The alphaviral capsid protein inhibits IRAK1-dependent TLR signaling to promote pathogenesis.

Alphaviruses are positive-sense RNA viruses spread by mosquitos. They can cause a severe multi-joint febrile arthritis or encephalitis resulting in death or life-long cognitive impairments. To date there are no approved antiviral therapeutics or vaccine strategies for the treatment of alphaviruses creating a critical need to better understand the host pathogen interactions of alphaviruses that enable pathogenesis. It is known that alphaviruses evade innate immune responses by shutting down host transcription and translation, but these methods are dependent on viral gene expression and leave a critical time frame during early infection before viral gene expression has begun that the virus can be identified and responded to by host cells. In order to identify potential viral products that could serve to mask the virus during early infection Sindbis virus, a model alphavirus, was tested for the expression of proteins that could interfere with intracellular immune defenses. Through these efforts we discovered that the alphavirus capsid protein (CP) interacts with host Interleukin 1 Receptor Associated Kinase 1 (IRAK1) in order to block Toll-Like Receptor Signaling (TLR). IRAK1 is a key signaling kinase for several pro-inflammatory immune pathways and CP interacting with it provides a possible mechanism of inhibiting detection by host cells. Pursuing this interaction, we discovered that CP from several members of the Alphavirus family are capable of binding IRAK1 and inhibiting IRAK1-dependent TLR signaling. We were able to map the necessary interaction determinates on CP which, when mutated, ablated IRAK1 binding and restored IRAK1-depdent signaling. Host cells infected with this mutant virus increased their expression of IFN-β in vitro, relative to cells infected with wild-type Sindbis virus. The mutant virus was also impaired in an in vivo model of infection where it failed to cause symptoms of alphavirus infection. Collectively these data show a novel interaction between alphavirus CP and host IRAK1 that allows the virus to evade the immune detection during early infection a crucial time when the virus has yet not been able to shut down host transcription and translation. This interaction was also found to be crucial for viral pathogenesis and the absence of it leaves the virus attenuated. The data presented in this dissertation offer insight into a newly observed method Alphavirus uses to evade detection by the innate immune system which could be a potential target for therapeutic intervention as well as a mutant virus that could be a candidate for a live-attenuated vaccine

Hopf algebras and Markov chains: Two examples and a theory

The operation of squaring (coproduct followed by product) in a combinatorial Hopf algebra is shown to induce a Markov chain in natural bases. Chains constructed in this way include widely studied methods of card shuffling, a natural "rock-breaking" process, and Markov chains on simplicial complexes. Many of these chains can be explictly diagonalized using the primitive elements of the algebra and the combinatorics of the free Lie algebra. For card shuffling, this gives an explicit description of the eigenvectors. For rock-breaking, an explicit description of the quasi-stationary distribution and sharp rates to absorption follow.Comment: 51 pages, 17 figures. (Typographical errors corrected. Further fixes will only appear on the version on Amy Pang's website, the arXiv version will not be updated.

Sustainability and professional sales: a review and future research agenda

Sustainability has become a consideration for every firm operating in today’s business landscape. Scholars are tasked with uncovering bridges and barriers to successfully implement sustainability strategies, and the academic community has largely responded. However, while sustainability research has proliferated across business disciplines, it is conspicuously missing from professional selling and sales management. This is partly due to conceptual ambiguity, but also because sustainability generally involves firm-level policies and programs, and therefore domains like consumer behavior, marketing strategy, and supply chain management have occupied the space. This is problematic because while executives develop sustainability strategies, the sales force is responsible for conveying those priorities to external stakeholders. Therefore, the goals of our manuscript are to: 1) organize and refine the definition of sustainability in a professional selling context, 2) review relevant literature that examines sustainability in that context, 3) explore emergent themes from this review that 4) reveal gaps in our understanding, and 5) present a research agenda for sales scholars to bridge these gaps and advance our understanding of the role of sustainability in sales and vice versa

Worst Case Resistance Testing: A Nonresponse Bias Solution for Today's Behavioral Research Realities

This study proposes a method of nonresponse assessment based on meta-analytical file-drawer techniques, also known as worst-case resistance testing (WCRT), and suitable for a wide range of data collection scenarios. A general method is devised to estimate the number of significantly different nonrespondents it would take to significantly alter the results of an analysis. Estimates of nonrespondents can be plotted against effect sizes using "n-curves", with similar interpretation to p-curves or power curves. Variants of the general method are derived for tests of means and correlations. A sample using a well-established survey instrument from previous behavioral research is used to test the method. The results suggest that employing worst-case resistance testing can be used on its own or in conjunction with wave analysis to precisely flag nonresponse risks

Improving universal prenatal screening for human immunodeficiency virus.

OBJECTIVE: To evaluate the effect of implementation of a human immunodeficiency virus (HIV) educational intervention on universal screening for HIV in a prenatal clinic setting. METHODS: In this retrospective cohort study, frequencies of offering and acceptance of HIV testing were compared before and after an educational intervention performed by an HIV-focused nurse. The records of 293 women seeking prenatal care before the intervention and 206 women seeking prenatal care after the intervention were reviewed for offering and acceptance of HIV testing. Fisher's exact test and logistic regression were used to evaluate the relationship between the educational intervention and the offering and acceptance of HIV testing. RESULTS: The frequency of HIV test offering at first visit and test acceptance before the educational intervention were 96.5% and 74.8%, respectively, and after the intervention were 99.5% and 84.3%, respectively. This improvement in offering (3% change) and acceptance (9.5% change) was statistically significant (offering at first visit: OR = 7.27, 95% CI = 1.02 to 316.9; test acceptance: OR = 1.82, 95% CI = 1.14 to 2.88). Test acceptance was statistically significantly improved in the post-intervention group after controlling for confounding variables (OR = 2.02, 95% CI = 1.2 to 3.39). CONCLUSION: The addition of an HIV-focused nurse to a clinic setting improved the frequency of test offering at first visit and of acceptance of HIV testing by pregnant women

High Rate of Severe Fetal Outcomes Associated with Maternal Parvovirus B19 Infection in Pregnancy

Objective. To augment the understanding of parvovirus B19 infection in pregnancy with respect to maternal characteristics and their corresponding fetal outcomes. Study Design. Retrospective case-series of all women referred to Magee-Women_s Hospital with serologically-documented parvovirus B19 infection during pregnancy from 1998–2001. Results. All 25 cases that are available for analysis occurred from January through June. The frequency of cases varied substantially from year to year, with 14 cases in 1998, 0 cases in 1999 and 2000, and 11 cases in 2001. In contrast to previous reports, the minority of women [4/25(16%)] experienced symptoms attributable to parvovirus B-19 infection although 3 of 25 (12%) fetuses developed hydrops fetalis and 4/25 (16%) suffered an intrauterine of fetal death. Conclusions. These findings suggest that parvovirus B19 infection in pregnancy follows seasonal and annual trend variation, may produce a lower frequency of maternal symptoms and a higher fetal loss rate than previously reported. Synopsis. Maternal parvovirus B19 infection follows seasonal and annual variation is often asymptomatic and may have higher fetal loss rates than previously reported. Continued surveillance is warranted