Transcriptome Analysis of Vaccine Responses to Francisella Tularensis or Venezuelan Equine Encephalitis Virus

The lack of vaccines for emerging and re-emerging diseases highlights technical gaps and indicates a need for innovative approaches to produce new vaccines. Vaccines may be improved by knowledge of host responses to vaccination, disease pathogenesis, and the effect of age and genetics on vaccine outcome. This study\u27s purpose was to quantitatively assess the molecular epidemiology of Francisella tularensis (Ft) and Venezuelan Equine Encephalitis Virus (VEEV). Study results support the Epidemiology Nexus model which holds that association of changes in gene expression to vaccination facilitate understanding the mechanisms of immune development and link public health and disease epidemiology. My research questions assessed the relationship between gene expression following vaccination, the relationship between age and vaccine response, and the association between Human Leukocyte Antigen (HLA) allele and vaccine response. The study was a novel secondary analysis of human data subjected to ANOVA to measure association between treatment and outcome, correlation to measure association of age with vaccine outcome, and Mann-Whitney U tests to measure association of HLA allele with vaccine outcome. Both Ft and VEEV vaccination elicited significant changes in gene expression. A highly positive relationship between age and vaccine outcome was shown for VEEV. The results may affect positive social change by contributing to a growing compendium of evidence of vaccine efficacy mechanisms that may function to assure the public of vaccine safety, combat vaccine hesitancy, and promote vaccine acceptance, as well as contribute mechanistic knowledge to reduce developmental costs of novel vaccines

Monitoring the regulation of gene expression in a growing organ using a fluid mechanics formalism

<p>Abstract</p> <p>Background</p> <p>Technological advances have enabled the accurate quantification of gene expression, even within single cell types. While transcriptome analyses are routinely performed, most experimental designs only provide snapshots of gene expression. Molecular mechanisms underlying cell fate or positional signalling have been revealed through these discontinuous datasets. However, in developing multicellular structures, temporal and spatial cues, known to directly influence transcriptional networks, get entangled as the cells are displaced and expand. Access to an unbiased view of the spatiotemporal regulation of gene expression occurring during development requires a specific framework that properly quantifies the rate of change of a property in a moving and expanding element, such as a cell or an organ segment.</p> <p>Results</p> <p>We show how the rate of change in gene expression can be quantified by combining kinematics and real-time polymerase chain reaction data in a mechanistic model which considers any organ as a continuum. This framework was applied in order to assess the developmental regulation of the two reference genes <it>Actin11 </it>and <it>Elongation Factor 1-β </it>in the apex of poplar root. The growth field was determined by time-lapse photography and transcript density was obtained at high spatial resolution. The net accumulation rates of the transcripts of the two genes were found to display highly contrasted developmental profiles. <it>Actin11 </it>showed pulses of up and down regulation in the accelerating and decelerating parts of the growth zone while the dynamic of <it>EF1β </it>were much slower. This framework provides key information about gene regulation in a developing organ, such as the location, the duration and the intensity of gene induction/repression.</p> <p>Conclusions</p> <p>We demonstrated that gene expression patterns can be monitored using the continuity equation without using mutants or reporter constructions. Given the rise of imaging technologies, this framework in our view opens a new way to dissect the molecular basis of growth regulation, even in non-model species or complex structures.</p

Self-monitoring of oral anticoagulation: does it work outside trial conditions?

Background: Patient self-monitoring (PSM) of oral anticoagulation therapy (OAT) can improve anticoagulant control, but poor uptake and high dropout rates have prompted suggestions that PSM is suitable for only a minority of patients in the UK.Aims: To determine whether PSM could be a viable alternative to regular hospital anticoagulant clinic attendance, if offered from the start of treatment.Methods: 318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. Primary outcome measures were uptake of PSM and the percentage time in target therapeutic INR range (TIR) compared to patients electing for routine clinic care.Results: Of 318 patients referred for OAT, 188 were eligible for PSM. 84 (26%) elected to self-monitor, of whom 72 (23%) remained self-monitoring or had completed their course of treatment at the end of the audit. Self-monitoring patients had significantly better anticoagulant control than those receiving routine hospital anticoagulation clinic care (TIR 71% vs 60%, p = 0.003) and significantly less time outside critical limits, ie, INR5.0 (0.45% vs 2.04%, p = 0.008).Conclusions: Patients offered PSM from the start of treatment show increased uptake compared to previous UK studies and a level of oral anticoagulation control comparable to that reported in previous clinical trials

Evidence for the disky origin of luminous Virgo dwarf ellipticals from the kinematics of their globular cluster systems

