All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

αV Integrin Induces Multicellular Radioresistance in Human Nasopharyngeal Carcinoma via Activating SAPK/JNK Pathway

BACKGROUND:Tumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell-matrix and cell-cell crosstalk. Integrins are the most important cell adhesion molecules, in which αV integrin mainly mediating the tight contact between tumor cells. METHODOLOGY/PRINCIPAL FINDINGS:To investigate the role of αV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of αV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of αV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic survival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of αV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of αV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with αV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts. CONCLUSIONS:Our results indicate a novel role of αV integrin in multi-cellular radioresistance of NPCs

When fast logic meets slow belief: Evidence for a parallel-processing model of belief bias.

Two experiments pitted the default-interventionist account of belief bias against a parallel-processing model. According to the former, belief bias occurs because a fast, belief-based evaluation of the conclusion pre-empts a working-memory demanding logical analysis. In contrast, according to the latter both belief-based and logic-based responding occur in parallel. Participants were given deductive reasoning problems of variable complexity and instructed to decide whether the conclusion was valid on half the trials or to decide whether the conclusion was believable on the other half. When belief and logic conflict, the default-interventionist view predicts that it should take less time to respond on the basis of belief than logic, and that the believability of a conclusion should interfere with judgments of validity, but not the reverse. The parallel-processing view predicts that beliefs should interfere with logic judgments only if the processing required to evaluate the logical structure exceeds that required to evaluate the knowledge necessary to make a belief-based judgment, and vice versa otherwise. Consistent with this latter view, for the simplest reasoning problems (modus ponens), judgments of belief resulted in lower accuracy than judgments of validity, and believability interfered more with judgments of validity than the converse. For problems of moderate complexity (modus tollens and single-model syllogisms), the interference was symmetrical, in that validity interfered with belief judgments to the same degree that believability interfered with validity judgments. For the most complex (three-term multiple-model syllogisms), conclusion believability interfered more with judgments of validity than vice versa, in spite of the significant interference from conclusion validity on judgments of belief

Adaptation of mammalian host-pathogen interactions in a changing arctic environment

Many arctic mammals are adapted to live year-round in extreme environments with low winter temperatures and great seasonal variations in key variables (e.g. sunlight, food, temperature, moisture). The interaction between hosts and pathogens in high northern latitudes is not very well understood with respect to intra-annual cycles (seasons). The annual cycles of interacting pathogen and host biology is regulated in part by highly synchronized temperature and photoperiod changes during seasonal transitions (e.g., freezeup and breakup). With a warming climate, only one of these key biological cues will undergo drastic changes, while the other will remain fixed. This uncoupling can theoretically have drastic consequences on host-pathogen interactions. These poorly understood cues together with a changing climate by itself will challenge host populations that are adapted to pathogens under the historic and current climate regime. We will review adaptations of both host and pathogens to the extreme conditions at high latitudes and explore some potential consequences of rapid changes in the Arctic

Comparative Study on the Therapeutic Potential of Neurally Differentiated Stem Cells in a Mouse Model of Multiple Sclerosis

Background: Transplantation of neural stem cells (NSCs) is a promising novel approach to the treatment of neuroinflammatory diseases such as multiple sclerosis (MS). NSCs can be derived from primary central nervous system (CNS) tissue or obtained by neural differentiation of embryonic stem (ES) cells, the latter having the advantage of readily providing an unlimited number of cells for therapeutic purposes. Using a mouse model of MS, we evaluated the therapeutic potential of NSCs derived from ES cells by two different neural differentiation protocols that utilized adherent culture conditions and compared their effect to primary NSCs derived from the subventricular zone (SVZ). Methodology/Principal Findings: The proliferation and secretion of pro-inflammatory cytokines by antigen-stimulated splenocytes was reduced in the presence of SVZ-NSCs, while ES cell-derived NSCs exerted differential immunosuppressive effects. Surprisingly, intravenously injected NSCs displayed no significant therapeutic impact on clinical and pathological disease outcomes in mice with experimental autoimmune encephalomyelitis (EAE) induced by recombinant myelin oligodendrocyte glycoprotein, independent of the cell source. Studies tracking the biodistribution of transplanted ES cellderived NSCs revealed that these cells were unable to traffic to the CNS or peripheral lymphoid tissues, consistent with the lack of cell surface homing molecules. Attenuation of peripheral immune responses could only be achieved through multiple high doses of NSCs administered intraperitoneally, which led to some neuroprotective effects within the CNS

