Validation of a chloroquine-induced cell death mechanism for clinical use against malaria

An alternative antimalarial pathway of an ‘outdated’ drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials. Conventionally, CQ is believed to interfere with hemozoin formation at nanomolar concentrations, but resistant parasites are able to efflux this drug from the digestive vacuole (DV). However, we show that the DV membrane of both resistant and sensitive laboratory and field parasites is compromised after exposure to micromolar concentrations of CQ, leading to an extrusion of DV proteases. Furthermore, only a short period of exposure is required to compromise the viability of late-stage parasites. To study the feasibility of this strategy, mice malaria models were used to demonstrate that high doses of CQ also triggered DV permeabilization in vivo and reduced reinvasion efficiency. We suggest that a time-release oral formulation of CQ may sustain elevated blood CQ levels sufficiently to clear even CQ-resistant parasites

Appropriate control methods for mobile virtual exhibitions

It is becoming popular to render art exhibitions in Virtual Reality (VR). Many of these are used to deliver at-home experiences on peoples’ own mobile devices, however, control options on mobile VR systems are necessarily less flexible than those of situated VR fixtures. In this paper, we present a study that explores aspects of control in such VR exhibitions - specifically comparing ‘on rails’ movement with ‘free’ movement.We also expand the concept of museum audio guides to better suit the VR medium, exploring the possibility of embodied characterguides. We compare these controllable guides with a more traditional audio-guide. The study uses interviews to explore users’ experience qualitatively, as well as questionnaires addressing both user experience and simulator sickness. The results suggest that users generally prefer to have control over both their movement and the guide, however, if relinquishing movement control, they prefer the uncontrolled guide. The paper presents three key findings: (1) users prefer to be able to directly control their movement; (2) this does not make a notable difference to simulator sickness; (3) embodied guides are potentially a good way to deliver additional information in VR exhibition settings

Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death

The ATP-dependent ClpQY protease system in Plasmodium falciparum is a prokaryotic machinery in the parasite. In the present study, we have identified the complete ClpQY system in P. falciparum and elucidated its functional importance in survival and growth of asexual stage parasites. We characterized the interaction of P. falciparum ClpQ protease (PfClpQ) and PfClpY ATPase components, and showed that a short stretch of residues at the C terminus of PfClpY has an important role in this interaction; a synthetic peptide corresponding to this region antagonizes this interaction and interferes with the functioning of this machinery in the parasite. Disruption of ClpQY function by this peptide caused hindrance in the parasite growth and maturation of asexual stages of parasites. Detailed analyses of cellular effects in these parasites showed features of apoptosis-like cell death. The peptide-treated parasites showed mitochondrial dysfunction and loss of mitochondrial membrane potential. Dysfunctioning of mitochondria initiated a cascade of reactions in parasites, including activation of VAD–FMK-binding proteases and nucleases, which resulted in apoptosis-like cell death. These results show functional importance of mitochondrial proteases in the parasite and involvement of mitochondria in programmed cell death in the malaria parasites

Predictors of sun protection behaviours and sunburn among Australian adolescents

BACKGROUND: Excessive sun exposure and sunburn increase individuals' risk of skin cancer. It is especially important to prevent sunburn in childhood due to the higher relative risk of skin cancer across the life span compared to risk associated with sunburn episodes experienced later in life. This study examined demographic and attitudinal factors associated with engagement in a range of sun protection behaviours (wearing a hat, wearing protective clothing, staying in the shade, and staying indoors during the middle of the day) and the frequency of sunburn among Western Australian adolescents to provide insights of relevance for future sun protection campaigns. METHODS: Cross-sectional telephone surveys were conducted annually with Western Australians between 2005/06 and 2014/15. The results from 4150 adolescents aged 14-17 years were used to conduct a path analysis of factors predicting various sun protection behaviours and sunburn. RESULTS: Significant primary predictors of the sun protection behaviours included in the study were skin type (sun sensitivity), gender, tanning-related attitudes and behaviours, and perceived relevance of public service advertisements that advocate sun protection. Of the four sun protection behaviours investigated, staying in the shade and staying indoors during the middle of the day were associated with a lower frequency of sunburn. CONCLUSION: There is a particular need to target sun protection messages at adolescent males who are less likely to engage in the most effective sun protection behaviours and demonstrate an increased propensity to experience sunburn. The results suggest that such future sun protection messages should include a focus on the importance of staying in the shade or indoors during periods of high UV radiation to increase awareness of the efficacy of these methods of avoiding skin cancer

