NF-kappaB signaling pathways in mammalian and insect innate immunity.
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Animals↗
Biomedical subjects
N Silverman
Publications and source records attributed to N Silverman.
Testing the taxonomic integrity of Paranthropus boisei sensu stricto.
The craniodental hypodigm of Paranthropus boisei sensu stricto is morphologically distinctive, but it has been suggested that the substantial variation in mandibular and dental size in that hypodigm may exceed that which is reasonable to subsume within a single hominin species. In this study, Fligner and Killeen, coefficient of variation (CV)-based and average taxonomic distance (ATD)-based bootstrap tests, were used to compare variation in size and shape of the mandibular corpus remains attributed to P. boisei s.s. with the variation observed in samples of great apes and modern humans. The degree of size variation in the P. boisei s.s. mandibular hypodigm is never observed in human and chimpanzee samples, is rare in gorillas, but is not uncommon in orangutans. However, the shape variation in the fossil group is comparable to the variation in the extant reference groups. Although the size variation in P. boisei s.s. is substantial, it is exaggerated by the effects of taphonomy. The small mandibles are more often abraded, whereas the large mandibles are more likely to have been infiltrated with matrix. On the basis of the results of this investigation of the mandibular corpus, there are no grounds for rejecting the "single-species" hypothesis for P. boisei s.s. When Sokal and Braumann's adjusted CV values were used to predict the index of sexual dimorphism (ISD) for the P. boisei s.s., despite the substantial geological time embraced by the mandibular corpus hypodigm, the predicted value of lnISD, when corrected for taphonomic factors, is comparable to the sexual dimorphism observed within Gorilla.
Animals↗
Prenatal diagnosis of congenital nephrosis by in utero kidney biopsy.
The diagnosis of congenital nephrosis is difficult during the antepartum period. The combination of an elevated amniotic fluid alpha-fetoprotein, a negative acetylcholinesterase, and a negative ultrasound examination is highly indicative of congenital nephrosis; however, these findings can also be associated with a normal gestation. This is the first report of pathologic confirmation of congenital nephrosis from an in utero fetal kidney biopsy.
Acetylcholinesterase↗
Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene.
Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage, and is implicated in cell growth and differentiation. Mice lacking the perlecan gene (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development.
Animals↗
A blood pressure sensor for long-term implantation.
An implantable flow-through blood pressure sensor prototype has been developed for use with an implantable left ventricular assist device (LVAD). This sensor incorporates a flat pressure-sensing diaphragm that is designed to be integral with the wall of a titanium tube that may be placed in the inlet or the outlet flow path of any LVAD. The interior tube flow geometry is transitioned from a round to a D-shape such that flow separation is eliminated. Bench testing of 3 sensors was performed to characterize the sensor. The worst-case results showed a maximum nonlinearity of 0.64 mm Hg, a maximum hysteresis of 0.87 mm Hg, and a maximum nonrepeatability of 0.87 mm Hg. Long-term drift studies of 2 sensors at 193 days and 112 days resulted in a projected annual drift rate of 1.4 and 2.0 mm Hg, respectively. The APEX pressure sensors were evaluated in 5 ventricular assist acute calf experiments in which the sensor outputs were compared with Millar pressure catheter sensors. Pressure output comparisons showed similar pressure tracings. No visible evidence of thrombus formation was found on the APEX sensor compared with thrombus formation found on the Millar catheter at the entrance to the flow path. Tests demonstrated that the blood pressure sensor can accurately measure blood pressure and indicate that it has long-term stability.
Animals↗
Maternal uniparental disomy of chromosome 16 and body stalk anomaly.
We report on a fetus with placental trisomy 16, maternal uniparental disomy (UPD), and body stalk anomaly. Body stalk anomaly is a rare, fatal developmental abnormality consisting of a defective abdominal wall with abdominal organs in a sac outside the abdominal cavity covered by amnion adherent to the placenta with absence or severe shortness of the umbilical cord. Trisomy 16 was identified in the placenta in all cells. Amniocentesis was karyotypically normal. Parental origin studies showed maternal UPD for chromosome 16 in post-termination fetal tissue. The cause of the body stalk anomaly is not clearly defined. There are no other reports of placental karyotype or UPD investigations with body stalk anomaly. To our knowledge, this is the first report of placental trisomy 16, UPD in fetus, and body stalk anomaly, suggesting placental insufficiency or imprinting effects as cause of this anomaly. Am. J. Med. Genet. 94:284-286, 2000.
