Effect of Extracellular Survivin and Lymphoma Exosomes on Natural Killer Cells

Tumors alter their microenvironment to promote survival using methods such as angiogenesis promotion, growth signals, and immune suppression. The immune system becomes unresponsive to transformed neoplastic cells through a variety of methods including T cell suppression, increased myeloid-derived suppressor cells (MDSCs), and reduced natural killer (NK) cell activity. NK cells have inherent killing capabilities and thus are among the first responders in recognizing and destroying abnormal cells. However, many types of cancers inhibit the surveillance and cytotoxic abilities of NK cells by releasing exosomes, vesicles that can modulate the tumor microenvironment (TME) and intercellular communication for the purpose of enhancing tumor malignancy. These 30-150 nm sized lipid bound vesicles are secreted by many cell types, including immune cells and tumor cells, and the specific protein, lipid, mRNA and miRNA contents contribute to the complex intercellular communication occurring between malignant and normal cells. Cancer patients often have increased numbers of exosomes circulating through their body, including patients with hematological malignancies, such as lymphoma. The focus of this research was to determine the interactions between B cell lymphoma exosomes and NK cells, and characterize the resultant effects on NK cell function. A specific objective of this research was to determine whether Survivin, an Inhibitor of Apoptosis protein recently found to be localized within exosomes, has a role in modulating NK cells similar to previous findings of T cell modulations. We report that lymphoma exosomes have low levels of internalization into NK cells, and no detectable presence of immune modulating proteins MICA/B or TGF-β. Exposure of NK cells to lymphoma exosomes did not result in observable changes in degranulation or cytotoxic ability. However, treatment with recombinant Survivin protein was able to decrease NKG2D receptor levels in NK cells stimulated with target cells, and decrease protein levels of TNF-α, IFN-γ, perforin, and Granzyme B. A better understanding of the underlying processes by which Survivin or exosomes suppress immune cells in the TME may pave the way to more efficacious immunological therapies against cancer

Colonization of malaria vectors under semi-field conditions as a strategy for maintaining genetic and phenotypic similarity with wild populations

Background Malaria still accounts for an estimated 207 million cases and 627,000 deaths worldwide each year. One proposed approach to complement existing malaria control methods is the release of genetically-modified (GM) and/or sterile male mosquitoes. As opposed to laboratory colonization, this requires realistic semi field systems to produce males that can compete for females in nature. This study investigated whether the establishment of a colony of the vector Anopheles arabiensis under more natural semi-field conditions can maintain higher levels of genetic diversity than achieved by laboratory colonization using traditional methods.<p></p> Methods Wild females of the African malaria vector An. arabiensis were collected from a village in southern Tanzania and used to establish new colonies under different conditions at the Ifakara Health Institute. Levels of genetic diversity and inbreeding were monitored in colonies of An. arabiensis that were simultaneously established in small cage colonies in the SFS and in a large semi-field (SFS) cage and compared with that observed in the original founder population. Phenotypic traits that determine their fitness (body size and energetic reserves) were measured at 10th generation and compared to founder wild population.<p></p> Results In contrast to small cage colonies, the SFS population of An. arabiensis exhibited a higher degree of similarity to the founding field population through time in several ways: (i) the SFS colony maintained a significantly higher level of genetic variation than small cage colonies, (ii) the SFS colony had a lower degree of inbreeding than small cage colonies, and (iii) the mean and range of mosquito body size in the SFS colony was closer to that of the founding wild population than that of small cage colonies. Small cage colonies had significantly lower lipids and higher glycogen abundances than SFS and wild population.<p></p> Conclusions Colonization of An. arabiensis under semi-field conditions was associated with the retention of a higher degree of genetic diversity, reduced inbreeding and greater phenotypic similarity to the founding wild population than observed in small cage colonies. Thus, mosquitoes from such semi-field populations are expected to provide more realistic representation of mosquito ecology and physiology than those from small cage colonies.<p></p&gt

Clarification of anomalies in the application of a 2La molecular karyotyping method for the malaria vector Anopheles gambiae

BACKGROUND:Chromosomal inversions have been considered to be potentially important barriers to gene flow in many groups of animals through their effect on recombination suppression in heterokaryotypic individuals. Inversions can also enhance local adaptation in different groups of organisms and may often represent species-specific differences among closely related taxa. We conducted a study to characterize the 2La inversion karyotypes of An. gambiae sensu stricto mosquitoes sampled from the Kilombero Valley (Tanzania) using a newly designed PCR assay.RESULTS:We frequently encountered a (687 bp) fragment which was only present in the Kilombero Valley populations. Laboratory crossing between An. gambiae s.s. from Njage (Tanzania) and Kisumu (Western Kenya) populations resulted in F1 offspring carrying the observed fragment. Karyotype analysis did not indicate differences in 2La region chromosome morphology between individuals carrying the PCR fragments, the 207 bp fragment, or the 687 bp fragement.CONCLUSION:The observed insertion/deletion polymorphism within the region amplified by the 2La PCR diagnostic test may confound the interpretation of this assay and should be well considered in order to maintain an acceptable level of reliability in studies using this assay to describe the distribution and frequency of the 2La inversion among natural populations of An. gambiae s.