A collaborative artefact reconstruction environment

A novel collaborative artefact reconstruction environment design is presented that is informed by experimental task observation and participatory design. The motivation for the design was to enable collaborative human and computer effort in the reconstruction of fragmented cuneiform tablets: millennia-old clay tablets used for written communication in early human civilisation. Thousands of joining cuneiform tablet fragments are distributed within and between worldwide collections. The reconstruction of the tablets poses a complex 3D jigsaw puzzle with no physically tractable solution. In reconstruction experiments, participants collaborated synchronously and asynchronously on virtual and physical reconstruction tasks. Results are presented that demonstrate the difficulties experienced by human reconstructors in virtual tasks compared to physical tasks. Unlike computer counterparts, humans have difficulty identifying joins in virtual environments but, unlike computers, humans are averse to making incorrect joins. A successful reconstruction environment would marry the opposing strengths and weaknesses of humans and computers, and provide tools to support the communications and interactions of successful physical performance, in the virtual setting. The paper presents a taxonomy of the communications and interactions observed in successful physical and synchronous collaborative reconstruction tasks. Tools for the support of these communications and interactions were successfully incorporated in the “i3D” virtual environment design presented

Lack of Galanin 3 Receptor Aggravates Murine Autoimmune Arthritis

Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells. However, since there are minimal in vivo data on the role of GAL3 in joint diseases, we analyzed its involvement in different inflammatory mechanisms of the K/BxN serum transfer-model of autoimmune arthritis employing GAL 3 gene-deficient mice. After arthritis induction, GAL3 knockouts demonstrated increased clinical disease severity and earlier hindlimb edema than wild types. Vascular hyperpermeability determined by in vivo fluorescence imaging was also elevated compared to the wild-type controls. However, neutrophil accumulation detected by in vivo luminescence imaging or arthritic mechanical hyperalgesia was not altered by the lack of the GAL3 receptor. Our findings suggest that GAL3 has anti-inflammatory properties in joints by inhibiting vascular hyperpermeability and consequent edema formation

DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage

Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature ageing. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with ageing. Here we show that the FOXO transcription factor DAF-16 is activated in response to DNA damage during development, whereas the DNA damage responsiveness of DAF-16 declines with ageing. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA-damage-induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16-mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists

COVIDiSTRESS diverse dataset on psychological and behavioural outcomes one year into the COVID-19 pandemic

During the onset of the COVID-19 pandemic, the COVIDiSTRESS Consortium launched an open-access global survey to understand and improve individuals’ experiences related to the crisis. A year later, we extended this line of research by launching a new survey to address the dynamic landscape of the pandemic. This survey was released with the goal of addressing diversity, equity, and inclusion by working with over 150 researchers across the globe who collected data in 48 languages and dialects across 137 countries. The resulting cleaned dataset described here includes 15,740 of over 20,000 responses. The dataset allows cross-cultural study of psychological wellbeing and behaviours a year into the pandemic. It includes measures of stress, resilience, vaccine attitudes, trust in government and scientists, compliance, and information acquisition and misperceptions regarding COVID-19. Open-access raw and cleaned datasets with computed scores are available. Just as our initial COVIDiSTRESS dataset has facilitated government policy decisions regarding health crises, this dataset can be used by researchers and policy makers to inform research, decisions, and policy. © 2022, The Author(s).U.S. Department of Education, ED: P031S190304; Texas A and M International University, TAMIU; National Research University Higher School of Economics, ВШЭThe COVIDiSTRESS Consortium would like to acknowledge the contributions of friends and collaborators in translating and sharing the COVIDiSTRESS survey, as well as the study participants. Data analysis was supported by Texas A&M International University (TAMIU) Research Grant, TAMIU Act on Ideas, and the TAMIU Advancing Research and Curriculum Initiative (TAMIU ARC) awarded by the US Department of Education Developing Hispanic-Serving Institutions Program (Award # P031S190304). Data collection by Dmitrii Dubrov was supported within the framework of the Basic Research Program at HSE University, RF