Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed

Analysing a mechanism of failure in retrieved magnetically controlled spinal rods

PURPOSE: We aim to describe a mechanism of failure in magnetically controlled growth rods which are used for the correction of the early onset scoliosis. METHODS: This retrieval study involved nine magnetically controlled growth rods, of a single design, revised from five patients for metal staining, progression of scoliosis, swelling, fractured actuator pin, and final fusion. All the retrieved rods were radiographed and assessed macroscopically and microscopically for material loss. Two implants were further analysed using micro-CT scanning and then sectioned to allow examination of the internal mechanism. No funding was obtained to analyse these implants. There were no potential conflicts interests. RESULTS: Plain radiographs revealed that three out of nine retrieved rods had a fractured pin. All had evidence of surface degradation on the extendable telescopic rod. There was considerable corrosion along the internal mechanism. CONCLUSIONS: We found that a third of the retrieved magnetically controlled growth rods had failed due to pin fracture secondary to corrosion of the internal mechanism. We recommend that surgeons consider that any inability of magnetically controlled growth rods to distract may be due to corrosive debris building up inside the mechanism, thereby preventing normal function

Identification of Native Defects (Vacancies and Antisites) in CdSiP2 Crystals

Electron paramagnetic resonance (EPR) is used to identify four native defects in single crystals of CdSiP2. This nonlinear optical material is used in optical parametric oscillators to generate tunable output in the mid-infrared. The performance of these frequency-conversion devices is limited when infrared absorption bands associated with native defects overlap a pump wavelength. Cadmium, silicon, and phosphorus vacancies and also silicon-on-cadmium antisites are present in the as-grown undoped CdSiP2 crystals. Using near-band-edge 632.8 nm light from a He-Ne laser, a paramagnetic charge state, and thus an EPR spectrum, is formed at liquid-helium temperatures for three of the four defects. The EPR spectrum from the singly ionized silicon vacancy (V-Si) is present without light and has five hyperfine lines due to equal interactions with the four neighboring 31P nuclei. In contrast, the photoinduced EPR spectrum from the singly ionized cadmium vacancy (V-Cd) has a three-line hyperfine pattern due to equal interactions with only two of its four neighboring 31P nuclei. The light-induced spectrum from the singly ionized silicon-on-cadmium antisite (Si+Cd) also has a three-line hyperfine pattern, thus indicating that the unpaired spin interacts primarily with only two 31P neighbors. For the neutral phosphorus vacancy (V0P), the unpaired spin is primarily localized on the nearest-neighbor silicon ions and the photoinduced EPR spectrum has no resolved 31P hyperfine interactions. The silicon and cadmium vacancies are acceptors, and the silicon-on-cadmium antisite and the phosphorus vacancy are donors

The evolution and ecology of land ownership

Land ownership norms play a central role in social-ecological systems, and have been studied extensively as a component of ethnographies. Yet only recently has the distribution of land ownership norms across cultures been examined from evolutionary and ecological perspectives. Here we incorporate evolutionary and macroecological modelling to test associations between land ownership norms and environmental, subsistence, and cultural contact predictors for societies in the Bantu language family. We find that Bantu land ownership norms likely evolved on a unilinear trajectory, but not necessarily one requiring consistent increase in exclusivity as suggested by prior theory. Our macroecological analyses suggest that Bantu societies are more likely to have some form of ownership when their neighbors also do. We also find an effect of environmental productivity, supporting resource defensibility theory, which posits that land ownership is more likely where productivity is predictable. We find less support for a proposed link between agricultural intensification and land ownership. Overall, we demonstrate the value of combining analytical approaches from evolution and ecology to test diverse hypotheses on land ownership across a range of disciplines.1. Introduction 2. Materials and methods 2.1 Data 2.2 Phylogenetic analyses of evolution of land ownership 2.3 Multi-model inference of drivers of spatial patterns in land ownership 3. Results 3.1 Evolutionary trajectories of land ownership 3.2 Drivers of spatial variation in land ownership 4. Discussio