Abdominal Muscles↗
A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity.
Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes. In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro. Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish. The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes. Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development. Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway.
Animals↗
Abnormal mitochondrial respiration in failed human myocardium.
Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced organelle size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.
Adult↗
Role of Drosophila IKK gamma in a toll-independent antibacterial immune response.
We have generated, by ethylmethane sulfonate mutagenesis, loss-of-function mutants in the Drosophila homolog of the mammalian I-kappa B kinase (IKK) complex component IKK gamma (also called NEMO). Our data show that Drosophila IKK gamma is required for the Relish-dependent immune induction of the genes encoding antibacterial peptides and for resistance to infections by Escherichia coli. However, it is not required for the Toll-DIF-dependent antifungal host defense. The results indicate distinct control mechanisms of the Rel-like transactivators DIF and Relish in the Drosophila innate immune response and show that Drosophila Toll does not signal through a IKK gamma-dependent signaling complex. Thus, in contrast to the vertebrate inflammatory response, IKK gamma is required for the activation of only one immune signaling pathway in Drosophila.
Animals↗
Association between a shift in vaginal flora on Papanicolaou smear and acute chorioamnionitis and preterm delivery.
Bacterial vaginosis has been implicated as a cause of acute chorioamnionitis and preterm delivery. This study was designed to determine any association between the detection of bacterial vaginosis on a prenatal Papanicolaou (Pap) smear, defined as a shift in vaginal flora, and the subsequent occurrence of acute chorioamnionitis or preterm labor. A 47-mo retrospective case-control analysis comparing 186 patients with histologically-proven acute chorioamnionitis (cases) and 186 controls was performed. Initial prenatal Pap smears were evaluated for the presence of altered vaginal flora. Pap smears from women with acute chorioamnionitis were more likely to have altered vaginal flora than those without chorioamnionitis (P < 0.01). Preterm delivery was also more common among women with a shift in vaginal flora (P < 0.01). In conclusion, women at risk for chorioamnionitis and/or preterm delivery may be able to be identified by the results of their prenatal Pap smear.
Acute Disease↗
The heparin-protamine interaction. A review.
The heparin-protamine interaction is a topic of intense scrutiny due to its mandatory use during cardiopulmonary bypass. It can be estimated that over 2,000,000 patients are exposed to the heparin-protamine interaction each year. From clinical and experimental observation it is known that protamine neutralization of heparin causes increased pulmonary artery pressures and decreased systolic and diastolic blood pressure, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. These multiple cardiovascular effects are mediated via complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation. This article reviews the current understanding of the heparin-protamine interaction from the world's literature.
Animals↗
Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes.
BACKGROUND: Alterations in K+ channel expression and gating are thought to be the major cause of action potential remodeling in heart failure (HF). We previously reported the existence of a late Na+ current (INaL) in cardiomyocytes of dogs with chronic HF, which suggested the importance of the Na+ channel in this remodeling process. The present study examined whether this INaL exists in cardiomyocytes isolated from normal and failing human hearts. METHODS AND RESULTS: A whole-cell patch-clamp technique was used to measure ion currents in cardiomyocytes isolated from the left ventricle of explanted hearts from 10 patients with end-stage HF and from 3 normal hearts. We found INaL was activated at a membrane potential of -60 mV with maximum density (0.34+/-0.05 pA/pF) at -30 mV in cardiomyocytes of both normal and failing hearts. The steady-state availability was sigmoidal, with an averaged midpoint potential of -94+/-2 mV and a slope factor of 6.9+/-0.1 mV. The current was reversibly blocked by the Na+ channel blockers tetrodotoxin (IC50=1.5 micromol/L) and saxitoxin (IC50=98 nmol/L) in a dose-dependent manner. Both inactivation and reactivation of INaL had an ultraslow time course (tau approximately 0.6 seconds) and were independent of voltage. The amplitude of INaL was independent of the peak transient Na+ current. CONCLUSIONS: Cardiomyocytes isolated from normal and explanted failing human hearts express INaL characterized by an ultraslow voltage-independent inactivation and reactivation.
