A potential library for primary MFL pedagogy: the case of Young Pathfinders

As readers of this journal will know very well, 2010 will see all KS2 (ages 7-11) pupils in England entitled to learn a modern foreign language in normal curriculum time. This development of the commitment to primary language learning should provide an excellent opportunity and experience for pupils, whilst at the same time requiring some radical changes for many teachers, schools and much of the wider language learning community. Recent research has indicated general trends suggesting an increase in primary languages already, in anticipation of this development and even beforehand. One of the most recent studies indicates that 43% of primary children currently learn a foreign language at KS2, either in class or as an extra-curricular activity, although the extent of this learning varies considerably (Driscoll, Jones and Macrory, 2004). It has also been suggested (Muijs et al, 2005) that there are certain aspects of the process that will be particularly demanding if the challenge of providing this entitlement are to be met

Development of machine learning support for reading whole body diffusion-weighted MRI (WB-MRI) in myeloma for the detection and quantification of the extent of disease before and after treatment (MALIMAR): protocol for a cross-sectional diagnostic test accuracy study.

INTRODUCTION: Whole-body MRI (WB-MRI) is recommended by the National Institute of Clinical Excellence as the first-line imaging tool for diagnosis of multiple myeloma. Reporting WB-MRI scans requires expertise to interpret and can be challenging for radiologists who need to meet rapid turn-around requirements. Automated computational tools based on machine learning (ML) could assist the radiologist in terms of sensitivity and reading speed and would facilitate improved accuracy, productivity and cost-effectiveness. The MALIMAR study aims to develop and validate a ML algorithm to increase the diagnostic accuracy and reading speed of radiological interpretation of WB-MRI compared with standard methods. METHODS AND ANALYSIS: This phase II/III imaging trial will perform retrospective analysis of previously obtained clinical radiology MRI scans and scans from healthy volunteers obtained prospectively to implement training and validation of an ML algorithm. The study will comprise three project phases using approximately 633 scans to (1) train the ML algorithm to identify active disease, (2) clinically validate the ML algorithm and (3) determine change in disease status following treatment via a quantification of burden of disease in patients with myeloma. Phase 1 will primarily train the ML algorithm to detect active myeloma against an expert assessment ('reference standard'). Phase 2 will use the ML output in the setting of radiology reader study to assess the difference in sensitivity when using ML-assisted reading or human-alone reading. Phase 3 will assess the agreement between experienced readers (with and without ML) and the reference standard in scoring both overall burden of disease before and after treatment, and response. ETHICS AND DISSEMINATION: MALIMAR has ethical approval from South Central-Oxford C Research Ethics Committee (REC Reference: 17/SC/0630). IRAS Project ID: 233501. CPMS Portfolio adoption (CPMS ID: 36766). Participants gave informed consent to participate in the study before taking part. MALIMAR is funded by National Institute for Healthcare Research Efficacy and Mechanism Evaluation funding (NIHR EME Project ID: 16/68/34). Findings will be made available through peer-reviewed publications and conference dissemination. TRIAL REGISTRATION NUMBER: NCT03574454

‘It’s my back…’; developing the coming to spinal clinic resource to improve the health literacy of young people with adolescent idiopathic scoliosis and their parents

This study focussed on identifying the key concerns and information needs of young people with Adolescent Idiopathic Scoliosis (AIS) and their parents and examined what resources might help improve young people’s ‘participativeness’ and health literacy during clinic consultations. A qualitative participatory design underpinned the study. Workshops involving multiple methods were used to engage with young people with AIS and their parents, who were recruited through a regional children’s hospital. The study design was informed by patient and public consultation with eight young people and two parents. 10 young people (aged 14–16 years) and 11 of their parents participated in the study. Young people and their parents reported uncertainty and anxiety before coming to clinic and faced issues participating in the consultation, being involved in decision-making and understanding the information and language. These challenges resulted in unmet information needs. Young people’s health literacy relating to an AIS diagnosis and treatment is facilitated by them being prepared and informed before coming to clinic and be actively supported to be involved during the consultation. We collaboratively developed the ‘Coming to Spinal Clinic’ resource to help young people with AIS and parents prepare for and get the most out of their visit

