Altering User Movement Behaviour in Virtual Environments.

In immersive Virtual Reality systems, users tend to move in a Virtual Environment as they would in an analogous physical environment. In this work, we investigated how user behaviour is affected when the Virtual Environment differs from the physical space. We created two sets of four environments each, plus a virtual replica of the physical environment as a baseline. The first focused on aesthetic discrepancies, such as a water surface in place of solid ground. The second focused on mixing immaterial objects together with those paired to tangible objects. For example, barring an area with walls or obstacles. We designed a study where participants had to reach three waypoints laid out in such a way to prompt a decision on which path to follow based on the conflict between the mismatching visual stimuli and their awareness of the real layout of the room. We analysed their performances to determine whether their trajectories were altered significantly from the shortest route. Our results indicate that participants altered their trajectories in presence of surfaces representing higher walking difficulty (for example, water instead of grass). However, when the graphical appearance was found to be ambiguous, there was no significant trajectory alteration. The environments mixing immaterial with physical objects had the most impact on trajectories with a mean deviation from the shortest route of 60 cm against the 37 cm of environments with aesthetic alterations. The co-existance of paired and unpaired virtual objects was reported to support the idea that all objects participants saw were backed by physical props. From these results and our observations, we derive guidelines on how to alter user movement behaviour in Virtual Environments

To Ban or Not to Ban: Foreign Lobbying and Cross National Externalities

This paper studies the costs and benefits of foreign lobbying. We show how and when foreign lobbying can help internalize cross national externalities. We argue that this is an often overlooked benefit of foreign lobbying. We also study under what conditions a constitutional rule banning foreign lobbying is in the national interest of a country. A key factor in this calculus is whether the interests of foreign lobby groups and domestic unorganized groups coincide or not. We illustrate the logic with examples from trade policy and environmental regulation

T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function

Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections

An oncogenic role for sphingosine kinase 2

While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. SK1 has well described roles in promoting cell survival, proliferation and neoplastic transformation. The roles of SK2, and its contribution to cancer, however, are much less clear. Some studies have suggested an antiproliferative/ pro-apoptotic function for SK2, while others indicate it has a prosurvival role and its inhibition can have anti-cancer effects. Our analysis of gene expression data revealed that SK2 is upregulated in many human cancers, but only to a small extent (up to 2.5-fold over normal tissue). Based on these findings, we examined the effect of different levels of cellular SK2 and showed that high-level overexpression reduced cell proliferation and survival, and increased cellular ceramide levels. In contrast, however, low-level SK2 overexpression promoted cell survival and proliferation, and induced neoplastic transformation in vivo. These findings coincided with decreased nuclear localization and increased plasma membrane localization of SK2, as well as increases in extracellular S1P formation. Hence, we have shown for the first time that SK2 can have a direct role in promoting oncogenesis, supporting the use of SK2-specific inhibitors as anti-cancer agents.Heidi A. Neubauer, Duyen H. Pham, Julia R. Zebol, Paul A.B. Moretti, Amanda L. Peterson, Tamara M. Leclercq, Huasheng Chan, Jason A. Powell, Melissa R. Pitman, Michael S. Samuel, Claudine S. Bonder, Darren J. Creek, Briony L. Gliddon and Stuart M. Pitso

Sulfur isotopes as biosignatures for Mars and Europa exploration

Sulfur (S) isotopes are used to trace metabolic pathways associated with biological S-cycling in past and present environments on Earth. These pathways (sulfate reduction, sulfur disproportionation, and sulfide oxidation) can produce unique S isotope signals that provide insight into biogeochemical S-cycling. The S cycle is also relevant for extraterrestrial environments and processes. On early Mars, sulfur existed in different redox states and was involved in a large range of surface processes (e.g., volcanic, atmospheric, hydrothermal, and aqueous brines). Sulfur compounds have also been detected on Europa's icy moon surface, with the S cycle implicated in Europa's surface and ocean geochemistry. Given the well-established utility of S isotopes in providing a record for past life on Earth, S isotopes are an valuable tool for identifying biosignatures on Mars and Europa. Here, we review S isotopes as a biosignature, in light of two recent advances in understanding the S cycle in both Mars and Europa: (i) the measurements of δ34S in situ at Gale Crater and quadruple S isotopes (QSI) in Martian meteorites, and (ii) the identification of a likely exogenous origin of sulfur on Europa's surface. We discuss important considerations for unravelling QSI biosignatures in Martian environments, considering high and low sulfur environments, atmospheric S-MIF signals, and metabolic energy-limited niches. For Europa, we describe the potential for S isotopes to probe biogeochemistry, and identify key knowledge gaps to be addressed in order to unlock S isotopic tools for future life detection efforts. The resulting picture demonstrates how S isotopes will be a valuable tool for Mars Sample Return, and how future missions can focus on the search for environments where QSI signatures of microbial S-cycling processes have a greater chance of being preserved. For Europa, the first step will be to account for the S isotope composition of the various S pools, to recognise or rule out non-biologically mediated S isotope values, with a focus on experimental examination of potential S isotope signatures from exogenous sulfur sources.Thematic collection: This article is part of the Sulfur in the Earth system collection available at: https://www.lyellcollection.org/cc/sulfur-in-the-earth-syste

Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Background:Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined. Methods:Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects. Results:Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect. Conclusion:Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.Peter G. Gibson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James ... et al

University-industry relationships and open innovation: Towards a research agenda

Accepted versio

Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

The interaction of germline variation and somatic cancer driver mutations is underinvestigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondriallyencoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D, Andre