Action Potentials↗
Recommendations for training in performance and interpretation of stress echocardiography. Committee on Physician Training and Education of the American Society of Echocardiography.
Stress echocardiography has emerged as a clinically useful procedure in the management of patients with ischemic heart disease and other conditions. However, the accuracy of this test relies on the ability of those who carry out the technical aspects of the test and depends critically on proper interpretation of the images. Appreciation of wall motion abnormalities is generally acknowledged as one of the most difficult skills to master in echocardiography. There is consensus that this is also one of the most difficult skills to teach. Appreciating stress-induced changes in wall motion, which sometimes are subtle, requires a significant commitment to initial training in this skill and its maintenance. This document provides recommendations for physician training in stress echocardiography.
Cardiology↗
ADA1, a novel component of the ADA/GCN5 complex, has broader effects than GCN5, ADA2, or ADA3.
The ADA genes encode factors which are proposed to function as transcriptional coactivators. Here we describe the cloning, sequencing, and initial characterization of a novel ADA gene, ADA1. Similar to the previously isolated ada mutants, ada1 mutants display decreases in transcription from various reporters. Furthermore, ADA1 interacts with the other ADAs in the ADA/GCN5 complex as demonstrated by partial purification of the complex and immunoprecipitation experiments. We estimate that the complex has a molecular mass of approximately 2 MDa. Previously, it had been demonstrated that ada5 mutants displayed more severe phenotypic defects than the other ada mutants (G. A. Marcus, J. Horiuchi, N. Silverman, and L. Guarente, Mol. Cell. Biol. 16:3197-3205, 1996; S. M. Roberts and F. Winston, Mol. Cell. Biol. 16:3206-3213, 1996). ada1 mutants display defects similar to those of ada5 mutants and different from those of the other mutants with respect to promoters affected, inositol auxotrophy, and Spt- phenotypes. Thus, the ADAs can be separated into two classes, suggesting that the ADA/GCN5 complex may have two separate functions. We present a speculative model on the possible roles of the ADA/GCN5 complex.
Acetylation↗
Estimation of total body and extracellular water in post-coronary artery bypass graft surgical patients using single and multiple frequency bioimpedance.
OBJECTIVE: To assess the value of bioimpedance as a clinical tool by determining the accuracy and bias of single and multiple frequency bioimpedance estimates of total body and extracellular water in comparison with values established by criterion reference techniques. DESIGN: Controlled, prospective, single-blind investigation. SETTING: Private, not-for-profit, university-affiliated, acute care hospital. PATIENTS: Eight male, post-elective coronary artery bypass graft surgical patients. INTERVENTIONS: Within 6 hrs after surgery, estimates of total body and extracellular water volumes were determined using single and multiple frequency bioimpedance techniques. These estimates were then compared with the gold standard volumes measured by deuterium oxide and bromine dilutional space determination, respectively. MEASUREMENTS AND MAIN RESULTS: The mean multiple frequency bioimpedance estimate of total body water of 47.7 +/- 9.4 L was statistically different from the single frequency bioimpedance and deuterium values of 52.5 +/- 9.4 (p < .006) and 53.3 +/- 11.6 L (p < .002), respectively. In comparison, the mean multiple and single frequency bioimpedance estimates of extracellular water, 26.3 +/- 5.4 and 29.2 +/- 5.4 L, respectively, were not statistically different from the bromine value of 27.5 +/- 6.9 L. In addition, the mean errors for multiple and single frequency bioimpedance determinations of extracellular water, -1.2 +/- 2.0 and 1.7 +/- 2.7 L, respectively, were statistically different (p = .001). CONCLUSIONS: In male, post-elective coronary artery bypass graft surgical patients, single frequency bioimpedance was a more accurate and less biased predictor of total body water than multiple frequency bioimpedance. The accuracy and bias of multiple frequency bioimpedance was superior to single frequency bioimpedance for the prediction of extracellular water. Whether this observation remains true for other populations of critically ill patients remains to be investigated.
