Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention

Road traffic fatalities in rural and remote Australia from 2006 to 2017: The need for targeted action

OBJECTIVE: To explore rural motor vehicle collision (MVC) fatalities by trends over time, mode of transport, age, state, sex, and Aboriginal and Torres Strait Islander status. DESIGN: A retrospective total population‐based time series was conducted using the Australian Bureau of Statistics (ABS) death registration data. SETTING: All statistical local area (SLA) within Australia from 2006 to 2017. PARTICIPANTS: Australian residents whose deaths were registered with the ABS between 01 January 2006 and 31 December 2017 where the underlying cause of death was related to unintentional transport accidents. MAIN OUTCOME MEASURES: Fatality rates were determined using population data collected from the 2006, 2011 and 2016 census. Trends over time by rurality were analysed by financial year. Rates of transport deaths by vehicle type were determined by rurality. Risk ratios were calculated to compare demographic groups based on sex, Aboriginal and Torres Strait Islander status and age. A 3‐year scorecard was organised by state and rurality using 99.7% confidence intervals. RESULTS: Motor vehicle collision fatalities increase with increasing remoteness. Females, children from 0 to 14 years, pedestrians, and Aboriginal and Torres Strait Islander peoples are at a significantly higher risk of fatal MVCs than their respective metropolitan counterparts. The 3‐year scorecard indicates that road fatality rates in the NT, WA, and all rural and remote areas required immediate attention and targeted action. CONCLUSIONS: There is a need for investment in MVC fatality prevention in rural Australia from inner regional to remote areas in order to meet the road safety targets established by the National Road Safety Strategy

Comparing rural traffic safety in Canada and Australia: a scoping review of the literature

Introduction: The reduction of road fatalities is a priority established by the WHO and ratified by the UN. Rates of road fatalities are disproportionately high in rural areas in both Australia and Canada, two Commonwealth countries with comparable healthcare systems and rural health challenges. The purpose of this review was to compare and contrast the epidemiology, risk factors and prevention strategies of rural road fatalities in both countries to inform the next steps for prevention. Methods: A scoping literature review was undertaken systematically to search for peer-reviewed literature published from January 2000 to June 2021. Articles were reviewed from five databases (EMCARE, Medline, CINAHL, Scopus and Informit). Search terms were adapted to suit each database and included combinations of keywords such as 'traffic accident', 'fatality', 'rural/remote', 'Australia' and 'Canada'. Themes and data associated with the research outcomes were extracted and tabulated. Results: Forty-three papers were identified as relevant: 14 exploring epidemiology, 25 investigating risk factors and 37 proposing prevention strategies. People living in rural locations were 3.2 (95% confidence interval: 3.0-3.5) times more likely than urban dwellers to die in road-related incidents, with rates of motor vehicle fatalities universally higher. Common risk factors included drugs and alcohol, speed, driver error and biological sex. Key prevention strategies included improved infrastructure, vehicle design, impaired driving prevention and education. Conclusion: Further research regarding preventative measures and significant investment in rural road safety in both Australia and Canada are needed to prevent future incidents

Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation

The transcription factor nuclear factor κB (NF-κB) rapidly reprograms gene expression in response to various stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation, methylation, and acetylation. The addition of O-linked b-N-acetylglucosamine (a process known as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions such as hyperglycemia and cellular stress. We report that the NF-κB subunit c-Rel is modified and activated by O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for the DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated c-Rel–mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T cell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins enhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)–induced expression of other NF-κB target genes, such as NFKBIA (which encodes IkBa) and TNFAIP3 (which encodes A20), occurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role for hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell–mediated autoimmunity in conditions such as type 1 diabetes by enhancing the production of T helper cell cytokines

Vortex Lattice Locking in Rotating Two-Component Bose-Einstein Condensates

The vortex density of a rotating superfluid, divided by its particle mass, dictates the superfluid's angular velocity through the Feynman relation. To find how the Feynman relation applies to superfluid mixtures, we investigate a rotating two-component Bose-Einstein condensate, composed of bosons with different masses. We find that in the case of sufficiently strong interspecies attraction, the vortex lattices of the two condensates lock and rotate at the drive frequency, while the superfluids themselves rotate at two different velocities, whose ratio is the ratio between the particle mass of the two species. In this paper, we characterize the vortex-locked state, establish its regime of stability, and find that it surives within a disk smaller than a critical radius, beyond which vortices become unbound, and the two Bose-gas rings rotate together at the frequency of the external drive.Comment: 6 pages, 2 figure

Searching for black holes in subways.

Abstract Current mobile agent algorithms for mapping faults in computer networks assume that the network is static. However, for large classes of highly dynamic networks (e.g., wireless mobile ad hoc networks, sensor networks, vehicular networks), the topology changes as a function of time. These networks, called delay-tolerant, challenged, opportunistic, etc., have never been investigated with regard to locating faults. We consider a subclass of these networks modelled on an urban subway system. We examine the problem of creating a map of such a subway. More precisely, we study the problem of a team of asynchronous computational entities (the mapping agents) determining the location of black holes in a highly dynamic graph, whose edges are defined by the asynchronous movements of mobile entities (the subway carriers). We determine necessary conditions for the problem to be solvable. We then present and analyze a solution protocol; we show that our algorithm solves the fault mapping problem in subway networks with the minimum number of agents possible, k = γ + 1, where γ is the number of carrier stops at black holes. The number of carrier moves between stations required by the algorithm in the worst case is , where n C is the number of subway trains, and l R is the length of the subway route with the most stops. We establish lower bounds showing that this bound is tight. Thus, our protocol is both agent-optimal and move-optimal