RAM is upregulated during T cell activation and is required for RNA cap formation and gene expression

On T cell activation, upregulation of gene expression produces the protein required for the differentiation and proliferation of effector cell populations. RAM, the co-factor of the RNA cap methyltransferase RNMT, is upregulated following activation. Formation of the RNA cap protects RNA during synthesis and guides RNA processing and translation. Using conditional gene deletion, we found that Ram expression stabilises RNMT protein in T cells and is required for its upregulation on activation. When the Ram gene is deleted in naïve T cells, there are major impacts on activation-induced RNA cap formation and gene expression. Activated T cell proliferation is dependent on increased ribosome production; in Ram knock-out T cells activation-induced expression of ribosomal protein genes and snoRNAs is most severely reduced. Consistent with these changes, Ram deletion resulted in reduced protein synthesis, and reduced growth and proliferation of CD4 T cells. Deletion of Ram results in a similar but milder phenotype to Rnmt deletion, supporting the role of RAM as a RNMT co-factor

Common genetic architecture underlying young children's food fussiness and liking for vegetables and fruit

Background: Food fussiness (FF) is common in early childhood and is often associated with the rejection of nutrient-dense foods such as vegetables and fruit. FF and liking for vegetables and fruit are likely all heritable phenotypes; the genetic influence underlying FF may explain the observed genetic influence on liking for vegetables and fruit. Twin analyses make it possible to get a broad-based estimate of the extent of the shared genetic influence that underlies these traits. Objective: We quantified the extent of the shared genetic influence that underlies FF and liking for vegetables and fruit in early childhood with the use of a twin design. Design: Data were from the Gemini cohort, which is a populationbased sample of twins born in England and Wales in 2007. Parents of 3-y-old twins (n = 1330 pairs) completed questionnaire measures of their children's food preferences (liking for vegetables and fruit) and the FF scale from the Children's Eating Behavior Questionnaire. Multivariate quantitative genetic modeling was used to estimate common genetic influences that underlie FF and liking for vegetables and fruit. Results: Genetic correlations were significant and moderate to large in size between FF and liking for both vegetables (20.65) and fruit (20.43), which indicated that a substantial proportion of the genes that influence FF also influence liking. Common genes that underlie FF and liking for vegetables and fruit largely explained the observed phenotypic correlations between them (68-70%). Conclusions: FF and liking for fruit and vegetables in young children share a large proportion of common genetic factors. The genetic influence on FF may determine why fussy children typically reject fruit and vegetables

RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.

Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR-induced expansion. These RBPs suppress an evolutionarily conserved posttranscriptional regulon consisting of messenger RNAs whose protein products cooperatively promote transition into the S phase of the cell cycle. This mechanism promotes VDJ recombination and effective selection of cells expressing immunoglobulin-μ at the pre-BCR checkpoint.This work was funded by the Biotechnology and Biological Sciences Research Council, a Medical Research Council CASE studentship with GSK, an MRC centenary award (A.G) and project grants from Bloodwise. DJH was supported by a Medical Research Council Clinician Scientist FellowshipThis is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via http://dx.doi.org/10.1126/science.aad597

Maternal feeding practices and fussy eating in toddlerhood: A discordant twin analysis

