Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency

In this study, we performed a genome-wide N-ethyl-N-mtrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued.d the Sylvia and Charles Viertel Charitable Foundation (Senior Medical Research Fellowship to D.J.C.

Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency

In this study, we performed a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued

A systems biology pipeline identifies regulatory networks for stem cell engineering

A major challenge for stem cell engineering is achieving a holistic understanding of the molecular networks and biological processes governing cell differentiation. To address this challenge, we describe a computational approach that combines gene expression analysis, previous knowledge from proteomic pathway informatics and cell signaling models to delineate key transitional states of differentiating cells at high resolution. Our network models connect sparse gene signatures with corresponding, yet disparate, biological processes to uncover molecular mechanisms governing cell fate transitions. This approach builds on our earlier CellNet and recent trajectory-defining algorithms, as illustrated by our analysis of hematopoietic specification along the erythroid lineage, which reveals a role for the EGF receptor family member, ErbB4, as an important mediator of blood development. We experimentally validate this prediction and perturb the pathway to improve erythroid maturation from human pluripotent stem cells. These results exploit an integrative systems perspective to identify new regulatory processes and nodes useful in cell engineering.National Institute of General Medical Sciences (NIGMS) (Grant R01-GM081336)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant R24-DK092760)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R24-DK49216

Nurture Early for Optimal Nutrition (NEON) participatory learning and action women’s groups to improve infant feeding and practices in South Asian infants: pilot randomised trial study protocol

Introduction Feeding practices developed in early life can impact a child’s nutrition, growth, dental health, cognitive development and lifetime risk of chronic diseases. Substantial evidence suggests ethnic health inequalities, and non-recommended complementary infant feeding practices among UK’s South Asian (SA) population. Nurture Early for Optimal Nutrition aims to use women’s group participatory learning and action (PLA) cycles to optimise infant feeding, care and dental hygiene practices in SA infants <2 years in East London.Methods and analysis A three-arm pilot feasibility cluster randomised controlled trial will assess feasibility, acceptability, costs and explore preliminary effectiveness for proposed primary outcome (ie, reporting on body mass index (BMI) z-score). Multilingual SA community facilitators will deliver the intervention, group PLA Cycle, to mothers/carers in respective ethnic/language groups. 12 wards are randomised to face-to-face PLA, online PLA and usual care arms in 1:1:1 ratio. Primary outcomes are feasibility and process measures (ie, BMI z-score, study records, feedback questionnaires, direct observation of intervention and sustainability) for assessment against Go/Stop criteria. Secondary outcomes are cluster-level and economic outcomes (ie, eating behaviour, parental feeding practices, network diffusion, children development performance, level of dental caries, general practitioner utilisation, costs, staff time). Outcomes are measured at baseline, every 2 weeks during intervention, 14 weeks and at 6 months by blinded outcome assessors where possible. This study will use concurrent mixed-methods evaluation. Quantitative analyses include descriptive summary with 95% CI and sample size calculation for the definitive trial. The intervention effect with CI will be estimated for child BMI z-score. Implementation will be evaluated qualitatively using thematic framework analysis.Ethics and dissemination Ethics approval was obtained from University College London (UCL), National Health Service (Health Research Authority (HRA) and Health and Care Research Wales (HRCW)). Results will be published in peer-reviewed journals, presented at scientific conferences/workshops with commissioners, partners and participating communities. Plain language summaries will be disseminated through community groups, websites and social media.Trial registration number IRAS-ID-296259 (ISRCTN10234623)