The impact of ADAM17 inhibition on L-selectin in murine influenza virus infection

L-selectin (CD62L) is a homing molecule on leucocytes. Previously, Lselectin maintenance on CD8 cytotoxic T lymphocytes (CTLs) improved homing to sites of virus infection and subsequent viral clearance in mouse models of influenza A virus (IAV) infection. This finding led us to believe that L-selectin could be a therapeutic target in viral infection. There are currently no pharmacological agents available which directly block the cleavage of Lselectin, however, ‘A disintegrin and metalloproteinase 17’ (ADAM17) proteolytically cleaves L-selectin from the cell surface. Anti-ADAM17 antibodies were tested for their ability to block shedding of L-selectin in CD8 T cells in vitro, and candidate A9(B8) was chosen to take forward to mouse studies with a 50% maximal inhibitory concentration (IC50) of >261 nM for L-selectin shedding. 10 mg/kg of A9(B8) did not reduce X31 IAV burden in mice over a 7-day infection. 15 mg/kg of A9(B8) was only able to block L-selectin shedding in vivo 6 hours post-administration; this was diminished by 4 days. Transgenic ADAM17 inhibition was then tested in vivo for effects on X31 IAV virus clearance using ADAM17-/- and ADAM17+/+ chimeric mice. Whilst L-selectin was maintained on the cell surface of ADAM17-/- CD8 T cells, these mice did not have reduced X31 titres 5 days post-infection. This timepoint may be too early to investigate T celldependent virus clearance and requires further investigation. Furthermore, ADAM17 chimeras revealed a novel role for ADAM17 in homeostatic shedding of L-selectin in B cells, but not T cells. Further in vitro studies showed that A9(B8) was less effective at blocking L-selectin shedding from B cells than T cells. However, A9(B8) was more effective at blocking TNF-a shedding with an IC50 of >75 nM. Together, these studies demonstrate that the proteolytic activity of ADAM17 is differentially controlled in T and B cells and is substrate dependent

Immune responses to IAV infection and the roles of L-selectin and ADAM17 in lymphocyte homing

Influenza A virus (IAV) infection is a global public health burden causing up to 650,000 deaths per year. Yearly vaccination programmes and anti-viral drugs currently have limited benefits; therefore, research into IAV is fundamental. Leukocyte trafficking is a crucial process which orchestrates the immune response to infection to protect the host. It involves several homing molecules and receptors on both blood vessels and leukocytes. A key mediator of this process is the transmembrane glycoprotein L-selectin, which binds to vascular addressins on blood vessel endothelial cells. L-selectin classically mediates homing of naïve and central memory lymphocytes to lymph nodes via high endothelial venules (HEVs). Recent studies have found that L-selectin is essential for homing of activated CD8+ T cells to influenza-infected lungs and reduction in virus load. A disintegrin and metalloproteinase 17 (ADAM17) is the primary regulator of cell surface levels of L-selectin. Understanding the mechanisms that regulate these two proteins are central to comprehending recruitment of T cells to sites of IAV infection. This review summarises the immune response to IAV infection in humans and mice and discusses the roles of L-selectin and ADAM17 in T lymphocyte homing during IAV infectio

The Impact of Cultural Symbols and Spokesperson Identity on Attitudes and Intentions

In today’s multicultural societies, ethnic targeting is increasingly important for marketing. Two main approaches to target ethnic minorities have emerged: messaging consumers when their ethnic identity is most salient, and featuring spokespeople who have the same heritage as the target. We conduct replications of two articles representative of these research streams: Forehand and Deshpandé (2001) and Deshpandé and Stayman (1994). Our findings identify generational status as an important boundary condition for these ethnic targeting strategies

Anthropological Study of Shain Library: Uses, Perceptions, and Recommendations

In the spring of 2009 professor Benoit’s Applied Anthropology class conducted a comprehensive study on Connecticut College’s Shain Library. The class met with the library staff multiple times before deciding how to tackle the project. The research question posed was, how do students use and perceive the library? Does the library satisfy student’s needs, and if not what changes could be implemented to better the student body? The class began by submitting a proposal of our project to the Institutional Review Board, and then proceeded with the investigation. Though the topic as a whole is an examination of Shain Library each member of the class took on a specific aspects of the research. The topics covered range from study habits such as multitasking to how students utilize library resources outside of the library. The class created a DVD of their research and presented their findings to the library staff. This is the complete report of the research to compliment the DVD presentation

New constraints on Lyman-α opacity with a sample of 62 quasars at z > 5.7

We present measurements of the mean and scatter of the IGM Lyman-{\alpha} opacity at 4.9 5.7, the largest sample assembled at these redshifts to date by a factor of two. The sample size enables us to sample cosmic variance at these redshifts more robustly than ever before. The spectra used here were obtained by the SDSS, DES-VHS and SHELLQs collaborations, drawn from the ESI and X-Shooter archives, reused from previous studies or observed specifically for this work. We measure the effective optical depth of Lyman-{\alpha} in bins of 10, 30, 50 and 70 cMpc h-1, construct cumulative distribution functions under two treatments of upper limits on flux and explore an empirical analytic fit to residual Lyman-{\alpha} transmission. We verify the consistency of our results with those of previous studies via bootstrap re-sampling and confirm the existence of tails towards high values in the opacity distributions, which may persist down to z = 5.2. Comparing our results with predictions from cosmological simulations, we find further strong evidence against models that include a spatially uniform ionizing background and temperature-density relation. We also compare to IGM models that include either a fluctuating UVB dominated by rare quasars or temperature fluctuations due to patchy reionization. Although both models produce better agreement with the observations, neither fully captures the observed scatter in IGM opacity. Our sample of 62 z > 5.7 quasar spectra opens many avenues for future study of the reionisation epoch

Spreading the Good News: Analyzing Socially Shared Inspirational News Content

Past research indicates that people often share awe-inspiring news online. However, little is known about the content of those stories. In this study, more broadly defined “inspirational” articles shared through The New York Times website over a 6-month period were analyzed, with the goals of describing the content and identifying characteristics that might predict inspirationality and measures of retransmission. The results provided a snapshot of content found within inspirational news stories; they also revealed that self-transcendent language use predicted the inspirationality of a news story, as well as how long an article appeared on a most shared list

Moderate threat causes longer lasting disruption to processing in anxious individuals

Anxiety is associated with increased attentional capture by threat. Previous studies have used simultaneous or briefly separated (<1 s) presentation of threat distractors and target stimuli. Here, we tested the hypothesis that high trait anxious participants would show a longer time window within which distractors cause disruption to subsequent task processing, and that this would particularly be observed for stimuli of moderate or ambiguous threat value. A novel temporally separated emotional distractor task was used. Face or house distractors were presented for 250 ms at short (∼1.6 s) or long (∼3 s) intervals prior to a letter string comprising Xs or Ns. Trait anxiety was associated with slowed identification of letter strings presented at long intervals after face distractors with part surprise/part fear expressions. In other words, these distractors had an impact on high anxious individuals' speed of target identification seconds after their offset. This was associated with increased activity in the fusiform gyrus and amygdala and reduced dorsal anterior cingulate recruitment. This pattern of activity may reflect impoverished recruitment of reactive control mechanisms to damp down stimulus-specific processing in subcortical and higher visual regions. These findings have implications for understanding how threat-related attentional biases in anxiety may lead to dysfunction in everyday settings where stimuli of moderate, potentially ambiguous, threat value such as those used here are fairly common, and where attentional disruption lasting several seconds may have a profound impact