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Author(s): V. Wood [1]; R. Gwilliam [1]; M.-A. Rajandream (corresponding author) [1]; M. Lyne [1]; R. Lyne [1]; A. Stewart [2]; J. Sgouros [2]; N. Peat [3]; J. Hayles [3]; [...]

Author(s): V. Wood; R. Gwilliam; M.-A. Rajandream; M. Lyne; R. Lyne; A. Stewart; J. Sgouros; N. Peat; J. Hayles; S. Baker; D. Basham; S. Bowman; K. Brooks; D. Brown; S. [...]

Abstract Background The ubiquitin(Ub)-proteasome pathway is implicated in the regulation of a variety of cellular functions and plays a major role in stress response in eukaryotic cells, by targeting misfolded and damaged proteins for degradation. In addition, in the presence of DNA damage, the Ub-proteasome system regulates proteins involved in sensing, repairing, and/or tolerating the damage. Antitumor agents such as cisplatin can activate the pathway, but the role of specific pathway components in cell sensitivity/response to the drug is not known. Since platinum compounds represent clinically relevant antitumor agents and a major limitation to their use is the development of drug resistance, there is an urgent need for identifying targets for improving their efficacy. Results In the present study, we performed a genome-wide screening for sensitivity to cisplatin using non-essential haploid deletion mutants of the fission yeast Schizosaccharomyces pombe, belonging to a collection of haploid strains constructed through homologous recombination. Using this approach, we identified three Ub-proteasome mutants exhibiting hypersensitivity to cisplatin (ubp16, ubc13 and pmt3) and ten mutants (including ufd2, beta7 20S, rpt6/let1) resistant to the drug. In addition, the importance of lub1 gene emerged from the comparison between the present screening and gene expression profile data previously obtained in fission yeast. Conclusions The factors identified in the present study allowed us to highlight most finely the close relationship between the Ub-proteasome system and DNA damage response mechanisms, thus establishing a comprehensive framework of regulators likely relevant also in higher eukaryotes. Our results provide the proof of principle of the involvement of specific genes modulated by cisplatin treatment in cell response to the drug, suggesting their potential role as targets for modulating cisplatin sensitivity. In this regard, the prospective identification of novel targets for modulation of cisplatin sensitivity in an eukaryotic model organism appears particularly intriguing towards the discovery of strategies to overcome cisplatin resistance in human tumors.

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced cardiomyopathy (PVC-CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200-220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC-CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC-CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store-operated Ca 2+ entry, calcineurin/NFAT pathway, β-myosin heavy chain, and skeletal type α-actin were unaltered in the PVC-CM group. In contrast, pro-hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC-CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti-hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro-hypertrophic factor VEGF-A and its receptor VEGFR2 were significantly elevated in the PVC-CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy., (© 2023 The Authors. IUBMB Life published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

PomBase (www.pombase.org), the model organism database (MOD) for the fission yeast Schizosaccharomyces pombe, supports research within and beyond the S. pombe community by integrating and presenting genetic, molecular, and cell biological knowledge into intuitive displays and comprehensive data collections. With new content, novel query capabilities, and biologist-friendly data summaries and visualization, PomBase also drives innovation in the MOD community., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

This study was designed to identify and investigate bioactive natural product compounds that alter the cellular shape of the fission yeast Schizosaccharomyces pombe and induce a "rounded" or "small" cellular morphological phenotype. Bioassays using a range of antifungal agents against a multidrug-sensitive fission yeast strain, SAK950 showed that many induced a "rounded" phenotype. We then investigated whether 46 of the actinomycete strains identified in our previous study as inducing a similar phenotype produced antifungal agents of similar classes. We show that five of the strains produced streptothricin and that 26 strains produced polyenes, including fungichromin, filipin and candicidin, the last of which was produced by 24 strains. A taxonomic study of the strains indicated that the majority of the candicidin only producers were Streptomyces hydrogenans and S. albidoflavus whilst those that additionally produced streptothricin were related to S. enissocaesilis. A follow-up study to investigate the natural products made by related strains indicated that they followed a similar pattern. The identification of several compounds from the actinomycete strains similar to the antifungal agents initially tested confirm the validity of an approach using the S. pombe morphological phenotype and actinomycete taxonomy as a predictive tool for natural product identification., (© 2021. The Author(s).)

Background: Nurse shortage is an international issue that has adverse effects on health and the quality of care of whole populations., Aims: The study aimed to explore attrition experienced by return-to-practice students attending higher education institutions in England., Methods: A mixed-methods design, involving questionnaires ( n =114) and in-depth interviews ( n =20), was used., Findings: Just over half (52%) of respondents left nursing after ≥10 years. Most of these (84%) stayed in alternative employment during their break from nursing. There were two distinct reasons for leaving nursing: the inability to maintain a positive work/life balance and a lack of opportunity for career advancement while retaining nursing registration. Respondents reflected positively on their nursing experience yet frequently reported significant personal or professional incidents prompting their decision to leave., Conclusion: The reasons nurses leave are complex. Professional bodies and managers need to work together to address concerns many nurses have during their careers that lead to them deciding to leave the profession.

