Pressurized water reactor in-core nuclear fuel management by tabu search

Optimization of the arrangement of fuel assemblies and burnable poisons when reloading pressurized water reactors has, in the past, been performed with many di erent algorithms in an attempt to make reactors more economic and fuel effi cient. The use of the tabu search algorithm in tackling reload core design problems is investigated further here after limited, but promising, previous investigations. The performance of the tabu search implementation developed was compared with established genetic algorithm and simulated annealing optimization routines. Tabu search outperformed these existing programs for a number of dffi erent objective functions on two di erent representative core geometries.This is the accepted manuscript. It is published by Elsevier here: http://www.sciencedirect.com/science/article/pii/S030645491400382X

Combining work and child care: The experiences of mothers in Accra, Ghana

Work-family research has focused predominantly on Western women. Yet the forms of economic labour in which women are typically involved and the meaning of motherhood are context-specific. This paper aims to explore the experience of combining economic activity and child care of mothers with young children using urban Ghana as a case study. Semi-structured interviews (n=24) were conducted in three locations in the Accra Metropolitan Area. Transcripts were analysed using the general inductive approach. The results found women’s experience of role conflict to be bi-directional. With regard to role enhancement, economic activity allowed women to provide materially for their children. The combination of work and child care had negative consequences for women’s wellbeing. This research questions policy makers’ strategy of frequently targeting women in their roles either as generators of income, or as the primary care-takers of children by highlighting the reality of women’s simultaneous performance of these roles

A Murder Mystery Gamification Session to Consolidate Analytical Biochemical Techniques Learning

This is the final version. Available on open access from the American Chemical Society via the DOI in this recordData Availability: A video explaining the scripts and giving an example of use can be found at (https://youtu.be/zfCNjB2KYDQ). R scripts are also available from GitHub (https://github.com/njharmer/Biochem-murder-mystery). R scripts can be run through a web browser at CodeOcean (https://codeocean.com/capsule/8095683/tree/v2). Users should read the packet metadata before running.Gamification has a strong track record of improving student engagement and learning in the chemical sciences. Meta-analyses of different approaches to gamification have highlighted that providing a game fiction, encouraging students to work in teams, and breaking games into smaller “quests” are particularly effective. Here, we aimed to increase students’ engagement and learning with four analytical biochemistry techniques (high-performance liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blot, and mass spectrometry) by creating a game that required them to use every method to solve a “murder mystery”. Our game was based on the popular games “Mafia” and “Among Us” and introduced an original game fiction relevant to our setting. Students attending the formative gamified session gave highly positive feedback. They indicated that they enjoyed the session and increased confidence in the methods involved. Free text comments praised many of the elements deliberately introduced into the game. To our surprise, the main criticism was that the session was not challenging enough. We developed a revised session that required students to undertake more detailed data interpretation, which students reported gave the expected increase in difficulty. All materials and code for running our session and generating new mysteries with original data are available online

Unique Data Sets and Bespoke Laboratory Videos: Teaching and Assessing of Experimental Methods and Data Analysis in a Pandemic

This is the final version. Available on open access from the American Chemical Society via the DOI in this recordThe COVID-19 pandemic necessitated the move to online teaching and assessment. This has created challenges in teaching laboratory skills and producing assessments that are robust and fair. Our solution was to use bespoke laboratory videos to provide laboratory training and to generate unique data sets for each student in coursework and exams. For assessments, R was used to produce student data packs comprising data and images, and associated staff answer files with plotted data and worked answers. In the new open-book online environment, this approach enabled us to create assessments that were the students’ own work with no evidence of student collusion. We observed no difference in student performance for the coursework or exam: The mean and median marks for the course remained the same as in previous years

A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth

Unraveling the B. pseudomallei Heptokinase WcbL: from structure to drug discovery

Journal ArticleOpen Access funded by Biotechnology and Biological Sciences Research Council under a Creative Commons Attribution 4.0 International Public LicenseGram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.Biotechnology and Biological Sciences Research Counci

