Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter

Although the promoters of both the Bax and p21 genes are activated by p53, they differ in the effect on this activation of the POU family transcription factor Brn-3a. Thus, Brn-3a inhibits activation of the Bax promoter by p53 but enhances the ability of p53 to activate the p21 promoter. We demonstrate that repression of p53-mediated activation of the Bax promoter involves a complex upstream sequence in which two Brn-3a response elements flank the p53 response element. In contrast, a minimal p21 promoter is activated by Brn-3a and such activation cannot be abolished without abolishing basal promoter activity. Moreover, synergistic activation by Brn-3a and p53 continues to be observed when the p53-binding sites in the p21 promoter are substituted by the Bax p53 site or by the region of the Bax promoter essential for Brn-3a-mediated repression, indicating that the p21 core promoter plays a central role in this response. The significance of these effects is discussed in terms of the different responses of the Bax and p21 promoters and the overlapping but distinct roles of Brn-3a and p53 in neuronal growth arrest and apoptosis

An Assessment of the Valuable Contributions and Abilities of African Americans Associated with the North American Fur Trade in the Trans-Mississippi West and Great Lakes Region from 1720-1840.

Morgan, MJThe goal of this paper will be to contend the reason African American fur traders were often included in fur trading parties was due to their linguistic abilities and cultural influence with Native American populations. This can especially be seen in the Trans-Mississippi West and Great Lakes region of North America from 1720-1840. Research methods include but are not limited to primary/secondary sources, letters, maps, journal, and diaries. The findings will show specific examples of African American contributions to fur trading parties via individual case studies

The HPV cellular transactivator Brn-3a can be used to predict cervical adenocarcinoma and squamous carcinoma precancer lesions in the developed and developing worlds

The cellular transactivator Brn-3a has previously been shown to be expressed at elevated levels in the cervix of women with squamous cell carcinoma of the cervix (SCC) and to activate the expression of HPV E6 mRNA. In this study, we show that common and rare cervical precancer lesions, including those of adenocarcinoma (AC), which are usually difficult to diagnose using classical procedures, also expressed high levels of Brn-3a and can be diagnosed by measuring the levels of Brn-3a and E6 mRNAs

Transcriptional Modulation of Heat-Shock Protein Gene Expression

Heat-shock proteins (Hsps) are molecular chaperones that are ubiquitously expressed but are also induced in cells exposed to stressful stimuli. Hsps have been implicated in the induction and propagation of several diseases. This paper focuses on regulatory factors that control the transcription of the genes encoding Hsps. We also highlight how distinct transcription factors are able to interact and modulate Hsps in different pathological states. Thus, a better understanding of the complex signaling pathways regulating Hsp expression may lead to novel therapeutic targets

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

Objective: Previous studies have shown the importance of somatic mutations and arginine residues in the complementarity-determining regions (CDRs) of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies in human and murine lupus, and in studies of murine antibodies, a role of mutations at position 53 in VH CDR2 has been demonstrated. We previously demonstrated in vitro expression and mutagenesis of the human IgG1 monoclonal antibody B3. The present study was undertaken to investigate, using this expression system, the importance of the arginine residue at position 53 (R53) in B3 VH. Methods: R53 was altered, by site-directed mutagenesis, to serine, asparagine, or lysine, to create 3 expressed variants of VH. In addition, the germline sequence of the VH3-23 gene (from which B3 VH is derived) was expressed either with or without arginine at position 53. These 5 new heavy chains, as well as wild-type B3 VH, were expressed with 4 different light chains, and the resulting antibodies were assessed for their ability to bind to nucleosomes, -actinin, cardiolipin, ovalbumin, 2-glycoprotein I (2GPI), and the N-terminal domain of 2GPI (domain I), using direct binding assays. Results: The presence of R53 was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of R53 reduced binding to -actinin, ovalbumin, 2GPI, and domain I of 2GPI. The combination B3 (R53S) VH/B3 VL bound human, but not bovine, 2GPI. Conclusion: The fact that the R53S substitution significantly alters binding of B3 to different clinically relevant antigens, but that the alteration is in opposite directions depending on the antigen, implies that this arginine residue plays a critical role in the affinity maturation of antibody B3

Selective internalization of sodium channels in rat dorsal root ganglion neurons infected with herpes simplex virus-1

The neurotropic virus, herpes simplex type 1 (HSV-1), inhibits the excitability of peripheral mammalian neurons, but the molecular mechanism of this effect has not been identified. Here, we use voltage-clamp measurement of ionic currents and an antibody against sodium channels to show that loss of excitability results from the selective, precipitous, and complete internalization of voltage-activated sodium channel proteins from the plasma membrane of neurons dissociated from rat dorsal root ganglion. The internalization process requires viral protein synthesis but not viral encapsulation, and does not alter the density of voltage-activated calcium or potassium channels. However, internalization is blocked completely when viruses lack the neurovirulence factor, infected cell protein 34.5, or when endocytosis is inhibited with bafilomycin A1 or chloroquine. Although it has been recognized for many years that viruses cause cell pathology by interfering with signal transduction pathways, this is the first example of viral pathology resulting from selective internalization of an integral membrane protein. In studying the HSV-induced redistribution of sodium channels, we have uncovered a previously unknown pathway for the rapid and dynamic control of excitability in sensory neurons by internalization of sodium channels

Water, oceanic fracture zones and the lubrication of subducting plate boundaries - insights from seismicity

We investigate the relationship between subduction processes and related seismicity for the Lesser Antilles Arc using the Gutenberg-Richter law. This power lawdescribes the earthquakemagnitude distribution, with the gradient of the cumulative magnitude distribution being commonly known as the b-value. The Lesser Antilles Arc was chosen because of its alongstrike variability in sediment subduction and the transition from subduction to strike-slip movement towards its northern and southern ends. The data are derived from the seismicity catalogues from the Seismic Research Centre of The University of the West Indies and the Observatoires Volcanologiques et Sismologiques of the Institut de Physique du Globe de Paris and consist of subcrustal events primarily from the slab interface. The b-value is found using a Kolmogorov-Smirnov test for a maximum-likelihood straight line-fitting routine. We investigate spatial variations in b-values using a grid-search with circular cells as well as an along-arc projection. Tests with different algorithms and the two independent earthquake cataloges provide confidence in the robustness of our results. We observe a strong spatial variability of the b-value that cannot be explained by the uncertainties. Rather than obtaining a simple north-south b-value distribution suggestive of the dominant control on earthquake triggering being water released from the sedimentary cover on the incoming American Plates, or a b-value distribution that correlates with on the obliquity of subduction, we obtain a series of discrete, high b-value 'bull's-eyes' along strike. These bull's-eyes, which indicate stress release through a higher fraction of small earthquakes, coincide with the locations of known incoming oceanic fracture zones on the American Plates. We interpret the results in terms of water being delivered to the Lesser Antilles subduction zone in the vicinity of fracture zones providing lubrication and thus changing the character of the related seismicity. Our results suggest serpentinization around mid-ocean ridge transform faults, which go on to become fracture zones on the incoming plate, plays a significant role in the delivery of water into the mantle at subduction zones

Evaluation of Murrell’s EKF-Based Attitude Estimation Algorithm for Exploiting Multiple Attitude Sensor Configurations

Pico- and nano-satellites, due to their form factor and size, are limited in accommodating multiple or redundant attitude sensors. For such satellites, Murrell\u27s implementation of the extended Kalman filter (EKF) can be exploited to accommodate multiple sensor configurations from a set of non redundant attitude sensors. The paper describes such an implementation involving a sun sensor suite and a magnetometer as attitude sensors. The implementation exploits Murrell\u27s EKF to enable three sensor configurations, which can be operationally commanded, for satellite attitude estimation. Among the three attitude estimation schemes, (i) sun sensor suite and magnetometer, (ii) magnetic field vector and its time derivative and (iii) magnetic field vector, it is shown that the third configuration is better suited for attitude estimation in terms of precision and accuracy, but can consume more time to converge than the other two