Aged↗
ADA5/SPT20 links the ADA and SPT genes, which are involved in yeast transcription.
In this report we described the cloning and characterization of ADA5, a gene identified by resistance to GAL4-VP16-mediated toxicity. ADA5 binds directly to the VP16 activation domain but not to a transcriptionally defective VP16 double point mutant. Double mutants with mutations in ada5 and other genes (ada2 or ada3) isolated by resistance to GAL4-VP16 grow like ada5 single mutants, suggesting that ADA5 is in the same pathway as the other ADA genes. Further, ADA5 cofractionates and coprecipitates with ADA3. However, an ada5 deletion mutant exhibits a broader spectrum of phenotypes than mutants with null mutations in the other ADA genes. Most interestingly, ADA5 is identical to SPT20 (S.M. Roberts and F. Winston, Mol. Cell. Biol. 16: 3206-3213, 1996), showing that it shares phenotypes with the ADA and SPT family of genes. Of the other SPT genes tested, mutants with mutations in SPT7 and, strikingly, SPT15 (encoding the TATA-binding protein) show resistance to GAL4-VP16. We present a speculative pathway of transcriptional activation involving the ADA2-ADA3-GCN5-ADA5 complex and the TATA-binding protein.
Amino Acid Sequence↗
Characterization of physical interactions of the putative transcriptional adaptor, ADA2, with acidic activation domains and TATA-binding protein.
RNA polymerase II transcription requires functional interactions between activator proteins bound to upstream DNA sites and general factors bound to the core promoter. Accessory transcription factors, such as adaptors and coactivators, have important, but still unclear, roles in the activation process. We tested physical interactions of the putative adaptor ADA2 with activation domains derived from acidic activator proteins and with certain general transcription factors. ADA2 associated with the herpesvirus VP16 and yeast GCN4 activation domains but not with the activation domain of yeast HAP4, which previously was shown to be independent of ADA2 function in vivo and in vitro. Furthermore, the amino terminus of ADA2 directly interacted with the VP16 activation domain, suggesting that ADA2 provides determinants for interaction between activation domains and the adaptor complex. Both TATA-binding protein (TBP) and TFIIB have previously been shown to interact directly with the VP16 activation domain in vitro (Stringer, K. F., Ingles, C. J., and Greenblatt, J. (1990) Nature 345, 783-786; Lin, Y. S., Ha, I., Maldonado, E., Reinberg, D., and Green, M. R. (1991) Nature 353, 569-571). Interestingly, when binding was tested between VP16 and these general factors in yeast nuclear extracts, both factors interacted with VP16, but only the TBP/VP16 association was dependent on ADA2. In addition, ADA2 physically associated with TBP, but not with TFIIB. These results suggest that the role of ADA2 in transcriptional activation is to promote physical interaction between activation domains and TBP.
CCAAT-Binding Factor↗
ADA3, a putative transcriptional adaptor, consists of two separable domains and interacts with ADA2 and GCN5 in a trimeric complex.
Mutations in yeast ADA2, ADA3, and GCN5 weaken the activation potential of a subset of acidic activation domains. In this report, we show that their gene products form a heterotrimeric complex in vitro, with ADA2 as the linchpin holding ADA3 and GCN5 together. Further, activation by LexA-ADA3 fusions in vivo are regulated by the levels of ADA2. Combined with a prior observation that LexA-ADA2 fusions are regulated by the levels of ADA3 (N. Silverman, J. Agapite, and L. Guarente, Proc. Natl. Acad. Sci. USA 91:11665-11668, 1994), this finding suggests that these proteins also form a complex in cells. ADA3 can be separated into two nonoverlapping domains, an amino-terminal domain and a carboxyl-terminal domain, which do not separately complement the slow-growth phenotype or transcriptional defect of a delta ada3 strain but together supply full complementation. The carboxyl-terminal domain of ADA3 alone suffices for heterotrimeric complex formation in vitro and activation of LexA-ADA2 in vivo. We present a model depicting the ADA complex as a coactivator in which the ADA3 amino-terminal domain mediates an interaction between activation domains and the ADA complex.
Blotting, Western↗