1,124 research outputs found
Civil Forfeiture: A Higher Form of Commercial Law?
In this Article, Messrs. Schwarcz and Rothman analyze the disquieting impact of civil forfeiture law on creditors\u27 rights. The Article begins by describing the historical origins of civil forfeiture and its development into current day law. The Article then explores the tension between forfeiture law and commercial and bankruptcy law by examining the effect of a forfeiture action on unsecured and undersecured creditors. The Article evaluates a recent model for balancing governmental and commercial law interests, and concludes by suggesting reforms to the present civil forfeiture scheme
Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection
Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA classswitched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection
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Simple Estimators of the Intensity of Seasonal Occurrence
Background: Edwards's method is a widely used approach for fitting a sine curve to a time-series of monthly frequencies. From this fitted curve, estimates of the seasonal intensity of occurrence (i.e., peak-to-low ratio of the fitted curve) can be generated. Methods: We discuss various approaches to the estimation of seasonal intensity assuming Edwards's periodic model, including maximum likelihood estimation (MLE), least squares, weighted least squares, and a new closed-form estimator based on a second-order moment statistic and non-transformed data. Through an extensive Monte Carlo simulation study, we compare the finite sample performance characteristics of the estimators discussed in this paper. Finally, all estimators and confidence interval procedures discussed are compared in a re-analysis of data on the seasonality of monocytic leukemia. Results: We find that Edwards's estimator is substantially biased, particularly for small numbers of events and very large or small amounts of seasonality. For the common setting of rare events and moderate seasonality, the new estimator proposed in this paper yields less finite sample bias and better mean squared error than either the MLE or weighted least squares. For large studies and strong seasonality, MLE or weighted least squares appears to be the optimal analytic method among those considered. Conclusion: Edwards's estimator of the seasonal relative risk can exhibit substantial finite sample bias. The alternative estimators considered in this paper should be preferred
T lymphocyte responses to flaviviruses — diverse cell populations affect tendency toward protection and disease
Dengue virus (DENV), Yellow Fever virus, West Nile virus, Japanese encephalitis virus and Zika virus are medically important flaviviruses transmitted to humans by mosquitoes and circulate in overlapping geographic areas. Cross-reactive immune responses have been demonstrated among the flaviviruses, particularly the four DENV serotypes. The immunological imprint left by a flavivirus infection can therefore have profound effects on the responses to subsequent infections. In this review we summarize recent research focusing on T cell responses to DENV using clinical samples from prospective cohort studies in Asia. These data suggest that durability of different T cell populations after natural infection or vaccination is an important consideration for the outcome of subsequent flavivirus exposures and we argue for continued investigation in the context of longitudinal cohort studies
A plasmid-based reporter system for live cell imaging of dengue infected cells
Cell culture models are used widely to study the effects of dengue virus (DENV) on host cell function. Current methods of identification of cells infected with an unmodified DENV requires fixation and permeablization of cells to allow DENV-specific antibody staining. This method does not permit imaging of viable cells over time. In this report, a plasmid-based reporter was developed to allow non-destructive identification of DENV-infected cells. The plasmid-based reporter was demonstrated to be broadly applicable to the four DENV serotypes, including low-passaged strains, and was specifically cleaved by the viral protease with minimal interference on viral production. This study reveals the potential for this novel reporter system to advance the studies of virus-host interactions during DENV infection
Analysis of Cell-Mediated Immune Responses in Support of Dengue Vaccine Development Efforts
Dengue vaccine development has made significant strides, but a better understanding of how vaccine-induced immune responses correlate with vaccine efficacy can greatly accelerate development, testing, and deployment as well as ameliorate potential risks and safety concerns. Advances in basic immunology knowledge and techniques have already improved our understanding of cell-mediated immunity of natural dengue virus infection and vaccination. We conclude that the evidence base is adequate to argue for inclusion of assessments of cell-mediated immunity as part of clinical trials of dengue vaccines, although further research to identify useful correlates of protective immunity is needed
Dengue virus induces mitochondrial elongation through impairment of Drp1-triggered mitochondrial fission
Mitochondria are highly dynamic organelles that undergo continuous cycles of fission and fusion to maintain essential cellular functions. An imbalance between these two processes can result in many pathophysiological outcomes. Dengue virus (DENV) interacts with cellular organelles, including mitochondria, to successfully replicate in cells. This study used live-cell imaging and found an increase in mitochondrial length and respiration during DENV infection. The level of mitochondrial fission protein, Dynamin-related protein 1 (Drp1), was decreased on mitochondria during DENV infection, as well as Drp1 phosphorylated on serine 616, which is important for mitochondrial fission. DENV proteins NS4b and NS3 were also associated with subcellular fractions of mitochondria. Induction of fission through uncoupling of mitochondria or overexpression of Drp1 wild-type and Drp1 with a phosphomimetic mutation (S616D) significantly reduced viral replication. These results demonstrate that DENV infection causes an imbalance in mitochondrial dynamics by inhibiting Drp1-triggered mitochondrial fission, which promotes viral replication
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