Background: Parental feeding practices are thought to play a causal role in shaping a child's fussiness; however, a child-responsive model suggests that feeding practices may develop in response to a child's emerging appetitive characteristics. We used a novel twin study design to test the hypothesis that mothers vary their feeding practices for twin children who differ in their 'food fussiness', in support of a child-responsive model. Methods: Participants were mothers and their 16 month old twin children (n=2026) from Gemini, a British twin birth cohort of children born in 2007. Standardized psychometric measures of maternal 'pressure to eat', 'restriction' and 'instrumental feeding', as well as child 'food fussiness', were completed by mothers. Within-family analyses examined if twin-pair differences in 'food fussiness' were associated with differences in feeding practices using linear regression models. In a subset of twins (n=247 pairs) who were the most discordant (highest quartile) on 'food fussiness' (difference score≥.50), Paired Samples T-test were used to explore the magnitude of differences in feeding practices between twins. Between-family analyses used Complex Samples General Linear Models to examine associations between feeding practices and 'food fussiness'. Results: Within-pair differences in 'food fussiness' were associated with differential 'pressure to eat' and 'instrumental feeding' (ps<.001), but not with 'restriction'. In the subset of twins most discordant on 'food fussiness', mothers used more pressure (p<.001) and food rewards (p<.05) with the fussier twin. Between-family analyses indicated that 'pressure to eat' and 'instrumental feeding' were positively associated with 'food fussiness', while 'restriction' was negatively associated with 'food fussiness' (ps<.001). Conclusions: Mothers appear to subtly adjust their feeding practices according to their perceptions of their toddler's emerging fussy eating behavior. Specifically, the fussier toddler is pressured more than their less fussy co-twin, and is more likely to be offered food rewards. Guiding parents on how to respond to fussy eating may be an important aspect of promoting feeding practices that encourage food acceptance

A novel methodology for macroscale, thermal characterization of carbon fiber-reinforced polymer for integrated aircraft electrical power systems

Carbon fiber-reinforced polymer (CFRP) is increasingly used for aero-structure applications due to their high strength-to-weight ratio. The integration of the on-board electrical power system (EPS) with CFRP is challenging due to the requirement to thermally and electrically isolate these systems to meet existing safety standards. By capturing the thermal characteristics of CFRP at a macro (component) scale for CFRP components, it is possible to understand, and design for, the increased integration of the EPS into CFRP aero-components. A significant challenge is to develop a macroscale characterization of CFRP, which is not only of an appropriate fidelity for compatibility with systems-level models of an EPS but also can be used to represent different geometries of CFRP components. This paper presents a novel methodology for capturing a transient, macroscale thermal characterization of CFRP with regard to component layup and geometry (thickness). The methodology uses experimentally derived thermal responses of specific resin and ply orientation CFRP samples to create a generalized relationship for the prediction of thermal transfer in other sample thicknesses of the same material type. This methodology can be used to characterize thermal gradients across CFRP components in aircraft EPS integration applications, ultimately informing the optimized integration of the EPS with CFRP

Enhancing current guidance for psoriatic arthritis and its comorbidities: recommendations from an expert consensus panel

Objectives Existing guidelines for psoriatic arthritis (PsA) cover many aspects of management. Some gaps remain relating to routine practice application. An expert group aimed to enhance current guidance and develop recommendations for clinical practice that are complementary to existing guidelines. Methods A steering committee comprising experienced, research-active clinicians in rheumatology, dermatology and primary care agreed on themes and relevant questions. A targeted literature review of PubMed and Embase following a PICO framework was conducted. At a second meeting, recommendations were drafted and subsequently an extended faculty comprising rheumatologists, dermatologists, primary care clinicians, specialist nurses, allied health professionals, non-clinical academic participants and members of the Brit-PACT patient group, was recruited. Consensus was achieved via an online voting platform when 75% of respondents agreed in the range of 7–9 on a 9-point scale. Results The guidance comprised 34 statements covering four PsA themes. Diagnosis focused on strategies to identify PsA early and refer appropriately, assessment of diagnostic indicators, use of screening tools and use of imaging. Disease assessment centred on holistic consideration of disease activity, physical functioning and impact from a patient perspective, and on how to implement shared decision-making. For comorbidities, recommendations included specific guidance for high-impact conditions such as depression and obesity. Management statements (which excluded extant guidance on pharmacological therapies) covered multidisciplinary team working, implementation of lifestyle modifications and treat-to-target strategies. Minimising corticosteroid use was recommended where feasible. Conclusion The consensus group have made evidence-based best practice recommendations for the management of PsA to enhance the existing guidelines