Pathways to social inequality

Social inequality is now pervasive in human societies, despite the fact that humans lived in relatively egalitarian, small-scale societies across most of our history. Prior literature highlights the importance of environmental conditions, economic defensibility, and wealth transmission for shaping early Holocene origins of social inequality. However, it remains untested whether the mechanisms that drive the evolution of inequality in recent human societies follow a similar trajectory. We conduct the first global analysis of pathways to inequality within modern human societies using structural equation modeling. Our analytical approach demonstrates that environmental conditions, resource intensification, and wealth transmission mechanisms impact various forms of social inequality via a complex web of causality. We further find that subsistence practices have a direct impact on some institutionalized forms of inequality. This work identifies drivers of social inequality in the modern world and demonstrates the application of structural equation modeling methods to investigate complex relationships between elements of human culture

Pathways to social inequality

Social inequality is now pervasive in human societies, despite the fact that humans lived in relatively egalitarian, small-scale societies across most of our history. Prior literature highlights the importance of environmental conditions, economic defensibility, and wealth transmission for shaping early Holocene origins of social inequality. However, it remains untested whether the mechanisms that drive the evolution of inequality in recent human societies follow a similar trajectory. We conduct the first global analysis of pathways to inequality within modern human societies using structural equation modeling. Our analytical approach demonstrates that environmental conditions, resource intensification, and wealth transmission mechanisms impact various forms of social inequality via a complex web of causality. We further find that subsistence practices have a direct impact on some institutionalized forms of inequality. This work identifies drivers of social inequality in the modern world and demonstrates the application of structural equation modeling methods to investigate complex relationships between elements of human culture

Conventional PCR primers for the detection of grapevine pathogens disseminated by propagating material

Polymerase chain reaction driven by sequence specific primers has become the most widely used diagnostic method to detect andidentify plant pathogens. The sensitive and cost-effective pathogen detection is exceptionally important in the production of propagatingmaterial. In this paper we have collected primer sequence data from the literature for the detection of the most important grapevine pathogensdisseminated by propagating stocks by conventional polymerase chain reaction. Basic protocols to obtain template nucleic acids have alsobeen briefly rewieved

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Non-invasive detection of ischemic vascular damage in a pig model of liver donation after circulatory death

Background and Aims: Liver graft quality is evaluated by visual inspection prior to transplantation, a process highly dependent on the surgeon's experience. We present an objective, noninvasive, quantitative way of assessing liver quality in real time using Raman spectroscopy, a laser-based tool for analyzing biomolecular composition. Approach and Results: A porcine model of donation after circulatory death (DCD) with normothermic regional perfusion (NRP) allowed assessment of liver quality premortem, during warm ischemia (WI) and post-NRP. Ten percent of circulating blood volume was removed in half of experiments to simulate blood recovery for DCD heart removal. Left median lobe biopsies were obtained before circulatory arrest, after 45 minutes of WI, and after 2 hours of NRP and analyzed using spontaneous Raman spectroscopy, stimulated Raman spectroscopy (SRS), and staining. Measurements were also taken in situ from the porcine liver using a handheld Raman spectrometer at these time points from left median and right lateral lobes. Raman microspectroscopy detected congestion during WI by measurement of the intrinsic Raman signal of hemoglobin in red blood cells (RBCs), eliminating the need for exogenous labels. Critically, this microvascular damage was not observed during WI when 10% of circulating blood was removed before cardiac arrest. Two hours of NRP effectively cleared RBCs from congested livers. Intact RBCs were visualized rapidly at high resolution using SRS. Optical properties of ischemic livers were significantly different from preischemic and post-NRP livers as measured using a handheld Raman spectrometer. Conclusions: Raman spectroscopy is an effective tool for detecting microvascular damage which could assist the decision to use marginal livers for transplantation. Reducing the volume of circulating blood before circulatory arrest in DCD may help reduce microvascular damage