Promoter prediction using physico-chemical properties of DNA

The ability to locate promoters within a section of DNA is known to be a very difficult and very important task in DNA analysis. We document an approach that incorporates the concept of DNA as a complex molecule using several models of its physico-chemical properties. A support vector machine is trained to recognise promoters by their distinctive physical and chemical properties. We demonstrate that by combining models, we can improve upon the classification accuracy obtained with a single model. We also show that by examining how the predictive accuracy of these properties varies over the promoter, we can reduce the number of attributes needed. Finally, we apply this method to a real-world problem. The results demonstrate that such an approach has significant merit in its own right. Furthermore, they suggest better results from a planned combined approach to promoter prediction using both physicochemical and sequence based techniques

Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements

Investigating the role that host erythrocyte proteins play in malaria infection is hampered by the genetic intractability of this anucleate cell. Here we report that reticulocytes derived through in vitro differentiation of an enucleation-competent immortalized erythroblast cell line (BEL-A) support both successful invasion and intracellular development of the malaria parasite Plasmodium falciparum. Using CRISPR-mediated gene knockout and subsequent complementation, we validate an essential role for the erythrocyte receptor basigin in P. falciparum invasion and demonstrate rescue of invasive susceptibility by receptor re-expression. Successful invasion of reticulocytes complemented with a truncated mutant excludes a functional role for the basigin cytoplasmic domain during invasion. Contrastingly, knockout of cyclophilin B, reported to participate in invasion and interact with basigin, did not impact invasive susceptibility of reticulocytes. These data establish the use of reticulocytes derived from immortalized erythroblasts as a powerful model system to explore hypotheses regarding host receptor requirements for P. falciparum invasion

Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements

Investigatingthe role host erythrocyteproteins play in malaria infection is hampered by the genetic intractability of this anucleate cell. Here we report that reticulocytes derived through in vitro differentiation of an enucleation-competent immortalized erythroblast cell line (BEL-A) support both successful invasion and intracellular development of the malaria parasite Plasmodium falciparum. Using CRISPR-mediated gene knockout and subsequent complementation, we validate an essential role for the erythrocyte receptor basigin in P. falciparum invasion and, for the first time, demonstrate rescueby receptor re-expression.Successful invasion of reticulocytes complemented with a truncated mutant excludes a functional role for the basigincytoplasmic domain during invasion. Contrastingly, knockout of cyclophilin B, reported to participate in invasion and interact with basigin, did not impactinvasive susceptibility of reticulocytes.These data establish the use of reticulocytes derived from immortalized erythroblasts as a powerful model system to explore hypotheses regarding host receptor requirements for P. falciparum invasion

PIEZO1 gain-of-function mutations delay reticulocyte maturation in hereditary xerocytosis

Dehydrated hereditary stomatocytosis 1 or hereditary xerocytosis (HX, OMIM 194380) is a rare hereditary autosomal dominant disorder characterized by hemolytic anemia and red blood cell (RBC) dehydration. The occurrence of HX is linked with gain-of-function mutations in PIEZO1, the gene encoding for the mechanosensitive non-specific cation channel PIEZO121 which is activated by shear-stress and in concert with other ion channels (particularly the Gardos potassium calcium-activated channel, KCNN4) regulates cell volume homeostasis and metabolic activity in the RBC.3 Intriguingly, PIEZO1 gain-of-function mutations have recently been reported to occur at a much higher frequency within the population than had been previously described and have also been implicated in malaria resistance,4 suggesting that the mechanisms underpinning HX may merit further investigation. Since reticulocytosis is one of the hallmarks of HX,5 we sought to determine whether altered reticulocyte maturation could be a causative agent of this phenotype. We characterize reticulocytes and erythrocytes from 10 HX patients in comparison to healthy controls, revealing alterations in deformability and vesicle content that implicate a maturational defect in HX. We further demonstrate that HX patients suffer from impaired reticulocyte maturation as assayed through differences in the extent and rate of loss of CD71 and RNA content over time and that this effect can be recapitulated in healthy reticulocytes upon chemically-induced PIEZO1 overactivation, providing a functional link to the reticulocytosis phenotype present in HX