We report evidence for dynamically significant rotation in the globular cluster systems of two luminous Virgo dwarf ellipticals, VCC1261 and VCC1528. Including previous results for VCC1087, the globular cluster systems of all three Virgo dwarf ellipticals studied in detail to date exhibit v_rot/sigma > 1. Taking the rotation seen in the globular clusters as maximal disk rotation, we find all three dEs lie on the r-band Tully-Fisher relation. We argue that these data support the hypothesis that luminous dEs are the remnants of transformed disk galaxies. We also obtained deep, longslit data for the stars in VCC1261 and VCC1528. Both these galaxies show rapid rotation in their inner regions, with spatial scales of ~0.5 kpc. These rotation velocities are similar to those seen in the GC systems. Since our longslit data for Virgo dEs extend out to 1-2 effective radii (typical of deep observations), whereas the globular clusters extend out to 4--7 effective radii, we conclude that non-detections of rotation in many luminous dEs may simply be due to a lack of radial coverage in the stellar data, and that globular clusters represent singularly sensitive probes of the dynamics of dEs. Based on these data, we suggest that gas disks are significant sites of globular cluster formation in the early universe.Comment: To appear in the AJ, corrected typographical errors in Table 1, added a referenc

BAMBI Is Expressed in Endothelial Cells and Is Regulated by Lysosomal/Autolysosomal Degradation

BACKGROUND: BAMBI (BMP and Activin Membrane Bound Inhibitor) is considered to influence TGFβ and Wnt signaling, and thereby fibrosis. Surprisingly data on cell type-specific expression of BAMBI are not available. We therefore examined the localization, gene regulation, and protein turnover of BAMBI in kidneys. METHODOLOGY/PRINCIPAL FINDINGS: By immunofluorescence microscopy and by mRNA expression, BAMBI is restricted to endothelial cells of the glomerular and some peritubular capillaries and of arteries and veins in both murine and human kidneys. TGFβ upregulated mRNA of BAMBI in murine glomerular endothelial cells (mGEC). LPS did not downregulate mRNA for BAMBI in mGEC or in HUVECs. BAMBI mRNA had a half-life of only 60 minutes and was stabilized by cycloheximide, indicating post-transcriptional regulation due to AU-rich elements, which we identified in the 3' untranslated sequence of both the human and murine BAMBI gene. BAMBI protein turnover was studied in HUVECs with BAMBI overexpression using a lentiviral system. Serum starvation as an inducer of autophagy caused marked BAMBI degradation, which could be totally prevented by inhibition of lysosomal and autolysosomal degradation with bafilomycin, and partially by inhibition of autophagy with 3-methyladenine, but not by proteasomal inhibitors. Rapamycin activates autophagy by inhibiting TOR, and resulted in BAMBI protein degradation. Both serum starvation and rapamycin increased the conversion of the autophagy marker LC3 from LC3-I to LC3-II and also enhanced co-staining for BAMBI and LC3 in autolysosomal vesicles. CONCLUSIONS/SIGNIFICANCE: 1. BAMBI localizes to endothelial cells in the kidney and to HUVECs. 2. BAMBI mRNA is regulated by post-transcriptional mechanisms. 3. BAMBI protein is regulated by lysosomal and autolysosomal degradation. The endothelial localization and the quick turnover of BAMBI may indicate novel, yet to be defined functions of this modulator for TGFβ and Wnt protein actions in the renal vascular endothelium in health and disease

In vitro antimicrobial and in vivo antioomycete activities of the novel antibiotic thiobutacin

BACKGROUND: A number of synthetic fungicides are not effective when confronted by oomycete pathogens because many fungicide targets are absent from oomycetes. Moreover, resistance to fungicides has already arisen in oomycete species, and thus development of new, effective and safe compounds for use in oomycete disease control is necessary. RESULTS: Zoospore lysis began at 10 µg mL −1 of thiobutacin, and most of the zoospores were collapsed at 50 µg mL −1 . Thiobutacin also revealed inhibitory activity against the cyst germination and hyphal growth of Phytophthora capsici at 50 µg mL −1 . Treatment with thiobutacin exhibited protective activity against development of Phytophthora disease on pepper plants. CONCLUSION: The authors verified in vitro antioomycete activity of thiobutacin against P. capsici and its control efficacy against Phytophthora blight in vivo . This is the first report to demonstrate in vivo antioomycete activity of the novel antibiotic thiobutacin against P. capsici infection. Copyright © 2007 Society of Chemical IndustryPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57925/1/1494_ftp.pd

Superconducting gap structure and pinning in disordered MgB2 films

We have performed a comparative study of two thin films of magnesium diboride (MgB2) grown by different techniques. The critical current density at different temperatures and magnetic fields was evaluated from magnetisation curves, the structure of superconducting order parameter was obtained from point-contact spectroscopy, and the scattering rates were evaluated by fitting the temperature dependent normal-state resistivity to the two-band model. The films have similar critical temperatures close to 39 K, but the upper critical fields were different by a factor of 2 (5.2T and 2.5 T at 20 K). We have found that the film with higher Hc2 also had stronger scattering in the sigma band and smaller value of the superconducting gap in this band. As the scattering in sigma band is primarily due to the defects in boron plane, our results are consistent with the assumption that disordering the boron planes leads to enhanced Hc2 and better pinning properties in magnetic field.Comment: Paper presented at EUCAS'0

The laurentian record of neoproterozoic glaciation, tectonism, and eukaryotic evolution in Death Vally, California

Neoproterozoic strata in Death Valley, California contain eukaryotic microfossils and glacial deposits that have been used to assess the severity of putative Snowball Earth events and the biological response to extreme environmental change. These successions also contain evidence for syn-sedimentary faulting that has been related to the rifting of Rodinia, and in turn the tectonic context of the onset of Snowball Earth. These interpretations hinge on local geological relationships and both regional and global stratigraphic correlations. Here we present new geological mapping, measured stratigraphic sections, carbon and strontium isotope chemostratigraphy, and micropaleontology from the Neoproterozoic glacial deposits and bounding strata in Death Valley. These new data enable us to refine regional correlations both across Death Valley and throughout Laurentia, and construct a new age model for glaciogenic strata and microfossil assemblages. Particularly, our remapping of the Kingston Peak Formation in the Saddle Peak Hills and near the type locality shows for the first time that glacial deposits of both the Marinoan and Sturtian glaciations can be distinguished in southeastern Death Valley, and that beds containing vase-shaped microfossils are slump blocks derived from the underlying strata. These slump blocks are associated with multiple overlapping unconformities that developed during syn-sedimentary faulting, which is a common feature of Cyrogenian strata along the margin of Laurentia from California to Alaska. With these data, we conclude that all of the microfossils that have been described to date in Neoproterozoic strata of Death Valley predate the glaciations and do not bear on the severity, extent or duration of Neoproterozoic Snowball Earth events

MicroRNAs and metazoan macroevolution: insights into canalization, complexity, and the Cambrian explosion

One of the most interesting challenges facing paleobiologists is explaining the Cambrian explosion, the dramatic appearance of most metazoan animal phyla in the Early Cambrian, and the subsequent stability of these body plans over the ensuing 530 million years. We propose that because phenotypic variation decreases through geologic time, because microRNAs (miRNAs) increase genic precision, by turning an imprecise number of mRNA transcripts into a more precise number of protein molecules, and because miRNAs are continuously being added to metazoan genomes through geologic time, miRNAs might be instrumental in the canalization of development. Further, miRNAs ultimately allow for natural selection to elaborate morphological complexity, because by reducing gene expression variability, miRNAs increase heritability, allowing selection to change characters more effectively. Hence, miRNAs might play an important role in shaping metazoan macroevolution, and might be part of the solution to the Cambrian conundrum

Compilation and Network Analyses of Cambrian Food Webs

A rich body of empirically grounded theory has developed about food webs—the networks of feeding relationships among species within habitats. However, detailed food-web data and analyses are lacking for ancient ecosystems, largely because of the low resolution of taxa coupled with uncertain and incomplete information about feeding interactions. These impediments appear insurmountable for most fossil assemblages; however, a few assemblages with excellent soft-body preservation across trophic levels are candidates for food-web data compilation and topological analysis. Here we present plausible, detailed food webs for the Chengjiang and Burgess Shale assemblages from the Cambrian Period. Analyses of degree distributions and other structural network properties, including sensitivity analyses of the effects of uncertainty associated with Cambrian diet designations, suggest that these early Paleozoic communities share remarkably similar topology with modern food webs. Observed regularities reflect a systematic dependence of structure on the numbers of taxa and links in a web. Most aspects of Cambrian food-web structure are well-characterized by a simple “niche model,” which was developed for modern food webs and takes into account this scale dependence. However, a few aspects of topology differ between the ancient and recent webs: longer path lengths between species and more species in feeding loops in the earlier Chengjiang web, and higher variability in the number of links per species for both Cambrian webs. Our results are relatively insensitive to the exclusion of low-certainty or random links. The many similarities between Cambrian and recent food webs point toward surprisingly strong and enduring constraints on the organization of complex feeding interactions among metazoan species. The few differences could reflect a transition to more strongly integrated and constrained trophic organization within ecosystems following the rapid diversification of species, body plans, and trophic roles during the Cambrian radiation. More research is needed to explore the generality of food-web structure through deep time and across habitats, especially to investigate potential mechanisms that could give rise to similar structure, as well as any differences