The essential Mcm7 protein PROLIFERA is localized to the nucleus of dividing cells during the G(1) phase and is required maternally for early Arabidopsis development

PROLIFERA (PRL) encodes a homologue of the DNA replication licensing factor Mcm7, a highly conserved protein found in all eukaryotes. Insertions in the PROLIFERA gene are lethal, resulting in decreased transmission through the female gametophyte, and homozygous embryonic lethality. We show here that PROLIFERA is specifically expressed in populations of dividing cells in sporophytic tissues of the plant body, such as the palisade layer of the leaf and founder cells of initiating flower primordia, Gene fusions with the green fluorescent protein (GFP) reveal that the PROLIFERA protein accumulates during the G(1) phase of the cell cycle, and is transiently localized to the nucleus. During mitosis, the fusion protein rapidly disappears, returning to daughter nuclei during G(1), PROLIFERA::GUS fusions are strongly expressed in the central cell nucleus of mature megagametophytes, which have a variety of arrest points reflecting a leaky lethality. Expression is also observed in the endosperm of mutant prl embryo sacs that arrest following fertilization. Crosses with wild-type pollen result in occasional embryonic lethals that also stain for GUS activity, In contrast, embryos resulting from crosses of wild-type carpels with PRL::GUS pollen do not stain and are phenotypically normal. In situ hybridization of GUS fusion RNA indicates transcription is equivalent from maternally and paternally derived alleles, so that accumulation of maternally derived gametophytic protein is likely to be responsible for the 'maternal' effect

Impact of social prescribing to address loneliness: a mixed methods evaluation of a national social prescribing programme

Loneliness is considered a global public health issue because of its detrimental impact on physical and mental health but little is known about which interventions can reduce loneliness. One potential intervention is social prescribing, where a link worker helps service‐users to access appropriate support such as community activities and social groups. Some qualitative studies have identified that social prescribing may help to reduce service‐users’ loneliness. Given this, the British Red Cross (a third sector organisation) developed and delivered a national social prescribing service in the United Kingdom to support people who were experiencing, or at risk of, loneliness. Service‐users could receive up to 12 weeks of support from a link worker. A mixed methods study was conducted to understand the impact of the support on loneliness, and to identify the facilitators and barriers to service delivery. The study included: (a) analysis of quantitative data collected routinely between May 2017 and December 2019 (n = 10,643) including pre‐post analysis of UCLA data (n = 2,250) and matched comparator work to measure changes in loneliness; (b) semi‐structured interviews with service‐users, link workers and volunteers (n = 60) and (c) a Social Return on Investment Analysis. The majority of the service‐users (72.6%, n = 1634/2250) felt less lonely after receiving support. The mean change in UCLA score was −1.84 (95% CI −1.91 to −1.77) of a maximum change of 6.00 (decrease indicates an improvement). Additional benefits included improved wellbeing, increased confidence and life having more purpose. The base case analysis estimated a social return on investment of £3.42 per £1 invested in the service. Having skilled link workers and support tailored to individual needs appeared key. However, challenges included utilising volunteers, meeting some service‐users’ needs in relation to signposting and sustaining improvements in loneliness. Nonetheless, the service appeared successful in supporting service‐users experiencing loneliness

Evaluation of the British Red Cross community connectors programme : final report, Social Return on Investment : May 2019

Background: A Social Return on Investment (SROI) was undertaken to evaluate the economic impact of the British Red Cross Community Connectors programme. The programme was a form of social prescribing, which was focused on alleviating loneliness. This type of analysis is particularly suited to interventions that include a wide range of benefits (Nicholls, Lawlor, Neitzert, & Goodspeed, 2009). Objectives: The SROI sought to address the following objectives. • Provide robust evidence to inform the British Red Cross decision making with regard to wider rollout and support advocacy • Understand the costs of service delivery and make judgments about its value of outcomes including reductions in the use of other services that might occur as a consequence of the support provided to service users Methods: The different benefits and costs included were informed by the literature and decided by stakeholders and local experts, using workshops, surveys and informal conversations. This approach promotes relevance of findings and encourages a collaborative focus. The SROI approach has been successfully used to evaluate wellbeing interventions. For example, a community befriending programme (Arvidson, Battye, & Salisbury, 2014). It is widely used and recognised by decision makers; for example, the Cabinet Office has issued guidance on how to use SROI. A key advantage of the SROI for evaluating the Community Connectors project is that it enables the economics model to develop over time, and be shaped by unanticipated cost and benefits. This enables any changes to the programme or its costs/benefits to be incorporated. This is important because of the innovative and developing nature of the Community Connectors programme. Findings: The Inputs taken into account (costs for delivering the project) are British Red Cross central organisational costs for the set-up and coordination of the project, British Red Cross project delivery costs and the time donated by volunteers for their training and participation in the Community Connector service. The outcomes (benefits) that are taken into account are improved wellbeing of volunteer, improved wellbeing of service-users (using SWEMWBS scores) and reduced missed health appointments. Wellbeing is valued using the wellbeing valuation approach (Fujiwara, 2013). Conclusion: The ultimate findings from these calculations included total inputs, outcomes, net present value and Social Return on Investment ratio. This demonstrates an economic return to society in general of £1.48 for each pound invested in the project. A range of sensitivity analyses were also conducted

