Detection of a Single Identical Cytomegalovirus (CMV) Strain in Recently Seroconverted Young Women

Infection with multiple CMV strains is common in immunocompromised hosts, but its occurrence in normal hosts has not been well-studied.We analyzed CMV strains longitudinally in women who acquired CMV while enrolled in a CMV glycoprotein B (gB) vaccine trial. Sequencing of four variable genes was performed in samples collected from seroconversion and up to 34 months thereafter.199 cultured isolates from 53 women and 65 original fluids from a subset of 19 women were sequenced. 51 women were infected with one strain each without evidence for genetic drift; only two women shed multiple strains. Genetic variability among strains increased with the number of sequenced genetic loci. Nevertheless, 13 of 53 women proved to be infected with an identical CMV strain based on sequencing at all four variable genes. CMV vaccine did not alter the degree of genetic diversity amongst strains.Primary CMV infection in healthy women nearly always involves shedding of one strain that remains stable over time. Immunization with CMVgB-1 vaccine strain is not selective against specific strains. Although 75% of women harbored their unique strain, or a strain shared with only one other woman, 25% shared a single common strain, suggesting that this predominant strain with a particular combination of genetic loci is advantageous in this large urban area

Serotonin Antagonism Improves Platelet Inhibition in Clopidogrel Low-Responders after Coronary Stent Placement: An In Vitro Pilot Study

Increased residual platelet reactivity remains a burden for coronary artery disease (CAD) patients who received a coronary stent and do not respond sufficiently to treatment with acetylsalicylic acid and clopidogrel. We hypothesized that serotonin antagonism reduces high on-treatment platelet reactivity. Whole blood impedance aggregometry was performed with arachidonic acid (AA, 0.5 mM) and adenosine diphosphate (ADP, 6.5 µM) in addition to different concentrations of serotonin (1–100 µM) in whole blood from 42 CAD patients after coronary stent placement and 10 healthy subjects. Serotonin increased aggregation dose-dependently in CAD patients who responded to clopidogrel treatment: After activation with ADP, aggregation increased from 33.7±1.3% to 40.9±2.0% in the presence of 50 µM serotonin (p<0.05) and to 48.2±2.0% with 100 µM serotonin (p<0.001). The platelet serotonin receptor antagonist ketanserin decreased ADP-induced aggregation significantly in clopidogrel low-responders (from 59.9±3.1% to 37.4±3.5, p<0.01), but not in clopidogrel responders. These results were confirmed with light transmission aggregometry in platelet-rich plasma in a subset of patients. Serotonin hence increased residual platelet reactivity in patients who respond to clopidogrel after coronary stent placement. In clopidogrel low-responders, serotonin receptor antagonism improved platelet inhibition, almost reaching responder levels. This may justify further investigation of triple antiplatelet therapy with anti-serotonergic agents

Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development

<p>Abstract</p> <p>Background</p> <p>Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives.</p> <p>Results</p> <p>E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days <it>in vitr</it>o. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-κB2, RelA, RelB, and Shh and Smad7 proteins.</p> <p>Conclusion</p> <p>Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-κB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.</p

Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer: A Systems Approach

MicroRNAs (miRNAs) are short (∼22 nucleotides) regulatory RNAs that can modulate gene expression and are aberrantly expressed in many diseases including cancer. Previous studies have shown that miRNAs inhibit the translation and facilitate the degradation of their targeted messenger RNAs (mRNAs) making them attractive candidates for use in cancer therapy. However, the potential clinical utility of miRNAs in cancer therapy rests heavily upon our ability to understand and accurately predict the consequences of fluctuations in levels of miRNAs within the context of complex tumor cells. To evaluate the predictive power of current models, levels of miRNAs and their targeted mRNAs were measured in laser captured micro-dissected (LCM) ovarian cancer epithelial cells (CEPI) and compared with levels present in ovarian surface epithelial cells (OSE). We found that the predicted inverse correlation between changes in levels of miRNAs and levels of their mRNA targets held for only ∼11% of predicted target mRNAs. We demonstrate that this low inverse correlation between changes in levels of miRNAs and their target mRNAs in vivo is not merely an artifact of inaccurate miRNA target predictions but the likely consequence of indirect cellular processes that modulate the regulatory effects of miRNAs in vivo. Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basis of these complexities in cancer cells before the therapeutic potential of miRNAs can be fully realized

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Early Gnathostome Phylogeny Revisited: Multiple Method Consensus

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.A series of recent studies recovered consistent phylogenetic scenarios of jawed vertebrates, such as the paraphyly of placoderms with respect to crown gnathostomes, and antiarchs as the sister group of all other jawed vertebrates. However, some of the hylogenetic relationships within the group have remained controversial, such as the positions of Entelognathus, ptyctodontids, and the Guiyu-lineage that comprises Guiyu, Psarolepis and Achoania. The revision of the dataset in a recent study reveals a modified phylogenetic hypothesis, which shows that some of these phylogenetic conflicts were sourced from a few inadvertent miscodings. The interrelationships of early gnathostomes are addressed based on a combined new dataset with 103 taxa and 335 characters, which is the most comprehensive morphological dataset constructed to date. This dataset is investigated in a phylogenetic context using maximum parsimony (MP), Bayesian inference (BI) and maximum likelihood (ML) approaches in an attempt to explore the consensus and incongruence between the hypotheses of early gnathostome interrelationships recovered from different methods. Our findings consistently corroborate the paraphyly of placoderms, all `acanthodians' as a paraphyletic stem group of chondrichthyans, Entelognathus as a stem gnathostome, and the Guiyu-lineage as stem sarcopterygians. The incongruence using different methods is less significant than the consensus, and mainly relates to the positions of the placoderm Wuttagoonaspis, the stem chondrichthyan Ramirosuarezia, and the stem osteichthyan LophosteusÐthe taxa that are either poorly known or highly specialized in character complement. Given that the different performances of each phylogenetic approach, our study provides an empirical case that the multiple phylogenetic analyses of morphological data are mutually complementary rather than redundant

Digitized narratives of sexual violence: Making sexual violence felt and known through digital disclosures

In this article, we argue that social media platforms like Tumblr and Twitter have facilitated an emergence of “digitized narratives” of sexual violence. These narratives are rooted in historical ways in which feminists have discursively articulated sexual violence, yet are shaped by distinctive “platform vernacular” or the conventions, affordances, and restrictions of the platforms in which they appear. Drawing on a qualitative content and critical discourse analysis of 450 texts from the Tumblr site Who Needs Feminism? and the hashtag #BeenRapedNeverReported, we argue that digital platforms such as Tumblr and Twitter produce new vernacular practices which shape how “digitized narratives” of sexual violence are not only disclosed and known, but felt and experienced across digital networks

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion