Fixed-term

Details How a cell determines its fate is one of the longstanding and fundamental questions in Biology. Compared with animal cells, plant cells demonstrate incredible plasticity in terms of cell fate changes. A differentiated plant somatic cell can be triggered to de-differentiate and to regain its pluripotency. Despite the potential agricultural impact and fundamental biological importance of this phenomenon, research on “triggered pluripotency” has been left largely unexplored in plants. Kalanchoë (Mother of thousands) species propagate asexually by forming baby plants (plantlets) on the edge of leaves. During plantlet formation, somatic cells in the leaf margin change their cell fate and regain pluripotency to form plantlets. However, little is known about the underlying molecular and genetic mechanisms and cues triggering such a cell fate change during plantlet initiation. The main aim of this project is to unravel the molecular genetic mechanisms involved in the plantlet initiation. Specifically, you will investigate the role of the embryogenesis regulators during this process. First, you will determine when and where the plantlet initiation occurs using a combination of state-of-the-art technologies. Then you will investigate the role of key embryogenesis genes during plantlet formation by inhibiting the pathways. You will also perform laser capture microdissection (LCM) and RNA-Seq to identify key regulators and pathways and to build an integrated model of this process. The multidisciplinary approaches used in this project will deliver novel insights into how biochemical, biophysical and specific molecular components cooperate to trigger pluripotency and initiate plantlet development, which can be used to explain broader developmental processes. As such, this project will provide a broad training in cutting-edge techniques in plant molecular sciences and allow you to make a substantive contribution to important developmental processes underlying food security. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum upper second-class honours degree (or equivalent) in a related area/subject. A life science undergraduate/master’s degree in disciplines such as Plant Sciences, Biochemistry, Cell Biology or Genetics. Candidates with experience in non-model plant species or with an interest in biotechnology improving crops are encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Genetics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 2 (medium) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Jácome-Blásquez, F., Ooi, J. P., Zeef, L. & Kim, M. (2022). Comparative transcriptome analysis of two Kalanchoë species during plantlet formation. Plants 11 (13), 1643. • McCready, K., Spencer, V., Jácome-Blásquez, F., Burnett, J., Sanchez, I., Riches, Z. & Kim, M. (2022). TARGET OF RAPAMYCIN is essential for asexual vegetative reproduction in Kalanchoë. Plant physiology 189 (1), 248-263. • McCready, K., Spencer, V. & Kim, M. (2020). The importance of TOR kinase in plant development. Frontiers in Plant Science 11, 16. • H Allen, L Zeef, K Morreel, G Goeminne, M Kumar, LD Gomez, AP Dean, A Eckmann, C Casiraghi, SJ McQueen-Mason, W Boerjan, SR Turner (2022). Flexible and digestible wood caused by virus-induced alteration of cell wall composition. Current Biology (In Press) • M Kumar, P Carr, SR Turner (2022). An atlas of Arabidopsis protein S-acylation reveals its widespread role in plant cell organisation and function. Nature Plants, 1-12

Details Cilia are microscopic hair-like structures that protrude from the surface of almost every vertebrate cell-type, and are critical to numerous biological functions. There are motile cilia found on cells such as those of the respiratory tract, responsible for moving fluids around the cells. Additionally, primary cilia serve as sensors for signal transduction in and out of the cell. If the important functions of cilia are disrupted, it can lead to disease. The collection of diseases caused by cilia dysfunction are called ciliopathies. There are multiple proteins that interact to form the cilium. Some proteins are required for the transport of cargo within the cilium, whereas others build up the three-dimensional specialised structure of the cilium. A recent discovery has shown that multiple proteins that are part of the pre-mRNA splicing machinery, termed the spliceosome, localise to the base of the cilium within the cytoplasm of cells. The functions that spliceosome proteins perform at the cilium are poorly understood. However, mutations