Maximizing the impact and value of scientific research requires efficient knowledge distribution, which increasingly depends on the integration of standardized published data into online databases. To make data integration more comprehensive and efficient for fission yeast research, PomBase has pioneered a community curation effort that engages publication authors directly in FAIR-sharing of data representing detailed biological knowledge from hypothesis-driven experiments. Canto, an intuitive online curation tool that enables biologists to describe their detailed functional data using shared ontologies, forms the core of PomBase's system. With 8 years' experience, and as the author response rate reaches 50%, we review community curation progress and the insights we have gained from the project. We highlight incentives and nudges we deploy to maximize participation, and summarize project outcomes, which include increased knowledge integration and dissemination as well as the unanticipated added value arising from co-curation by publication authors and professional curators., (© The Author(s) 2020. Published by Oxford University Press.)

PomBase (www.pombase.org), the model organism database for the fission yeast Schizosaccharomyces pombe, has undergone a complete redevelopment, resulting in a more fully integrated, better-performing service. The new infrastructure supports daily data updates as well as fast, efficient querying and smoother navigation within and between pages. New pages for publications and genotypes provide routes to all data curated from a single source and to all phenotypes associated with a specific genotype, respectively. For ontology-based annotations, improved displays balance comprehensive data coverage with ease of use. The default view now uses ontology structure to provide a concise, non-redundant summary that can be expanded to reveal underlying details and metadata. The phenotype annotation display also offers filtering options to allow users to focus on specific areas of interest. An instance of the JBrowse genome browser has been integrated, facilitating loading of and intuitive access to, genome-scale datasets. Taken together, the new data and pages, along with improvements in annotation display and querying, allow users to probe connections among different types of data to form a comprehensive view of fission yeast biology. The new PomBase implementation also provides a rich set of modular, reusable tools that can be deployed to create new, or enhance existing, organism-specific databases.

Here, we briefly outline the history of fission yeast, its life cycle, and aspects of its biology that make it a useful model organism for studying problems of eukaryotic molecular and cell biology., (© 2018 Cold Spring Harbor Laboratory Press.)

This study was designed to identify bioactive compounds that alter the cellular shape of the fission yeast Schizosaccharomyces pombe by affecting functions involved in the cell cycle or cell morphogenesis. We used a multidrug-sensitive fission yeast strain, SAK950 to screen a library of 657 actinomycete bacteria and identified 242 strains that induced eight different major shape phenotypes in S. pombe These include the typical cell cycle-related phenotype of elongated cells, and the cell morphology-related phenotype of rounded cells. As a proof of principle, we purified four of these activities, one of which is a novel compound and three that are previously known compounds, leptomycin B, streptonigrin and cycloheximide. In this study, we have also shown novel effects for two of these compounds, leptomycin B and cycloheximide. The identification of these four compounds and the explanation of the S. pombe phenotypes in terms of their known, or predicted bioactivities, confirm the effectiveness of this approach., Competing Interests: Competing interestsN.E.E.A. and J.E. hold shares, or share options, in Demuris Ltd., (© 2017. Published by The Company of Biologists Ltd.)

Schizosaccharomyces pombe has been used extensively as a model organism, however it is only recently that the first prion in this organism, a copper transporter protein encoded by ctr4, has been conclusively demonstrated. Prions are found in a wide range of organisms and have been implicated in a number of human neurodegenerative diseases. Research into the biology of prions has been carried out mainly in the budding yeast Saccharomyces cerevisiae, however there are many questions still to be addressed . Now, with the identification of the Ctr4 prion in S. pombe, further work in the two yeasts and comparisons of prion biology in these organisms should lead to a greater understanding of prions and their role in disease., Competing Interests: Conflict of interest: There is no conflict of interest resulting from this article.

We have carried out a haploinsufficiency (HI) screen in fission yeast using heterozygous deletion diploid mutants of a genome-wide set of cell cycle genes to identify genes encoding products whose level determines the rate of progression through the cell cycle. Cell size at division was used as a measure of advancement or delay of the G2-M transition of rod-shaped fission yeast cells. We found that 13 mutants were significantly longer or shorter (greater than 10%) than control cells at cell division. These included mutants of the cdc2, cdc25, wee1 and pom1 genes, which have previously been shown to play a role in the timing of entry into mitosis, and which validate this approach. Seven of these genes are involved in regulation of the G2-M transition, 5 for nuclear transport and one for nucleotide metabolism. In addition we identified 4 more genes that were 8-10% longer or shorter than the control that also had roles in regulation of the G2-M transition or in nuclear transport. The genes identified here are all conserved in human cells, suggesting that this dataset will be useful as a basis for further studies to identify rate-limiting steps for progression through the cell cycle in other eukaryotes.