Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models

Correlations Between Life-Detection Techniques and Implications for Sampling Site Selection in Planetary Analog Missions

We conducted an analog sampling expedition under simulated mission constraints to areas dominated by basaltic tephra of the Eldfell and Fimmvorouhals lava fields (Iceland). Sites were selected to be homogeneous at a coarse remote sensing resolution (10-100m) in apparent color, morphology, moisture, and grain size, with best-effort realism in numbers of locations and replicates. Three different biomarker assays (counting of nucleic-acid-stained cells via fluorescent microscopy, a luciferin/luciferase assay for adenosine triphosphate, and quantitative polymerase chain reaction (qPCR) to detect DNA associated with bacteria, archaea, and fungi) were characterized at four nested spatial scales (1m, 10m, 100m, and >1km) by using five common metrics for sample site representativeness (sample mean variance, group F tests, pairwise t tests, and the distribution-free rank sum H and u tests). Correlations between all assays were characterized with Spearman's rank test. The bioluminescence assay showed the most variance across the sites, followed by qPCR for bacterial and archaeal DNA; these results could not be considered representative at the finest resolution tested (1m). Cell concentration and fungal DNA also had significant local variation, but they were homogeneous over scales of >1km. These results show that the selection of life detection assays and the number, distribution, and location of sampling sites in a low biomass environment with limited a priori characterization can yield both contrasting and complementary results, and that their interdependence must be given due consideration to maximize science return in future biomarker sampling expeditions. Key Words: AstrobiologyBiodiversityMicrobiologyIcelandPlanetary explorationMars mission simulationBiomarker. Astrobiology 17, 1009-1021

Genetic Inactivation of Trpml3 Does Not Lead to Hearing and Vestibular Impairment in Mice

TRPML3, a member of the transient receptor potential (TRP) family, is an inwardly rectifying, non-selective Ca2+-permeable cation channel that is regulated by extracytosolic Na+ and H+ and can be activated by a variety of small molecules. The severe auditory and vestibular phenotype of the TRPML3(A419P) varitint-waddler mutation made this protein particularly interesting for inner ear biology. To elucidate the physiological role of murine TRPML3, we conditionally inactivated Trpml3 in mice. Surprisingly, lack of functional TRPML3 did not lead to circling behavior, balance impairment or hearing loss

Family Physicians’ Attitudes and Practices Regarding Assessments of Medical Fitness to Drive in Older Persons

BACKGROUND: Higher crash rates per mile driven in older drivers have focused attention on the assessment of older drivers. OBJECTIVE: To examine the attitudes and practices of family physicians regarding fitness-to-drive issues in older persons. DESIGN: Survey questionnaire. PARTICIPANTS: The questionnaire was sent to 1,000 randomly selected Canadian family physicians. Four hundred sixty eligible physicians returned completed questionnaires. MEASUREMENTS: Self-reported attitudes and practices towards driving assessments and the reporting of medically unsafe drivers. RESULTS: Over 45% of physicians are not confident in assessing driving fitness and do not consider themselves to be the most qualified professionals to do so. The majority (88.6%) feel that they would benefit from further education in this area. About 75% feel that reporting a patient as an unsafe driver places them in a conflict of interest and negatively impacts on the patient and the physician–patient relationship. Nevertheless, most (72.4%) agree that physicians should be legally responsible for reporting unsafe drivers to the licensing authorities. Physicians from provinces with mandatory versus discretionary reporting requirements are more likely to report unsafe drivers (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.58 to 4.91), but less likely to perform driving assessments (OR, 0.58; 95% CI, 0.39 to 0.85). Most driving assessments take between 10 and 30 minutes, with much variability in the components included. CONCLUSIONS: Family physicians lack confidence in performing driving assessments and note many negative consequences of reporting unsafe drivers. Education about assessing driving fitness and approaches that protect the physician–patient relationship when reporting occurs are needed

Leukocyte Tyrosine Kinase Functions in Pigment Cell Development

A fundamental problem in developmental biology concerns how multipotent precursors choose specific fates. Neural crest cells (NCCs) are multipotent, yet the mechanisms driving specific fate choices remain incompletely understood. Sox10 is required for specification of neural cells and melanocytes from NCCs. Like sox10 mutants, zebrafish shady mutants lack iridophores; we have proposed that sox10 and shady are required for iridophore specification from NCCs. We show using diverse approaches that shady encodes zebrafish leukocyte tyrosine kinase (Ltk). Cell transplantation studies show that Ltk acts cell-autonomously within the iridophore lineage. Consistent with this, ltk is expressed in a subset of NCCs, before becoming restricted to the iridophore lineage. Marker analysis reveals a primary defect in iridophore specification in ltk mutants. We saw no evidence for a fate-shift of neural crest cells into other pigment cell fates and some NCCs were subsequently lost by apoptosis. These features are also characteristic of the neural crest cell phenotype in sox10 mutants, leading us to examine iridophores in sox10 mutants. As expected, sox10 mutants largely lacked iridophore markers at late stages. In addition, sox10 mutants unexpectedly showed more ltk-expressing cells than wild-type siblings. These cells remained in a premigratory position and expressed sox10 but not the earliest neural crest markers and may represent multipotent, but partially-restricted, progenitors. In summary, we have discovered a novel signalling pathway in NCC development and demonstrate fate specification of iridophores as the first identified role for Ltk

Attention-deficit/hyperactivity disorder (ADHD) symptoms and academic entrepreneurial preference: is there an association?

Although commercialization of research activities has drawn some research attention, more studies are warranted to clearly understand the drivers behind academic entrepreneurship. The present paper investigates the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and academic entrepreneurial preference. ADHD symptoms have typically been associated with impaired occupational functioning among wage employees. Recent studies, however, indicate that the same symptoms of ADHD that are a liability for wage employees may work out differently for entrepreneurs. Building on previous studies that link ADHD symptoms to entrepreneurship, and using the theoretical lens of person-environment fit, we hypothesize that ADHD symptoms (at the so-called subclinical level) are associated with academic entrepreneurial preference. Results of our data from academic researchers in France, Spain, and Italy (N = 534) show that there is a negative association between attention-deficit symptoms and academic entrepreneurial preference. However, there is no link between hyperactivity symptoms and academic entrepreneurial preference

Corporate reputation past and future: a review and integration of existing literature and a framework for future research

The concept of corporate reputation is steadily growing in interest among management researchers and practitioners. In this article, we trace key milestones in the development of reputation literature over the past six decades to suggest important research gaps as well as to provide contextual background for a subsequent integration of approaches and future outlook. In particular we explore the need for better categorised outcomes; a wider range of causes; and a deeper understanding of contingencies and moderators to advance the field beyond its current state while also taking account of developments in the macro business environment. The article concludes by presenting a novel reputation framework that integrates insights from reputation theory and studies, outlines gaps in knowledge and offers directions for future research