in these specific spliceosome proteins cause retinitis pigmentosa, a disease that is linked to cilia defects, indicating that these proteins play an important role in the function of cilia. In this project we seek to understand how spliceosome proteins are localised to the cilium and identify the roles these proteins have in cilia function. We will use bioinformatic analysis to search for putative cilia localisation signals within the protein sequences of spliceosome proteins known to localise to the cilia. We will use fish and mouse Prpf8 mutant models to investigate whether the roles of Prpf8 in the spliceosome and at the cilium are independent. These discoveries will further our understanding of the fundamental biological functions of cilia, as well as provide insights into diseases such as retinitis pigmentosa which are caused by cilia defects. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in genetics, developmental biology, biomedical sciences, cell biology or biochemistry (or related subjects). Candidates with prior research experience in cilia biology or splicing factors are encouraged to apply. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Genetics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Jiang F, Boylan M, Maxwell DW, Qureshi WMS, Rowlands CF, Tenin G, Mitchell K, Stephen LA, Vasconcelos EJR, Wang D, Chen T, Zha J, Liu J, Althali N, Leordean DV, Gallagher MT, Basu B, Szymanska K, Veeraghanta A, Keavney B, Humphries MJ, Ellingford J, Smith D, Johnson CA, O’Keefe RT, Roy S, Hentges KE. 2025. The RNA splicing factor PRPF8 is required for left-right organiser cilia function and determination of cardiac left-right asymmetry via regulation of Arl13b splicing. bioRxiv [Preprint]. May 27:2025.05.22.654869. doi: 10.1101/2025.05.22.654869. PMID: 40501629 Maxwell DW, O’Keefe RT, Roy S, Hentges KE. (2021) The role of splicing factors in retinitis pigmentosa: links to cilia. Biochem Soc Trans. 49(3):1221-1231.

Details Biomechanical and behavioral techniques are widely used to examine how selection shapes an organism’s phenotype. However, such examinations are far from straight forward, as selection rarely acts on phenotypic traits in isolation. Instead, natural and/or sexual selection act on multiple traits simultaneously and can be constrained by trade-offs among phenotypic traits. Furthermore, data on locomotor biomechanics, which can constrain selection, aren’t known for most species, particularly in the wild, restricting the insights that can be gained from animals in their natural environment. Birds are a good model for understanding how sexual selection acts as they display a variety of behaviours and associated morphologies that have evolved because of sexual selection. The Svalbard rock ptarmigan lives in the high Arctic and is endemic to Svalbard. Detailed biomechanics of locomotion (including investigating seasonal and sex effects on the energetics and kinematics of level and incline treadmill locomotion) have been characterized in the Svalbard rock ptarmigan. These data have shown that males of this species are capable of three distinct locomotor gaits (walking, grounded running and aerial running). Remarkably, male ptarmigan demonstrate energetic saving upon the switch to aerial locomotion – providing the first evidence for energy savings with gait change in a small crouched-postured vertebrate. There are also differences between male and female locomotion and we have recently hypothesized that sexual selection may act on locomotor performance in the Svalbard ptarmigan, providing a fascinating new area for research. Here we investigate how sexual selection, and biomechanical constraints influence male ptarmigan in the wild. This proposal will use lab and field experiments (focussing on genetics, ecological, physiological and biomechanics datasets) to yield powerful insights into how selection is shaping phenotypes in an endemic high Arctic species, the Svalbard rock ptarmigan. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in Biology or Zoology. Candidates with experience in whole animal biology or with an interest in biomechanics, animal physiology and field work are encouraged to apply. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Biology, Zoology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 2 (med) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Marmol Guijarro AC, Nudds RL, Folkow LP, Lees JJ & Codd JR (2021) Does posture explain the kinematic differences in a grounded running gait between male and female Svalbard rock ptarmigan (Lagopus muta hyperborea) moving on snow? Polar Biol. 44(6): 1141-1152 (https://doi.org/10.1007/s00300-021-02872-x). IF 2.310, Rank 30/60 Biodiversity & Conservation Marmol Guijarro AC, Nudds RL, Folkow LP, Sellers WI, Falkingham P & Codd JR (2021) The influence of snow properties on speed and gait in the Svalbard rock ptarmigan. Int. Org. Biol. 3(1): 1-11 (https://doi.org/10.1093/iob/obab021). IF 2.149 Rank 52/93 Biology. Marmol Guijarro AC, Nudds RL, Folkow LP & Codd JR (2020) Examining the accuracy of trackways for predicting gait selection and speed of locomotion. Frontiers Zool. 17: 17 (https://doi.org/10.1186/s12983-020-00363-z). IF 3.172 Rank 11/174 Zoology. Marmol Guijarro AC, Nudds RL, Marrin J, Folkow LP & Codd JR (2019) Terrestrial locomotion of the Svalbard rock ptarmigan: comparing field and treadmill studies Nature Sci. Reports 9:11451. (https://10.1038/s41598-019-47989-6). Nature Sci. Reports. IF 5.133, Rank 17/72 Multidisciplinary. Nudds RL, Folkow LP, Lees JJ, Tickle PG, Stokkan K-A & Codd JR (2011) Evidence for energy savings from aerial running in the Svalbard rock ptarmigan (Lagopus muta hyperborea). Proc. R. Soc. B. 278: 2646-2653 (doi:10.1098/rspb.2010.2742). IF 5.349 Rank 13/93 Biology

Details Quantitative proteomics via mass spectrometry is now a cornerstone methodology for biomedical health research and bioscience. However, current methods ignore the massive disparity in evidence quality across proteins, leading to bias in downstream clinical biomarker discovery, understanding of health and disease, and applications seeking to classify or stratify patient samples. Much of this bias stems from uncertainty in measuring protein levels, which can be confounded by the multiple versions (i.e. proteoforms) of a protein expressed from a single gene in the human genome and which influence cell state, function and disease. Current methods routinely ignore this evidence, collapsing signals into one protein per gene. We will use a range of mass spectrometry-driven proteomics and bioinformatics approaches, inclusive of advanced machine learning, to develop and deploy methods to infer the presence and abundance of protein isoforms present in a sample. This will include a more considered approach to dealing with proteins that share common peptides, and using isoform-specific peptides, which can be used identify and ultimately quantify different protein isoforms. We will compare and contrast label-free proteomics methods with targeted mass spectrometry approaches to assess the utility of these approaches. We will exploit existing experimental systems human derived plasma and tissue as well as standard model cell lines to show this is a more informative and unbiased signal of benefit to biomedicine and health. Finally, we seek to show these approaches can enhance bioscience and biomedical proteomics, by co-creating a best practice workflow for incorporating isoform-resolved protein quantities and their uncertainty into downstream biomarker-based classification for diagnostics and prognostics, so that reproducible research principles and interpretability are baked in. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject which could include any bioscience, chemistry, physics or mathematical science. Candidates with experience in proteomics, bioinformatics, computational biology and/or general interest in biomarker discovery, genomics/post-genomics and/or biotechnology, and encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Bioinformatics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 1 (low) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Plubell DL, Käll L, Webb-Robertson BJ, Bramer LM, Ives A, Kelleher NL, Smith LM, Montine TJ, Wu CC, MacCoss MJ. Putting Humpty Dumpty Back Together Again: What Does Protein Quantification Mean in Bottom-Up Proteomics? J Proteome Res. 2022 21:891-98. PMID: 35220718 Creamer DR, Beynon RJ, Hubbard SJ, Ashe MP, Grant CM. Isoform-specific sequestration of protein kinase A fine-tunes intracellular signaling during heat stress. Cell Rep. 2024, 43:114360. PMID: 38865242. Rusilowicz M, Newman DW, Creamer DR, Johnson J, Adair K, Harman V, Grant CM, Beynon RJ, Hubbard SJ. AlacatDesigner ─ computational design of peptide concatamers for protein quantitation. J Proteome Res. 2023, 22:594-604. PMID: 36688735 Phillips AM, Unwin RD, Hubbard SJ, Dowsey AW. (2023). Uncertainty-Aware Protein-Level Quantification and Differential Expression Analysis of Proteomics Data with seaMass. Methods Mol Biol. 2426:141-162.

Details The interface between biochemistry and cell biology is a major scientific challenge; while we can dissect complex biological mechanisms in vitro, studying them in the context of a living cell is more difficult. This issue is even more challenging when we consider cell-to-cell heterogeneity. Methodological advances in studying biology at the single cell level have revealed heterogeneity within various model systems. To advance our knowledge of heterogeneity further, we need innovative technological advances to study molecular changes at the single cell level. We have recently shown that colorectal cancer cells exhibit unexpected molecular heterogeneity in the way they respond to some chemotherapies. This heterogeneity sees a subset of cells slowing their rates of translation elongation via an unknown signalling pathway. Translation elongation has not been previously analysed at the single cell level, in part due to a lack of tools to enable this. However, our observations provide evidence that this heterogeneity exists and could explain different response to chemotherapy. Importantly, we have also developed novel methods to analyse this heterogeneity in multiple model systems, including longitudinal analysis of living cells and within tissues from cancer patients. This studentship will use models of colorectal cancer as a platform to investigate heterogeneous regulation of translation elongation. This will be directly relevant to colorectal cancer, where elongation rates are commonly upregulated, but also other cancers and disease states with elongation dysregulation. The student will determine how heterogeneity arises, what the consequences of heterogeneity are and explore how pervasive this phenomenon is. Our aim is to understand the drivers of heterogeneity and how their modulation could benefit disease management by altering the fate of specific subpopulations of cell. The project design and supervision provided during this studentship will allow the student to develop technical and transferable skills for their future careers. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a subject related to biological sciences. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cancer sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Knight J, Vlahov N, Gay D, Ridgway R, Faller W, Proud C, Mallucci G, von der Haar T, Smales M, Willis A and Sansom O (2021). Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. Elife. (doi.org/10.7554/eLife.69729). In this paper, John Knight defined the requirement for fast translation elongation in colorectal cancer and identified a signature for this in human tissue. We also identified a way to suppress elongation that suppressed tumour proliferation. Knight J, Alexandrou C, Skalka G, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, (28 authors), Bushell M and Sansom O (2021). MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer Discovery. (doi:10.1158/2159-8290.CD-20-0652). Here John Knight found consistently elevated rates of translation elongation in colorectal cancer models and a protective resistance mechanism driven by mutant KRAS that ensures rapid elongation is maintained. Kershaw C, Nelson M, Lui J, Bates C, Jennings M, Hubbard S, Ashe M and Grant C (2021). Integrated multi-omics reveals common properties underlying stress granule and P-body formation. RNA Biology. (doi.org/10.1080/15476286.2021.1976986). Here the Ashe group used ribosome profiling, among other biochemical and imaging analyses, to determine the effects of condensate formation on translation. Kershaw C, Nelson M, Castelli L, Pavitt G, Hubbard S and Ashe M (2023). Translation factor and RNA binding protein mRNA interactomes support broader RNA regulons for posttranscriptional control. Journal of Biological Chemistry. (doi.org/10.1016/j.jbc.2023.105195). This work from the Ashe group demonstrates the supervisory team’s expertise in the molecular analysis of protein synthesis, including data analysis from large omics experiments. Coulson-Gilmer C, Morgan R, Nelson L, Barnes B, Tighe A, Wardenaar R, Spierings D, (4 authors) McGrail J, Taylor S (2021). Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models. Journal of Experimental & Clinical Cancer Research. (doi.org/10.1186/s13046-021-02124-0) In this paper, the Taylor group utilised high-content imaging using phospho-protein biomarkers to characterise drug responses.

Details RAC1 is a signalling protein that regulates many cellular processes and is essential during embryonic development. We recently discovered a novel genetic disease called RAC1-related neurodevelopmental disorder (RAC1-NDD) that results from mutations in the RAC1 gene. Individuals with this condition have a variety of neurological abnormalities, but the nature of abnormalities differ between individuals with different mutations. This project will explore the molecular and cellular mechanisms by which the RAC1 mutations identified in patients give rise to neurological abnormalities and why different mutations in the RAC1 gene result in different abnormalities. This will be done using a combination of cell culture and model organism approaches. Cell culture will be used to explore how different RAC1 mutations affect cell morphology and behaviour. The fruit fly Drosophila will be used as a simple animal model to investigate how RAC1 mutations affect neuronal development and function. We then plan to use the frog Xenopus to model the effect of selected RAC1 mutations on vertebrate brain development. In addition, computational bioinformatic approaches will be used to identify and characterise novel disease mutations in RAC1 and related genes. This is a truly inter-disciplinary project led by basic scientists and a clinical academic who will bring complementary areas of expertise. The project will equip the student with a range of versatile skills including bioinformatic analysis of human genome/exome sequences, cell culture, modelling human disease in model organisms and cloning/transgenesis techniques such as CRISPR. The skills and knowledge provided by project will provide a solid foundation for a future career in disease-gene discovery, precision medicine, translational medicine or neuroscience. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Neuroscience Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 2 med fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, Sito H, Prasad P, Anyane-Yeboa K, Badalato L, Dimitrov B, Fitzpatrick D, Hurst ACE, Jansen AC, Kelly MA, Krantz I, Rieubland C, Ross M, Rudy NL, Sanz J, Stouffs K, Xu ZL, Malliri A, Kazanietz MG, Millard TH. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology. Brain (2022) 145, 4232-4245. doi: 10.1093/brain/awac049. PMID: 35139179 Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, Clayton-Smith J, Corning K, Jones JR, Lam WWK, Mancini GMS, Marcelis C, Mohammed S, Pfundt R, Roifman M, Cohn R, Chitayat D; Deciphering Developmental Disorders Study, Millard TH, Katsanis N, Brunner HG, Banka S. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am. J. Hum. Genet. (2017) 101 466-477.

Details In humans, approximately a quarter of all pregnancies end before 6 weeks’ gestation, often around the time of implantation, before the pregnancy has become apparent. Reasons behind early pregnancy losses are still poorly understood. Therefore, identifying factors that contribute to successful development and establishment of functional mother-foetus connection is so important to shedding light on causes of early miscarriages and early pregnancy pathologies. Dynamic relations between local cell neighbourhood and the changing architecture of developing organisms are a crucial part of the developmental process, albeit rarely investigated in detail due to the complexity of the issue and the lack of appropriate tools. As a result, little is known about what constitutes correct organisation of early mammalian embryo. The overarching aim in this project is to understand the link between changing architecture of preimplantation mammalian embryo and the genetic factors that controls the development. Specifically, this project will involve: •  identifying the critical stages in early mammalian development that can be linked to embryo viability with the use of machine learning pipeline created in the lab •  create interactive 4D map of the developing mammalian embryo using newly developed in the lab architecture assessment tool •  testing the correlation between embryo architecture, cell micro-environment and embryo viability in order to identify markers of health vs disrupted development •  describe the link between differences in embryo architecture and genetic control of the early development. This work will provide an understanding of the fundamental processes during early development and contribute to improvements in the safety and efficiency of IVF techniques. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in biology, biomedical research or physics. Candidates with experience in machine learning or with an interest in image analysis are encouraged to apply. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.    Before you Apply  Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply  To be considered for this project you MUST submit a formal online application form – on the application form select PhD Developmental Biology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion   Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References The student will be instructed how to perform all necessary lab techniques by myself and subsequently will be working closely with me. We will be meeting weekly to discuss progress of the project. Recent publications: 1. Forsyth, J.E., Al-Anbaki, A.H., Plusa, B., Cotter, S.L. Application to cell matching across imaging modalities. Statistics and Computing, 2023, 33(5), 100 2. Forsyth J.E, Al-Anbaki A.H, de la Fuente R, Modare N, Perez-Cortes D, Rivera I, Seaton Kelly R, Cotter S, Plusa B. IVEN: A quantitative tool to describe 3D cell position and neighbourhood reveals architectural changes in FGF4-treated preimplantation embryos. PLoS Biology, 2021, 19(7), e3001345. doi: 10.1371/journal.pbio.3001345 3. Plusa B, Piliszek A, Common principles of early mammalian embryo self-organisation. Development (Cambridge), 2020, 147(14), dev183079. doi.org/10.1242/dev.183079

