• Ultra-Structural Imaging Provides 3D Organization of 46 Chromosomes of a Human Lymphocyte Prophase Nucleus

      Sajid, Atiqa; email: atiqa.sajid@aku.edu; Lalani, El-Nasir; email: elnasir.lalani@aku.edu; Chen, Bo; orcid: 0000-0001-7515-3042; email: bo.chen@tongji.edu.cn; Hashimoto, Teruo; email: T.Hashimoto@Manchester.ac.uk; Griffin, Darren K.; orcid: 0000-0001-7595-3226; email: D.K.Griffin@kent.ac.uk; Bhartiya, Archana; email: a.bhartiya@ucl.ac.uk; Thompson, George; email: george.thompson@manchester.ac.uk; Robinson, Ian K.; orcid: 0000-0003-4897-5221; email: i.robinson@ucl.ac.uk; Yusuf, Mohammed; email: mohammed.yusuf@aku.edu (MDPI, 2021-06-01)
      Three dimensional (3D) ultra-structural imaging is an important tool for unraveling the organizational structure of individual chromosomes at various stages of the cell cycle. Performing hitherto uninvestigated ultra-structural analysis of the human genome at prophase, we used serial block-face scanning electron microscopy (SBFSEM) to understand chromosomal architectural organization within 3D nuclear space. Acquired images allowed us to segment, reconstruct, and extract quantitative 3D structural information about the prophase nucleus and the preserved, intact individual chromosomes within it. Our data demonstrate that each chromosome can be identified with its homolog and classified into respective cytogenetic groups. Thereby, we present the first 3D karyotype built from the compact axial structure seen on the core of all prophase chromosomes. The chromosomes display parallel-aligned sister chromatids with familiar chromosome morphologies with no crossovers. Furthermore, the spatial positions of all 46 chromosomes revealed a pattern showing a gene density-based correlation and a neighborhood map of individual chromosomes based on their relative spatial positioning. A comprehensive picture of 3D chromosomal organization at the nanometer level in a single human lymphocyte cell is presented.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy-Marqueste, Caroline; Porter, Andrew; orcid: 0000-0002-3353-7002; Kay, Emily; Gurung, Shilpa; Earnshaw, Charles H.; orcid: 0000-0002-7926-8506; Roeck, Katharina; Craig, Sarah; orcid: 0000-0003-1928-582X; Traves, Víctor; Krutmann, Jean; orcid: 0000-0001-8433-1517; et al. (Nature Publishing Group UK, 2021-05-12)
      Abstract: Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

      Budden, Timothy; Gaudy-Marqueste, Caroline; Porter, Andrew; orcid: 0000-0002-3353-7002; Kay, Emily; Gurung, Shilpa; Earnshaw, Charles H; orcid: 0000-0002-7926-8506; Roeck, Katharina; Craig, Sarah; orcid: 0000-0003-1928-582X; Traves, Víctor; Krutmann, Jean; orcid: 0000-0001-8433-1517; et al. (2021-05-12)
      Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

      Budden, Timothy; Gaudy-Marqueste, Caroline; Porter, Andrew; orcid: 0000-0002-3353-7002; Kay, Emily; Gurung, Shilpa; Earnshaw, Charles H; orcid: 0000-0002-7926-8506; Roeck, Katharina; Craig, Sarah; orcid: 0000-0003-1928-582X; Traves, Víctor; Krutmann, Jean; orcid: 0000-0001-8433-1517; et al. (2021-05-12)
      Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
    • UN treaty-based bodies and the Islamic Republic of Iran: Human rights dialogue (1990–2016)

      Moinipour, Shabnam; orcid: 0000-0003-1764-0832; Bendall, Mark (Informa UK Limited, 2018-03-02)
    • Unbiased estimation of the gradient of the log-likelihood in inverse problems

      Jasra, Ajay; Law, Kody J. H.; orcid: 0000-0003-3133-2537; email: kody.law@manchester.ac.uk; Lu, Deng (Springer US, 2021-03-03)
      Abstract: We consider the problem of estimating a parameter θ∈Θ⊆Rdθ associated with a Bayesian inverse problem. Typically one must resort to a numerical approximation of gradient of the log-likelihood and also adopt a discretization of the problem in space and/or time. We develop a new methodology to unbiasedly estimate the gradient of the log-likelihood with respect to the unknown parameter, i.e. the expectation of the estimate has no discretization bias. Such a property is not only useful for estimation in terms of the original stochastic model of interest, but can be used in stochastic gradient algorithms which benefit from unbiased estimates. Under appropriate assumptions, we prove that our estimator is not only unbiased but of finite variance. In addition, when implemented on a single processor, we show that the cost to achieve a given level of error is comparable to multilevel Monte Carlo methods, both practically and theoretically. However, the new algorithm is highly amenable to parallel computation.
    • Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

      Eales, James M; orcid: 0000-0001-6238-5952; Jiang, Xiao; orcid: 0000-0002-1442-8927; Xu, Xiaoguang; orcid: 0000-0003-4568-1623; Saluja, Sushant; Akbarov, Artur; Cano-Gamez, Eddie; McNulty, Michelle T; Finan, Christopher; orcid: 0000-0002-3319-1937; Guo, Hui; orcid: 0000-0003-0282-6933; Wystrychowski, Wojciech; et al. (2021-05-06)
      The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
    • Underlying Thinking Pattern Profiles Predict Parent-Reported Distress Responses in Autism Spectrum Disorder.

      Tollerfield, Isobel; orcid: 0000-0002-8398-3414; email: isobel.tollerfield@nhs.net; Chapman, Hazel M; Lovell, Andrew (2021-05-29)
      Appreciating autistic neurodiversity is important when supporting autistic people who experience distress. Specifically, use of a profiling model can reveal less visible autistic differences, including strengths and abilities. Binary logistic regressions showed that the likelihood of extreme distress responses could be interpreted based on parent-reported autistic thinking pattern profiles for 140 young people. Perspective-taking (specifically empathy), extreme demand avoidance, and over-sensory sensitivity each contributed to the combined regression models. From the clinical perspective of autism as a multi-dimensional and inter-connected construct, there may be implications for planning support and building positive self-understanding. Individually tailored adjustments and support strategies may be identified more easily after delineating variables found across four core aspects: sensory coherence, flexible thinking, perspective-taking, and regulation.
    • Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: An expert elicitation exercise

      Martin, Antony P.; orcid: 0000-0003-4383-6038; Burke, Tom; Asghar, Sohaib; Noone, Declan; Pedra, Gabriel; orcid: 0000-0002-2023-5224; O'Hara, Jamie (Wiley, 2020-04-08)
    • Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: An expert elicitation exercise

      Martin, Antony P.; orcid: 0000-0003-4383-6038; Burke, Tom; Asghar, Sohaib; Noone, Declan; Pedra, Gabriel; orcid: 0000-0002-2023-5224; O'Hara, Jamie (Wiley, 2020-04-08)
    • Understanding the links between hearing impairment and dementia: development and validation of the Social and Emotional Impact of Hearing Impairment (SEI-HI) questionnaire

      Littlejohn, Jenna; orcid: 0000-0001-7447-3810; email: jenna.littlejohn@manchester.ac.uk; Blackburn, Daniel; Venneri, Annalena (Springer International Publishing, 2020-06-10)
      Abstract: Background: The links between hearing impairment (HI) and dementia have been well documented, but factors mediating this relationship remain unknown. Major consequences of HI are social and emotional dysfunction, and as the risk of dementia increases linearly with the severity of HI, it is plausible that socio-emotional difficulties may play a role in this association. Objective: The aim of this study was to develop and validate a tool to analyse levels of hearing-related disability, to investigate ultimately whether subjective disability contributes to risk of cognitive impairment compared with hearing thresholds alone. Methods: Development and validation of the questionnaire, the Social and Emotional Impact of Hearing Impairment (SEI-HI), was conducted in four phases: (1) content; (2) scoring and outcomes; (3) validation; (4) feasibility in a sample of people with cognitive impairment. Results: Considerable evidence was found for the internal and external reliability of the tool with high construct validity, concurrent validity and test-retest values of the SEI-HI questionnaire. A feasibility check on 31 patients with mild cognitive impairment or dementia showed the SEI-HI questionnaire was easy to administer and well-received. Conclusion: The SEI-HI questionnaire is a relevant instrument to assess hearing-related disability which can be used in people with cognitive decline to assess further impact on risk of developing dementia.
    • Understandings of creative practice and pedagogy by teacher education communities in West Bank, Palestine, and North West England

      Adams, Jeff; orcid: 0000-0003-1635-9280; Al-Yamani, Hala; Arya-Manesh, Emma; Mizel, Omar; Owens, Allan; Qurie, Dua’a (Informa UK Limited, 2020-01-27)
    • Uneven solidarity: the school strikes for climate in global and intergenerational perspective

      Walker, Catherine; orcid: 0000-0003-3390-9272; email: catherine.walker-2@manchester.ac.uk (BioMed Central, 2020-05-29)
      Abstract: Background: The school strikes for climate (henceforth, the school strikes) initiated by Greta Thunberg have brought young people’s environmental concerns to the global stage. However, there is a danger of considering youth environmental concerns only through the actions of highly mobilised young people who are heavily concentrated in the urban Global North. This article revisits qualitative data collected before the school strikes to consider how 11–14-year-olds in India and England interpreted and responded to environmental hazards and degradation in their everyday lives, and connected their situated experiences to narratives of global environmental crisis. The young people occupied a range of socio-economic positions and were experiencing different degrees of vulnerability to environmental hazards. Results: All of the research participants were concerned about the future of the planet and their immediate environments. However, for the most environmentally vulnerable participants, future- and globally-oriented environmental concerns were overpowered by more immediate concerns. Although the young people were engaged in responses to environmental concerns, they did not see themselves as acting alone but rather with others around them, often adults. Some young people expressed doubt about the extent to which they as generationally-positioned individuals could make a difference to the problems discussed. These findings in many ways anticipate the school strikes, wherein young people are taking action to call upon adults to respond to environmental problems that young people recognise are beyond their individual capacities to resolve. Conclusion: The environmental activism of a significant minority of young people is to be applauded, however, the interest in youth activism prompted by the school strikes runs the risk of flattening global inequalities in young people’s exposure to environmental hazards, access to education and global knowledge networks. There is a need to look beyond such high-profile activities to understand how young people around the world are interpreting and responding to environmental concerns as generationally-positioned individuals operating within broader regimes of power.
    • University College Chester: the impact of investment in electronic resources

      Fiander, Wendy; Peters, Lisa (Library and Information Research Group, 2005)
      This article discusses the impact of electronic information services on teaching and learning, the production of "impact indicators" to evaludate the usefulness of electronic resources, and how to increase the percieved value of electronic resources in the academic community.
    • ‘University is a non‐Muslim experience, you know? The experience is as good as it can be’: Satisfied settling in Muslim students’ experiences and implications for Muslim student voice

      Islam, Maisha; orcid: 0000-0001-5763-2381; email: maisha.islam@winchester.ac.uk; email: Maisha.Islam@winchester.ac.uk; Mercer‐Mapstone, Lucy; orcid: 0000-0001-7441-6568 (2021-06-06)
      We report findings from a cross‐institutional investigation testing the applicability of a new concept, ‘satisfied settling’, which describes the ways in which students are unconsciously ‘settling for less’ in terms of their university experiences. The context of exploration for this article was that of Muslim students’ experiences as a critical area which has received little previous focus. Our results describe a staged cognitive process undertaken by students to subconsciously excuse institutional failures to support their religious needs by settling for lower levels of satisfaction. The ‘counter stories’ told by 19 Muslim students (via semi‐structured interviews) detail how their voices are heard or silenced around the deep importance of religious provisions in their university experiences. Satisfied settling was ultimately found to translate across institutional contexts, and the applicability of the concept is discussed in extending to other marginalised student groups.
    • Using process data to generate an optimal control policy via apprenticeship and reinforcement learning

      Mowbray, Max; orcid: 0000-0003-1398-0469; email: max.mowbray@manchester.ac.uk; Smith, Robin; email: robin.smith@manchester.ac.uk; Del Rio‐Chanona, Ehecatl A.; email: a.del-rio-chanona@imperial.ac.uk; Zhang, Dongda; orcid: 0000-0001-5956-4618; email: dongda.zhang@manchester.ac.uk (John Wiley & Sons, Inc., 2021-05-15)
      Abstract: Reinforcement learning (RL) is a data‐driven approach to synthesizing an optimal control policy. A barrier to wide implementation of RL‐based controllers is its data‐hungry nature during online training and its inability to extract useful information from human operator and historical process operation data. Here, we present a two‐step framework to resolve this challenge. First, we employ apprenticeship learning via inverse RL to analyze historical process data for synchronous identification of a reward function and parameterization of the control policy. This is conducted offline. Second, the parameterization is improved online efficiently under the ongoing process via RL within only a few iterations. Significant advantages of this framework include to allow for the hot‐start of RL algorithms for process optimal control, and robust abstraction of existing controllers and control knowledge from data. The framework is demonstrated on three case studies, showing its potential for chemical process control.
    • Using the CLA scanning licence to offer 24x7 access to in-demand book chapters and journal articles at the University of Chester

      Peters, Lisa; University of Chester (SCONUL, 2009-12)
      This article discusses the implementation and operation of the CLA scanning licence at the University of Chester library.