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

Intellectual disability health content within the nursing curriculum: an audit of what our future nurses are taught

Background: Individuals with intellectual disability experience chronic and complex health issues, but face considerable barriers to healthcare. One such barrier is inadequate education of healthcare professionals

Sulfated glycans engage the Ang–Tie pathway to regulate vascular development

The angiopoietin (Ang)–Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang–Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS–Tie1 interaction promoted Tie1–Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS–Tie1 binding using CRISPR–Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang–Tie signaling and are important for the development and maintenance of the vasculature

Specific and general autobiographical knowledge in adults with autism spectrum disorders: The role of personal goals

Autobiographical knowledge is stored hierarchically, at both specific and general levels of representation. It has also been proposed that the self is the structure around which autobiographical memories are organised. The current series of studies assessed whether the autobiographical memory difficulties observed in adults with autism spectrum disorders (ASD) could be due to problems in using the self as an effective memory cue. A series of cueing paradigms were used to assess the accessibility of both specific and general autobiographical knowledge relating to (i) currently pursued goals (either high or low in self-concordance) and (ii) goals that participants were not currently pursuing. Results demonstrated that while event-specific knowledge was impaired in the ASD group, general event knowledge appeared relatively intact. Moreover, while both event-specific and general event knowledge were organised around goals of the self in control participants, a corresponding relationship was only observed for general event knowledge in the ASD group

Sulfation patterns of glycosaminoglycans encode molecular recognition and activity

Although glycosaminoglycans contribute to diverse physiological processes, an understanding of their molecular mechanisms has been hampered by the inability to access homogeneous glycosaminoglycan structures. Here, we assembled well-defined chondroitin sulfate oligosaccharides using a convergent, synthetic approach that permits installation of sulfate groups at precise positions along the carbohydrate backbone. Using these defined structures, we demonstrate that specific sulfation motifs function as molecular recognition elements for growth factors and modulate neuronal growth. These results provide both fundamental insights into the role of sulfation and direct evidence for a 'sulfation code' whereby glycosaminoglycans encode functional information in a sequence-specific manner analogous to that of DNA, RNA and proteins

The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/− bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/− chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology

The Practitioner's Dilemma: How to Assess the Credibility of Downscaled Climate Projections

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101803/1/eost2013EO460005.pd

A community health worker led approach to cardiovascular disease prevention in the UK—SPICES-Sussex (scaling-up packages of interventions for cardiovascular disease prevention in selected sites in Europe and Sub-saharan Africa): an implementation research project

BackgroundThis paper describes a UK-based study, SPICES-Sussex, which aimed to co-produce and implement a community-based cardiovascular disease (CVD) risk assessment and reduction intervention to support under-served populations at moderate risk of CVD. The objectives were to enhance stakeholder engagement; to implement the intervention in four research sites and to evaluate the use of Voluntary and Community and Social Enterprises (VCSE) and Community Health Worker (CHW) partnerships in health interventions.MethodsA type three hybrid implementation study design was used with mixed methods data. This paper represents the process evaluation of the implementation of the SPICES-Sussex Project. The evaluation was conducted using the RE-AIM framework.ResultsReach: 381 individuals took part in the risk profiling questionnaire and forty-one women, and five men participated in the coaching intervention. Effectiveness: quantitative results from intervention participants showed significant improvements in CVD behavioural risk factors across several measures. Qualitative data indicated high acceptability, with the holistic, personalised, and person-centred approach being valued by participants. Adoption: 50% of VCSEs approached took part in the SPICES programme, The CHWs felt empowered to deliver high-quality and mutually beneficial coaching within a strong project infrastructure that made use of VCSE partnerships. Implementation: Co-design meetings resulted in local adaptations being made to the intervention. 29 (63%) of participants completed the intervention. Practical issues concerned how to embed CHWs in a health service context, how to keep engaging participants, and tensions between research integrity and the needs and expectations of those in the voluntary sector. Maintenance: Several VCSEs expressed an interest in continuing the intervention after the end of the SPICES programme.ConclusionCommunity-engagement approaches have the potential to have positively impact the health and wellbeing of certain groups. Furthermore, VCSEs and CHWs represent a significant untapped resource in the UK. However, more work needs to be done to understand how links between the sectors can be bridged to deliver evidence-based effective alternative preventative healthcare. Reaching vulnerable populations remains a challenge despite partnerships with VCSEs which are embedded in the community. By showing what went well and what did not, this project can guide future work in community engagement for health