Aedes aegypti Saliva Alters Leukocyte Recruitment and Cytokine Signaling by Antigen-Presenting Cells during West Nile Virus Infection

West Nile virus (WNV) is transmitted during mosquito bloodfeeding. Consequently, the first vertebrate cells to contact WNV are cells in the skin, followed by those in the draining lymph node. Macrophages and dendritic cells are critical early responders in host defense against WNV infection, not just because of their role in orchestrating the immune response, but also because of their importance as sites of early peripheral viral replication. Antigen-presenting cell (APC) signals have a profound effect on host antiviral responses and disease severity. During transmission, WNV is intimately associated with mosquito saliva. Due to the ability of mosquito saliva to affect inflammation and immune responses, and the importance of understanding early events in WNV infection, we investigated whether mosquito saliva alters APC signaling during arbovirus infection, and if alterations in cell recruitment occur when WNV infection is initiated with mosquito saliva. Accordingly, experiments were performed with cultured dendritic cells and macrophages, flow cytometry was used to characterize infiltrating cell types in the skin and lymph nodes during early infection, and real-time RT-PCR was employed to evaluate virus and cytokine levels. Our in vitro results suggest that mosquito saliva significantly decreases the expression of interferon-β and inducible nitric oxide synthase in macrophages (by as much as 50 and 70%, respectively), whilst transiently enhancing interleukin-10 (IL-10) expression. In vivo results indicate that the predominate effect of mosquito feeding is to significantly reduce the recruitment of T cells, leading the inoculation site of mice exposed to WNV alone to have up to 2.8 fold more t cells as mice infected in the presence of mosquito saliva. These shifts in cell population are associated with significantly elevated IL-10 and WNV (up to 4.0 and 10 fold, respectively) in the skin and draining lymph nodes. These results suggest that mosquito saliva dysregulates APC antiviral signaling, and reveal a possible mechanism for the observed enhancement of WNV disease mediated by mosquito saliva via a reduction of T lymphocyte and antiviral activity at the inoculation site, an elevated abundance of susceptible cell types, and a concomitant increase in immunoregulatory activity of IL-10

Tradition and Prudence in Locke's Exceptions to Toleration

Why did Locke exclude Catholics and atheists from toleration? Not, I contend, because he was trapped by his context, but because his prudential approach and practica ljudgments led him to traditiona ltexts. I make this argumentfirst by outlining the connections among prudential exceptionality, practical judgments, and traditional texts. I then describe important continuities betweenc onventional English understandings of the relationship between state and religion and Locke's writings on toleration, discuss Locke's conception of rights, and illustrate his use of prudential exceptions and distinctions. I conclude by arguing that Locke's problems are relevant to assessingc ontemporary liberal discussions of tolerationa nd the separation of state and religion that lean heavily on practical justification

Behavioral sensitivity to interaural time differences in the rabbit

An important cue for sound localization and separation of signals from noise is the interaural time difference (ITD). Humans are able to localize sounds within 1–2° and can detect very small changes in the ITD (10–20 μs). In contrast, many animals localize sounds with less precision than humans. Rabbits, for example, have sound localization thresholds of ~22°. There is only limited information about behavioral ITD discrimination in animals with poor sound localization acuity that are typically used for the neural recordings. For this study, we measured behavioral discrimination of ITDs in the rabbit for a range of reference ITDs from 0 to ± 300 μs. The behavioral task was conditioned avoidance and the stimulus was band-limited noise (500–1500 Hz). Across animals, the average discrimination threshold was 50–60 μs for reference ITDs of 0 to ± 200 μs. There was no trend in the thresholds across this range of reference ITDs. For a reference ITD of ± 300 μs, which is near the limit of the physiological window defined by the head width in this species, the discrimination threshold increased to ~100 μs. The ITD discrimination in rabbits less acute than in cats, which have a similar head size. This result supports the suggestion that ITD discrimination, like sound localization (see Heffner, 1997, Acta Otolaryngol Suppl 532:46–53, 1997) is determined by factors other than head size

Study protocol: a mixed methods study to assess mental health recovery, shared decision-making and quality of life (Plan4Recovery)

BACKGROUND: Recovery in mental health care is complex, highly individual and can be facilitated by a range of professional and non-professional support. In this study we will examine how recovery from mental health problems is promoted in non-medical settings. We hypothesise a relationship between involvement in decisions about care, social support and recovery and quality of life outcomes. METHODS: We will use standardised validated instruments of involvement in decision-making, social contacts, recovery and quality of life with a random sample of people accessing non-statutory mental health social care services in Wales. We will add to this important information with detailed one to one case study interviews with people, their family members and their support workers. We will use a series of these interviews to examine how people build recovery over time to help us understand more about their involvement in decisions and the social links they build. DISCUSSION: We want to see how being involved in decisions about care and the social links people have are related to recovery and quality of life for people with experience of using mental health support services. We want to understand the different perspectives of the people involved in making recovery possible. We will use this information to guide further studies of particular types of social interventions and their use in helping recovery from mental health problems

Seeing the way: visual sociology and the distance runner's perspective

Employing visual and autoethnographic data from a two‐year research project on distance runners, this article seeks to examine the activity of seeing in relation to the activity of distance running. One of its methodological aims is to develop the linkage between visual and autoethnographic data in combining an observation‐based narrative and sociological analysis with photographs. This combination aims to convey to the reader not only some of the specific subcultural knowledge and particular ways of seeing, but also something of the runner's embodied feelings and experience of momentum en route. Via the combination of narrative and photographs we seek a more effective way of communicating just how distance runners see and experience their training terrain. The importance of subjecting mundane everyday practices to detailed sociological analysis has been highlighted by many sociologists, including those of an ethnomethodological perspective. Indeed, without the competence of social actors in accomplishing these mundane, routine understandings and practices, it is argued, there would in fact be no social order

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection

Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4)

BACKGROUND: α-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of α-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of α-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge. The S4 is a multicenter, cross-sectional, observational study evaluating α-synuclein in multiple tissues and biofluids in PD and healthy controls (HC). OBJECTIVE: To describe the baseline characteristics of the S4 cohort and safety and feasibility of this study. METHODS: Participants underwent motor and non-motor clinical assessments, dopamine transporter SPECT, biofluid collection (cerebrospinal fluid, saliva, and blood), and tissue biopsies (skin, sigmoid colon, and submandibular gland). Biopsy adequacy was determined based on presence of adequate target tissue. Tissue sections were stained with the 5C12 monoclonal antibody against unmodified α-synuclein. All specimens were acquired and processed in a standardized manner. Adverse events were systematically recorded. RESULTS: The final cohort consists of 82 participants (61 PD, 21 HC). In 68 subjects (83%), all types of specimens were obtained but only 50 (61%) of subjects had all specimens both collected and evaluable for α-synuclein. Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred. CONCLUSION: Multicenter tissue and biofluid sampling for α-synuclein is feasible and generally safe. S4 will inform understanding of the concurrent distribution of α-synuclein pathology and biomarkers in biofluids and peripheral nervous system in PD

Coactivator condensation at super-enhancers links phase separation and gene control

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes.National Institutes of Health (U.S.) (Grant GM123511)National Institutes of Health (U.S.) (Grant P01-CA042063)National Science Foundation (U.S.) (Grant PHY-1743900)National Cancer Institute (U.S.) (Grant P30-CA14051