Details The dyadic cleft is the biological structure responsible for the contraction of the cardiac myocyte and it is made of a calcium storage unit, the junctional sarcoplasmic reticulum (jSR) and a trigger unit the transverse tubule (t-tubule). In healthy individuals the juxtaposition of these units is defined by a strict geometry that allows the low voltage gated calcium channels (LTCCs), on the t-tubules, to stimulate the release of a well-regulated amount of calcium by the ryanodine receptors (RyR2) on the jSR. When this geometry is altered problems ensue affecting calcium release. If the calcium released in the myoplasm is not synchronised with the cell’s demands or is too abundant it causes arrhythmias. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by the onset of life-threatening arrhythmias during exercise or emotional stress. CPVT is caused by mutations of the ryanodine receptors (RyR2) or calsequestrin (CSQ2 and accessory protein of RyR2). These mutations predispose to calcium leak from the jSR that can lead to arrhythmias. Recent studies have shown that in CPVT caused by CSQ2 mutations there are significant alterations of the structure of the jSR with significant increase in jSR volume and surface area. To date no information is available on the structure of the jSR in CPVT caused by RyR2 mutations We hypothesise that: The jSR and the geometry of the dyadic cleft is altered in all forms of CPVT. A mouse model of RyR2 mutation (R2474S), closely reproducing the one found in human, and age matched controls will be used to test the hypothesis via the following aims and objectives: • Altered dyadic cleft distance in CPVT. In control animals this distance has been verified to be ~15 nm. Electron microscopy will be used to obtain high resolution data in CPVT animals and compare them to controls. • Altered jSR volume or surface area. Electron tomography will be used to compare jSR geometries in CPVT mice to those found in controls. • Altered distribution/density of RyR2 on the jSR in CPVT. Electron tomography will be used, for the first time, to understand if the distribution of the RyR2 is different in CPVT compared to controls. This project will establish if RyR2 mutations found in CPVT are linked to an altered geometry of the dyadic cleft or rather to a different distribution or density of the RyR2 on the jSR. Arrhythmia caused by CPVT will be linked to dyadic cleft remodelling or more precisely to RyR2 redistribution. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.   Candidates with experience in electron microscopy or with an interest in image analysis are encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cardiovascular Sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References On the dyadic cleft structure: https://www.flickr.com/photos/bhforguk/7401357054/ Robinson VM, Di Diego JM, Bowes MT, Kowey PR, Antzelevitch C, Venetucci L. Increased susceptibility to ventricular arrhythmia at low-normal and moderately low levels of extracellular potassium in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2022 Aug;19(8):1389-1391. doi: 10.1016/j.hrthm.2022.04.005. Epub 2022 Apr 13. PMID: 35429650. Sheard TMD, Kharche SR, Pinali C, Shiels HA. 3D ultrastructural organisation of calcium release units in the avian sarcoplasmic reticulum. J Exp Biol. 2019 Apr 1;222(Pt 7):jeb197640. doi: 10.1242/jeb.197640. PMID: 30814295. Rizzi N, Liu N, Napolitano C, Nori A, Turcato F, Colombi B, Bicciato S, Arcelli D, Spedito A, Scelsi M, Villani L, Esposito G, Boncompagni S, Protasi F, Volpe P, Priori SG. Unexpected structural and functional consequences of the R33Q homozygous mutation in cardiac calsequestrin: a complex arrhythmogenic cascade in a knock in mouse model. Circ Res. 2008 Aug 1;103(3):298-306. doi: 10.1161/CIRCRESAHA.108.171660. Epub 2008 Jun 26. PMID: 18583715. Knollmann BC, Chopra N, Hlaing T, Akin B, Yang T, Ettensohn K, Knollmann BE, Horton KD, Weissman NJ, Holinstat I, Zhang W, Roden DM, Jones LR, Franzini-Armstrong C, Pfeifer K. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2006 Sep;116(9):2510-20. doi: 10.1172/JCI29128. Epub 2006 Aug 24. PMID: 16932808; PMCID: PMC1551934.