Explosion risk assessment model for underground mine atmosphere

In the coal mining industry, explosions or mine fires present the most hazardous safety threats for coal miners or mine rescue members. Hence, the determination of the mine atmosphere explosibility and its evolution are critical for the success of mine rescues or controlling the severity of a mine accident. However, although there are numbers of methods which can be used to identify the explosibility, none of them could well indicate the change to the explosion risk time evolution. The reason is that the underground sealed atmospheric compositions are so complicated and their dynamical changes are also affected by various influence factors. There is no one method that could well handle all such considerations. Therefore, accurately knowing the mine atmospheric status is still a complicated problem for mining engineers. Method of analyzing the explosion safety margin for an underground sealed atmosphere is urgently desired. This article is going to propose a series of theoretical explosion risk assessment models to fully analyze the evolution of explosion risk in an underground mine atmosphere. Models are based on characteristics of the Coward explosibility diagram with combining mathematical analyzing approaches to address following problems: (1) for an "not-explosive" atmosphere, judging the evolution of explosion risk and estimating the change-of-state time span from "not-explosive" to "explosive" and (2) for an "explosive" atmosphere, estimating the "critical" time span of moving out of explosive zone and stating the best risk mitigation strategy. Such research efforts could not only help mine operators understand the explosibility risk of a sealed mine atmosphere but also provide a useful tool to wisely control explosive atmosphere away from any dangers. In order to demonstrate research findings, case studies for derived models are shown and are also used to instruct readers how to apply them. The results provide useful information for effectively controlling an explosive underground sealed atmosphere

Expert chess memory: Revisiting the chunking hypothesis

After reviewing the relevant theory on chess expertise, this paper re-examines experimentally the finding of Chase and Simon (1973a) that the differences in ability of chess players at different skill levels to copy and to recall positions are attributable to the experts' storage of thousands of chunks (patterned clusters of pieces) in long-term memory. Despite important differences in the experimental apparatus, the data of the present experiments regarding latencies and chess relations between successively placed pieces are highly correlated with those of Chase and Simon. We conclude that the 2-second inter-chunk interval used to define chunk boundaries is robust, and that chunks have psychological reality. We discuss the possible reasons why Masters in our new study used substantially larger chunks than the Master of the 1973 study, and extend the chunking theory to take account of the evidence for large retrieval structures (templates) in long-term memory

Intestinal region-specific Wnt signalling profiles reveal interrelation between cell identity and oncogenic pathway activity in cancer development.

BACKGROUND: Cancer results from the accumulation of mutations leading to the acquisition of cancer promoting characteristics such as increased proliferation and resistance to cell death. In colorectal cancer, an early mutation leading to such features usually occurs in the APC or CTNNB1 genes, thereby activating Wnt signalling. However, substantial phenotypic differences between cancers originating within the same organ, such as molecular subtypes, are not fully reflected by differences in mutations. Indeed, the phenotype seems to result from a complex interplay between the cell-intrinsic features and the acquired mutations, which is difficult to disentangle when established tumours are studied. METHODS: We use a 3D in vitro organoid model to study the early phase of colorectal cancer development. From three different murine intestinal locations we grow organoids. These are transformed to resemble adenomas after Wnt activation through lentiviral transduction with a stable form of β-Catenin. The gene expression before and after Wnt activation is compared within each intestinal origin and across the three locations using RNA sequencing. To validate and generalize our findings, we use gene expression data from patients. RESULTS: In reaction to Wnt activation we observe downregulation of location specific genes and differentiation markers. A similar effect is seen in patient data, where genes with significant differential expression between the normal left and right colon are downregulated in the cancer samples. Furthermore, the signature of Wnt target genes differs between the three intestinal locations in the organoids. The location specific Wnt signatures are dominated by genes which have been lowly expressed in the tissue of origin, and are the targets of transcription factors that are activated following enhanced Wnt signalling. CONCLUSION: We observed that the region-specific cell identity has a substantial effect on the reaction to Wnt activation in a simple intestinal adenoma model. These findings provide a way forward in resolving the distinct biology between left- and right-sided human colon cancers with potential clinical relevance

ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer

The estrogen receptor-α (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1–2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 h. Gene set enrichment analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1–ER–E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumour cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER–ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance