to predict mechanisms by which proteins interact with RNA in the ribosome.
Relationships of race and socioeconomic status with prevalence, severity, and symptoms of asthma in Chicago school children.
BACKGROUND: Asthma mortality rates in Chicago are among the highest in the United States, with substantially greater rates in poor and minority populations. How much of the differential can be attributed to differences in prevalence versus severity or access to care has not been determined. OBJECTIVE: To examine rates of asthma prevalence, severity, and symptoms and to explore the relationships of these rates to race and socioeconomic status in a random sample of Chicago school children. METHODS: Self-administered survey. RESULTS: Overall, rates of asthma were higher than previously reported, with 16% of students in the stratified cluster random sample of 3,670 children in the 7th and 8th grades having had asthma. Prevalence rates were significantly higher in schools with >98% African Americans than in other schools, with the highest prevalence rates seen in African American schools in low income neighborhoods. Rates were associated with the percent of African American children in the school and with median income of the school's census tract. Relationships were most consistent with indices of more severe disease. CONCLUSIONS: Asthma prevalence is higher than previously noted, with rates greatest in minority and low income populations. Differences are more striking for measures of severity than for symptoms of wheezing, but are far less than previously reported differences in mortality, suggesting that additional factors, such as differential access to continuous health care, may be affecting high death rates from asthma in Chicago.
Investigation of PAR-1-type thrombin receptors in rat glioma C6 cells with a novel monoclonal anti-PAR-1 antibody (Mab COR7-6H9).
Rat glioma C6 cells have been demonstrated to be a suitable model in the investigation of PAR-1-type thrombin receptors in brain. However, anti-PAR-1 antibodies, which should be very helpful tools in studying PAR-1 in rat cells, have not been available up until now. Therefore, we prepared a monoclonal anti-thrombin receptor antibody (Mab COR7-6H9) directed against the peptide sequence GRAVYLNKSRFPPMPPPPFISEDASG in the N-terminus below the thrombin cleavage site of the rat PAR-1-type thrombin receptor. Using this antibody, we demonstrated the presence of PAR-1 binding sites on the plasma membrane of rat glioma C6 cells both with confocal laser fluorescence and with scanning electron microscopy. In addition, Mab COR7-6H9 was shown to block PAR-1-mediated transmembranal signaling as demonstrated by measurement of free intracellular calcium and cyclic AMP. This novel anti-PAR-1 antibody is therefore likely to be a very helpful tool in studying PAR-1-type thrombin receptors in rat brain.
Endoscopically assisted gracilis harvest for use as a free and pedicled flap.
Endoscopic assistance in soft tissue surgery may prove to greatly aid in the improvement of cosmesis and reduction of morbidity in certain procedures. The scar produced from open gracilis harvest is the most common complaint following surgery. We present five cases of endoscopically assisted gracilis harvest for use as a neosphincter and in foot reconstruction. The operative technique is described.
Re: Breast reconstruction after mastectomy without additional scarring: application of endoscopic latissimus dorsi muscle harvest.
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Structure of the yeast histone acetyltransferase Hat1: insights into substrate specificity and implications for the Gcn5-related N-acetyltransferase superfamily.
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Asthma prevalence and risk factors in selected Head Start sites in Chicago.
Prevalence of and risk factors for asthma were examined in 1085 Head Start families at 18 Head Start sites in four high-risk community areas in 1994. A total of 13.9% of the families reported diagnosed asthma in their Head Start child and 18.8% reported that their child wheezed in the last 12 months. A total of 26.9% of respondents reported asthma in the immediate family of the child. Low birth weight (1500-2499 g), very low birth weight (<1500 g), and self-reported exposure to dampness or mold in the last 12 months were significantly associated with self-reported diagnosed asthma (OR = 1.93; 95% CI 1.17-8.73), (OR = 4.5; 95% CI 1.25-16.3), and (OR = 1.94; 95% CI 1.23-3.04), respectively. The young age of the children in Head Start, as well as the high prevalence of asthma in their families, suggest that the Head Start programs offer an unusual opportunity for asthma prevention programs.
Intermediates of prothrombin activation induce intracellular calcium mobilization in rat aortic smooth muscle cells.
While effects of alpha-thrombin have been well characterized in different cell types, the biological function of intermediates of prothrombin activation is still undefined. Meizothrombin could be shown to be a potent agonist for vascular contraction which seems to be mediated by an interaction with the vascular smooth muscle. To explore this effect at intracellular signaling level, we used rat aortic smooth muscle cells and investigated the effect of the intermediates formed by cleavage of human prothrombin with ecarin, the prothrombin activator from Echis carinatus venom, on mobilization of free intracellular calcium. The ecarin-activated prothrombin induced very rapidly transient calcium mobilization in SMC's comparable to that observed with alpha-thrombin. We conclude that meizothrombin/meizothrombin desF1 (MT/MT desF1) are the most likely candidates for this effect. Furthermore, our results suggest the involvement of PAR-1-type thrombin receptors in MT/MT desF1-induced calcium signaling in rat aortic smooth muscle cells.
Adaptation to the loss of the stereoscopic image in microsurgery.
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Biogenesis of L-glyceric aciduria, oxalosis and renal injury in rats simulating type II primary hyperoxaluria.
Tracer experiments in rats mimicking type II primary hyperoxaluria, with an expanded intracellular pool of hydroxypyruvate, showed that the excess formation of oxalate did not originate from its immediate precursor glyoxylate. In these animals, the hepatic and kidney activities of oxalate synthesising enzymes such as lactate dehydrogenase and glycolate oxidase were normal, but tissue lipid peroxidation was significantly higher. In vitro experiments established that in a mild alkaline solution, hydroxypyruvate underwent auto-oxidation to form oxalate and H2O2 and also inhibited lactate dehydrogenase and glycolate oxidase from oxidising glyoxylate to oxalate. On the basis of the experimental evidence, we suggest that in type II primary hyperoxaluria, the accumulating hydroxypyruvate could reduce the intracellular pool of glyoxylate and on ageing, give rise to excess oxalate and H2O2, to cause oxalosis in the former and free radical mediated-cell injuries in the latter.
Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies.
The biological effects of platelet-derived growth factor (PDGF) are mediated by alpha- and beta-PDGF receptors (PDGFR), which have an intracellular tyrosine kinase domain and an extracellular region comprising five immunoglobulin-like domains (D1-D5). Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region. In the case of alpha-PDGFR, 125I-PDGF AA and 125I-PDGF BB bound to the full-length extracellular domain, D1-D5, and D2-D3 with equal affinity (Kd = 0.21-0.42 nM). Identical results were obtained for 125I-PDGF BB binding to beta-PDGFR mutants D1-D5 and D2-D3, establishing that D1, D4, and D5 do not contribute to PDGF binding. Monoclonal antibodies (mAb) directed against individual PDGFR Ig-like domains were used to extend these observations. The anti-D1 mAb 1E10E2 and anti-D5 mAb 2D4G10 had no effect on alpha- or beta-PDGFR function, respectively. In contrast, mAb 2H7C5 and 2A1E2 directed against D2 of the alpha- and beta-receptor, respectively, blocked PDGF binding, receptor autophosphorylation and mitogenic signaling with IC50 values of 0.1-3.0 nM. An anti-D4 mAb 1C7D5 blocked beta-receptor autophosphorylation and signaling without inhibiting PDGF binding consistent with the observation that D4 is essential for PDGFR dimerization (Omura, T., Heldin, C.-H., and Ostman, A. (1997) J. Biol. Chem. 272, 12676-12682). mAbs identified here act as potent PDGFR antagonists that can be used as research tools and potentially as therapeutic agents for the treatment of diseases involving unwanted PDGFR signaling.
Twists and turns of the nucleosome: tails without ends.
The high-resolution structure of a nucleosome core particle gives us our first detailed look at the primary level of eukaryotic DNA organization. The structure reveals the nature of histone-DNA contacts and provides some surprises regarding the histone tails and their possible involvement in higher levels of chromatin organization.
The structure of ribosomal protein S7 at 1.9 A resolution reveals a beta-hairpin motif that binds double-stranded nucleic acids.
BACKGROUND: Ribosomal protein S7, a crucial RNA-binding component of the ribosome, is one of two proteins that initiates assembly of the 30S ribosomal subunit. It is required for proper folding of a large 3' domain of 16S ribosomal RNA. S7 regulates its own synthesis by binding to its own mRNA. This ability of S7 to bind both messenger and ribosomal RNAs makes determination of its mode of RNA recognition particularly interesting. RESULTS: The crystal structure of S7 from Thermus thermophilus was determined by a two-wavelength anomalous diffraction experiment using the LIII edge of mercury. The S7 structure consists of a bundle of six helices and an extended beta hairpin between helices 3 and 4, with two or more RNA-binding sites on its surface. The hairpin, along with portions of helices 1, 4 and 6, forms a large, positively charged, concave surface that has the appropriate curvature and dimensions to bind double-stranded RNA. A second putative RNA-binding site comprises parts of loop 2 and the helix 4-loop 5 turn. CONCLUSIONS: Structural similarity between S7 and the IHF/HU family of proteins strongly suggests that the beta hairpin of S7 binds to a groove of double-stranded RNA. The beta hairpin of S7 is also similar to those from other nucleic acid binding proteins, such as ribosomal protein L14 and BIV Tat, suggesting that it belongs to an extended family of such motifs, all of which bind to a groove of double-stranded nucleic acid. The residues in S7 loop 2 that belong to the second putative RNA-binding site may have a role analogous to the N-terminal residues of IHF/HU which grip an unbent portion of double helix.
Identification of a cohort of male and female twins aged 65 years or more in the United States.
In this paper, a method with which to identify a national cohort of elderly twins is proposed. Record linkage algorithms were developed and applied to the > 30 million records contained in the Medicare beneficiary file. The matching algorithm for male/male pairs used race (black or white), last name, date of birth, and state of issuance of the Social Security number. Female/female and male/female pairs were selected with matching on race, date of birth, and the first seven digits of the Social Security number to compensate for the absence of maiden names. A stratified random sample of same-sex and opposite-sex white and black pairs (six groups) were selected and surveyed for determination of the actual prevalence of twins. On the basis of these results, the authors conclude that this method could identify an estimated 18,308 male/male, 7,544 female/female, and 204 male/female pairs of twins aged 65 years or more. This would be the largest sample of older twins ever assembled in the United States and represents a significant new resource for epidemiologic studies of the aging population.
Venous enhancement of a distally-based islanded fasciocutaneous flap.
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