Details Human tissues are complex architectures made up of a combination of cells spatially organised within distinct matrices. Cells make and maintain this matrix, through which they receive biochemical, mechanical, and topological stimuli that are crucial to establish and maintain tissue function. This relationship is central to our understanding of a diverse range of biological processes, from development to ageing, and in diseases such as fibrosis and cancer. However, cell-matrix relationships are poorly defined to date due to a lack of defined model systems that can precisely mimic 3D cellular microenvironments. We are particularly interested in the study of breast cancer, the second highest cause of mortality in women. After ageing, the highest risk predictor for breast cancer is high mammographic density (MD) – the opacity of breast tissue observed in a mammogram. Little is known about why high MD correlates with risk, although our work suggests that it is in part due to a fault in mechanical signalling. Our understanding of cancer has been improved by the use of 3D-matrix model systems based on Matrigel, a complex mixture of proteins derived from tumours grown in mice. However, Matrigel is difficult to work with: its composition is highly variable, and its mechanical properties are unreflective of physiology. To successfully model human breast tissue, we require: (i) a synthetic basement membrane (BM) matrix that can support the growth of epithelial cells and (ii) a synthetic stromal matrix to support the growth of fibroblast cells. The synthetic matrices should incorporate appropriate cell adhesion ligands, possess excellent mechanical integrity, facilitate control over topological features such as porosity, and be printable to enable spatial patterning through interfacing distinct cell-matrix compartments. In this project, the student will develop a Matrigel alternative using biocompatible polymers that incorporate functional matrix-specific proteins through recombinant engineering and peptide synthesis strategies. Eligibility Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a subject related to the proposal, but including: biomedical sciences, cell biology, cancer biology, molecular biology, biochemistry, polymer chemistry, or biophysics. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cell Matrix Research Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Jones, M., Percival, H., Hales, A., Wood, A., Sun, H., Tennant, F., Broadberry, E., Skaria, E., Barnes, H., Zindy, E., Lawless, C. , Streuli, C., Swift, J., Brennan, K., and Gilmore, AP. (2025). Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation. Sci. Rep. https://doi.org/10.1038/s41598-025-12880-0 Lingard, E., Dong, S., Hoyle, A., Appleton, E., Hales, A., Skaria, E., Lawless, C., Taylor-Hearn, I., Saadati, S., Chu, Q., Miller, A.F., Domingos, M., Saiani, A., Swift, J. and Gilmore, A.P. (2024). Optimising a self-assembling peptide hydrogel as a Matrigel alternative for 3-dimensional mammary epithelial cell culture. Biomater. Adv. https://doi.org/10.1016/j.bioadv.2024.213847 Chaudhuri, O., Cooper-White, J., Janmey, P., Mooney, D.J., Shenoy, V.B. (2020). Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature. https://doi.org/10.1038/s41586-020-2612-2 Aisenbrey, E.A., Murphy, W.L. (2020). Synthetic alternatives to Matrigel. Nat. Rev. Mater. https://doi.org/10.1038/s41578-020-0199-8

Details Genetic studies have identified numerous variants within the human genome associated with susceptibility to common complex inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis (UC). Many of these lie near to immune-related genes and show extensive overlap between diseases. Recent single cell studies have identified molecularly distinct immune cell populations from disease relevant tissues which are associated with pathological inflammation. However, while the overlap of fibroblast sub-types has been explored, the extent of overlap between immune cell populations or their relevance to the genetic basis of the diseases has not. This project aims to explore this overlap to identify shared states which could drive common inflammatory mechanisms within these diseases and to elucidate the genetic basis behind them. This will be achieved by integrating the wealth of publicly available single cell and bulk omics data to generate an annotated, shared resource across inflammatory diseases which has the potential to identify novel drug targets or inform the selection of existing therapies based on genetic risk. Eligibility Applicants are expected to hold (or about to obtain) an undergraduate honours degree (or equivalent) in either a biological subject area with a strong emphasis on bioinformatics or computational subject area with a strong emphasis on biology. Research experience in data analysis, epigenomics and single cell genomics is desirable. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Bioinformatics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Ge, X., Frank-Bertoncelj, M., Klein, K., McGovern, A., Kuret, T., Houtman, M., Burja, B., Micheroli, R., Shi, C., Marks, M., Filer, A., Buckley, C. D., Orozco, G., Distler, O., Morris, A. P., Martin, P., Eyre, S., & Ospelt, C. (2021). Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability. Genome Biology, 22(1), 247. https://doi.org/10.1186/s13059-021-02460-6 Korsunsky, I., Wei, K., Pohin, M., Kim, E. Y., Barone, F., Major, T., Taylor, E., Ravindran, R., Kemble, S., Watts, G. F. M., Jonsson, A. H., Jeong, Y., Athar, H., Windell, D., Kang, J. B., Friedrich, M., Turner, J., Nayar, S., Fisher, B. A., … Raychaudhuri, S. (2022). Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med, 3(7), 481-518.e14. https://doi.org/10.1016/j.medj.2022.05.002