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia

Funding: This work was supported by the Chief Scientist Office (grant number ETM/250).Background. The frequent lack of a microbiological diagnosis in community-acquired pneumonia (CAP) impairs pathogen-directed antimicrobial therapy. This study assessed the use of comprehensive multibacterial, multiviral molecular testing, including quantification, in adults hospitalized with CAP. Methods. Clinical and laboratory data were collected for 323 adults with radiologically-confirmed CAP admitted to 2 UK tertiary care hospitals. Sputum (96%) or endotracheal aspirate (4%) specimens were cultured as per routine practice and also tested with fast multiplex real-time polymerase-chain reaction (PCR) assays for 26 respiratory bacteria and viruses. Bacterial loads were also calculated for 8 bacterial pathogens. Appropriate pathogen-directed therapy was retrospectively assessed using national guidelines adapted for local antimicrobial susceptibility patterns. Results. Comprehensive molecular testing of single lower respiratory tract (LRT) specimens achieved pathogen detection in 87% of CAP patients compared with 39% with culture-based methods. Haemophilus influenzae and Streptococcus pneumoniae were the main agents detected, along with a wide variety of typical and atypical pathogens. Viruses were present in 30% of cases; 82% of these were codetections with bacteria. Most (85%) patients had received antimicrobials in the 72 hours before admission. Of these, 78% had a bacterial pathogen detected by PCR but only 32% were culture-positive (P < .0001). Molecular testing had the potential to enable de-escalation in number and/or spectrum of antimicrobials in 77% of patients. Conclusions. Comprehensive molecular testing significantly improves pathogen detection in CAP, particularly in antimicrobial-exposed patients, and requires only a single LRT specimen. It also has the potential to enable early de-escalation from broad-spectrum empirical antimicrobials to pathogen-directed therapy.Publisher PDFPeer reviewe

Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress

Regenerative medicine approaches to enhancing beta cell growth and survival represent potential treatments for diabetes. It is known that growth factors such as insulin, IGF-1 and HGF support beta cell growth and survival, but in people with type 2 diabetes the destructive effects of metabolic stress predominate and beta cell death or dysfunction occurs. In this study we explore the novel hypothesis that regulation of growth factor receptor trafficking can be used to promote islet beta cell survival. Growth factor signalling is dependent on the presence of cell surface receptors. Endosomal trafficking and subsequent recycling or degradation of these receptors is controlled by the Rab GTPase family of proteins. We show that Rab7a siRNA inhibition enhances IGF-1 and HGF signalling in beta cells and increases expression of the growth factor receptors IGF-1R and c-Met. Furthermore, Rab7a inhibition promotes beta cell growth and islet survival, and protects against activation of apoptosis and autophagy pathways under conditions of metabolic stress. This study therefore demonstrates that Rab7a-mediated trafficking of growth factor receptors controls beta cell survival. Pharmaceutical Rab7a inhibition may provide a means to promote beta cell survival in the context of metabolic stress and prevent the onset of type 2 diabetes

Noninvasive Prenatal Diagnosis for Cystic Fibrosis: Implementation, Uptake, Outcome, and Implications

BACKGROUND: Noninvasive prenatal diagnosis (NIPD) for monogenic disorders has a high uptake by families. Since 2013, our accredited public health service laboratory has offered NIPD for monogenic disorders, predominantly for de novo or paternally dominantly inherited mutations. Here we describe the extension of this service to include definitive NIPD for a recessive condition, cystic fibrosis (CF). // METHODS: Definitive NIPD for CF was developed using next-generation sequencing. Validation was performed on 13 cases from 10 families before implementation. All cases referred for CF NIPD were reviewed to determine turnaround times, genotyping results, and pregnancy outcomes. // RESULTS: Of 38 referrals, 36 received a result with a mean turnaround of 5.75 days (range, 3-11 days). Nine cases were initially inconclusive, with 3 reported unaffected because the low-risk paternal allele was inherited and 4 cases in which the high-risk paternal allele was inherited, receiving conclusive results following repeat testing. One case was inconclusive owing to a paternal recombination around the mutation site, and one case was uninformative because of no heterozygosity. Before 2016, 3 invasive referrals for CF were received annually compared with 38 for NIPD in the 24 months since offering a definitive NIPD service. // CONCLUSIONS: Timely and accurate NIPD for definitive prenatal diagnosis of CF is possible in a public health service laboratory. The method detects recombinations, and the service is well-received as evidenced by the significant increase in referrals. The bioinformatic approach is gene agnostic and will be used to expand the range of conditions tested for