Perspective influences eye movements during real-life conversation: Mentalising about self versus others in autism

Socio-communication is profoundly impaired among autistic individuals. Difficulties representing others’ mental states have been linked to modulations of gaze and speech, which have also been shown to be impaired in autism. Despite these observed impairments in ‘real-world’ communicative settings, research has mostly focused on lab-based experiments, where the language is highly structured. In a pre-registered experiment, we recorded eye movements and verbal responses while adults (N=50) engaged in a real-life conversation. Using a novel approach, we also manipulated the perspective that participants adopted by asking them questions that were related to the self, a familiar other, or an unfamiliar other. Results replicated previous work, showing reduced attention to socially-relevant information among autistic participants (i.e. less time looking at the experimenter’s face, and more time looking around the background), compared to typically-developing controls. Importantly, perspective modulated social attention in both groups; talking about an unfamiliar other reduced attention to potentially distracting or resource-demanding social information, and increased looks to non-social background. Social attention did not differ between self and familiar other contexts, reflecting greater shared knowledge for familiar/similar others. Autistic participants spent more time looking at the background when talking about an unfamiliar other vs. themselves. Future research should investigate the developmental trajectory of this effect and the cognitive mechanisms underlying it

Information retention and overload in first-time hearing aid users: an interactive multimedia educational solution

Purpose: An educational intervention to improve knowledge of hearing aids and communication in first-time hearing aid users was assessed. This intervention was based on the concept of reusable learning objects (RLOs). Method: A randomized controlled trial was conducted. One group received the educational intervention, and the other acted as a control group. RLOs were delivered online and through DVD for television and personal computer. Knowledge of both practical and psychosocial aspects of hearing aids and communication was assessed using a free-recall method 6 weeks postfitting. Results: Knowledge of both practical and psychosocial issues was significantly higher in the group that received the RLOs than in the control group. Moderate to large effect sizes indicated that these differences were clinically significant. Conclusion: An educational intervention that supplements clinical practice results in improved knowledge in first-time hearing aid users

The impact of low erythrocyte density in human blood on the fitness and energetic reserves of the African malaria vector Anopheles gambiae

Background Anaemia is a common health problem in the developing world. This condition is characterized by a reduction in erythrocyte density, primarily from malnutrition and/or infectious diseases such as malaria. As red blood cells are the primary source of protein for haematophagous mosquitoes, any reduction could impede the ability of mosquito vectors to transmit malaria by influencing their fitness or that of the parasites they transmit. The aim of this study was to determine the impact of differences in the density of red blood cells in human blood on malaria vector (Anopheles gambiae sensu stricto) fitness. The hypotheses tested are that mosquito vector energetic reserves and fitness are negatively influenced by reductions in the red cell density of host human blood meals commensurate with those expected from severe anaemia. Methods Mosquitoes (An. gambiae s.s.) were offered blood meals of different packed cell volume(PCV) of human blood consistent with those arising from severe anaemia (15%) and normalPCV (50%). Associations between mosquito energetic reserves (lipid, glucose and glycogen)and fitness measures (reproduction and survival) and blood meal PCV were investigated. Results The amount of protein that malaria vectors acquired from blood feeding (indexed by haematin excretion) was significantly reduced at low blood PCV. However, mosquitoes feeding on blood of low PCV had the same oviposition rates as those feeding on blood of normal PCV, and showed an increase in egg production of around 15%. The long-term survival of An. gambiae s.s was reduced after feeding on low PCV blood, but PCV had no significant impact on the proportion of mosquitoes surviving through the minimal period required to develop and transmit malaria parasites (estimated as 14 days post-blood feeding). The impact of blood PCV on the energetic reserves of mosquitoes was relatively minor. Conclusions These results suggest that feeding on human hosts whose PCV has been depleted due to severe anaemia does not significantly reduce the fitness or transmission potential of malaria vectors, and indicates that mosquitoes may be able exploit resources for reproduction more efficiently from blood of low rather than normal PCV

Ecology: a prerequisite for malaria elimination and eradication

* Existing front-line vector control measures, such as insecticide-treated nets and residual sprays, cannot break the transmission cycle of Plasmodium falciparum in the most intensely endemic parts of Africa and the Pacific * The goal of malaria eradication will require urgent strategic investment into understanding the ecology and evolution of the mosquito vectors that transmit malaria * Priority areas will include understanding aspects of the mosquito life cycle beyond the blood feeding processes which directly mediate malaria transmission * Global commitment to malaria eradication necessitates a corresponding long-term commitment to vector ecolog