Environmental effects and individual body condition drive seasonal fecundity of rabbits: identifying acute and lagged processes

The reproduction of many species is determined by seasonally-driven resource supply. But it is difficult to quantify whether the fecundity is sensitive to short- or long-term exposure to environmental conditions such as rainfall that drive resource supply. Using 25 years of data on individual fecundity of European female rabbits, Oryctolagus cuniculus, from semiarid Australia, we investigate the role of individual body condition, rainfall and temperature as drivers of seasonal and long-term and population-level changes in fecundity (breeding probability, ovulation rate, embryo survival). We built distributed lag models in a hierarchical Bayesian framework to account for both immediate and time-lagged effects of climate and other environmental drivers, and possible shifts in reproduction over consecutive seasons. We show that rainfall during summer, when rabbits typically breed only rarely, increased breeding probability immediately and with time lags of up to 10 weeks. However, an earlier onset of the yearly breeding period did not result in more overall reproductive output. Better body condition was associated with an earlier onset of breeding and higher embryo survival. Breeding probability in the main breeding season declined with increased breeding activity in the preceding season and only individuals in good body condition were able to breed late in the season. Higher temperatures reduce breeding success across seasons. We conclude that a better understanding of seasonal dynamics and plasticity (and their interplay) in reproduction will provide crucial insights into how lagomorphs are likely to respond and potentially adapt to the influence of future climate and other environmental change.Konstans Wells, Robert B. O’Hara, Brian D. Cooke, Greg J. Mutze, Thomas A.A. Prowse, Damien A. Fordha

Studies on chronic versus transient intestinal nematode infections in mice I. A comparison of responses to excretory/secretory (ES) products of Nippostrongylus brasilinesis and Nematospiroides dubius worms

Summary Previous reports have demonstrated that after implantation of intestinal worms or after exposure to infective third stage larvae, the duration of infection with Nematospiroides dubius is markedly prolonged in intact mice relative to infection with Nippostrongylus brasiliensis. The rapid rejection of N. brasiliensis adults appears T‐cell dependent in that adults persist for longer periods in hypothymic nude mice than in intact mice. Excretory/secretory (ES) products harvested from N. dubius or N. brasiliensis intestinal worms did not differ obviously in the following characteristics: rate of production and degree of complexity of proteins, in vitro mitogenicity, allergenicity, or in their abilities to induce or elicit delayed type hypersensitivity reactions in naive and infected mice, respectively. Two differences between N. brasiliensis‐ and N. dubius‐infected mice were an IgG1 hypergammaglobulinaemia and readily detected anti‐ES precipitating antibodies in the circulation; both responses were confined to the chronic N. dubius infection. One difference between N. brasiliensis and N. dubius ES products was that the former, but not the latter, induced protection against homologous infection when injected with Freund's complete adjuvant. By contrast, intraperitoneal implantation of either type of adult worm induced protection against homologous infection at least in female Balb/c mice. After intestinal implantation of both N. dubius and N. brasiliensis intestinal worms, the rejection of N. brasiliensis was not influenced by, nor did it alter, persistence of N. dubius adults. In support of conclusions drawn by others, the differences in persistence of infection between these two nematodes probably reflect differences in the ability to resist both specific and nonspecific components of the complex intestinal rejection process. The chronicity of N. dubius infection and nonpersistence of N. brasiliensis