Energy performance contracting (EPC): a suitable mechanism for achieving energy savings in housing cooperatives? Results from a Norwegian pilot project

The barriers to energy savings in institutions and private homes are well known and include people’s lack of interest, awareness, knowledge and human and financial capacity. Experiences made in several countries show that EPC—energy performance contracting—may be used for overcoming many of these barriers. A typical EPC project is delivered by an energy service company (ESCO) and the contract is accompanied with a guarantee for energy savings. EPC is increasingly taken in use in the professional market (firms and the public sector), but is less common in the residential sector market. It has been suggested that there are several barriers for using EPC in the domestic sector such as the uncertainty involved in estimating forthcoming reductions in private consumption. In this paper, we present the results from a pilot project on the use of EPC in a housing cooperative in Oslo. The project was initiated and observed by the researchers. The research followed a transdisciplinary methodology in that it was conducted by both researcher and practitioner (co-authors) in close collaboration with members of the housing cooperative and the ESCOs, who also contributed to the interpretation of results. We document the process in terms of why the Board decided to join the EPC pilot, the call for offers from ESCOs who guaranteed that purchased annual energy would be reduced by one third, the responses to and negotiations of the offer from the ESCO who became contracted in the initial phase and up to the moment when the General Assembly finally decided to not invest in the proposed energy saving measures. We find that the residents not only had limited interest in energy savings but also lacked confidence in the EPC process. This contributed to the outcome. We discuss the findings in relation to the barriers to using EPC among housing cooperatives. We highlight the need for more knowledge about the client side for understanding how barriers may be overcome. Three specific recommendations for how EPC may successfully be employed among housing cooperatives are suggested as follows: (i) include refurbishment and not only energy savings in the EPC, (ii) identify the residents’ needs in an early phase and (iii) communicate the EPC principle to the residents throughout the process

Reticulocyte and red blood cell deformation triggers specific phosphorylation events

The capacity to undergo substantial deformation is a defining characteristic of the red blood cell (RBC), facilitating transit through the splenic interendothelial slits and microvasculature. Establishment of this remarkable property occurs during a process of reticulocyte maturation that begins with egress through micron-wide pores in the bone marrow and is completed within the circulation. The requirement to undertake repeated cycles of deformation necessitates that both reticulocytes and erythrocytes regulate membrane-cytoskeletal protein interactions in order to maintain cellular stability. In the absence of transcriptional activity, modulation of these interactions in RBCs is likely to be achieved primarily through specific protein posttranslational modifications, which at present remain undefined. In this study, we use high-throughput methods to define the processes that underlie the response to deformation and shear stress in both reticulocytes and erythrocytes. Through combination of a bead-basedmicrosphiltration assay with phosphoproteomics we describe posttranslational modification of RBC proteins associated with deformation. Using microsphiltration and microfluidic biochip-based assays, we explore the effect of inhibiting kinases identified using this dataset. We demonstrate roles for GSK3 and Lyn in capillary transit and maintenance of membrane stability following deformation and show that combined inhibition of these kinases significantly decreases reticulocyte capacity to undergo repeated deformation. Finally, we derive a comprehensive and integrative phosphoproteomic dataset that provides a valuable resource for further mechanistic dissection of the molecular pathways that underlie the RBC's response to mechanical stimuli and for the study of reticulocyte maturation