• Molecular characterization of fast-growing melanomas.

      Gaudy-Marqueste, Caroline; email: caroline.gaudy@ap-hm.fr; Macagno, Nicolas; Loundou, Anderson; Pellegrino, Eric; Ouafik, L'houcine; Budden, Timothy; Mundra, Piyushkumar; Gremel, Gabriela; Akhras, Victoria; Lin, Lijing; et al. (2021-07-16)
      The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM), and its potential to stratify patients at high risk of death, has not been comprehensively studied. To investigate the epidemiological, clinical and mutational profile of primary cutaneous melanomas with a thickness ≥ 1mm, stratified by rate of growth (ROG). Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin embedded primary melanoma samples. Comparison of FGMM (ROG >0.5mm/month) and non-FGMM (ROG≤0.5 mm/month). Two hundred patients were enrolled among which 70 were FGMM. The relapse free survival was lower in the FGMM group (p=0.014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than non-FGMM (p=0.033). Ulceration (p=0.032), thickness (p=0.006), lower sun exposure (p=0.049), and FGFR2 mutations (p=0.037) were significantly associated with fast growth. Single-center study, cohort size, potential memory bias, number of investigated genes. Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness and FGFR2 mutations associate with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM which are probably good candidates for adjuvant therapies. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • Molecular characterization of HEK293 cells as emerging versatile cell factories.

      Pulix, Michela; Lukashchuk, Vera; Smith, Daniel C; Dickson, Alan J; email: alan.dickson@manchester.ac.uk (2021-05-28)
      HEK293 cell lines are used for the production of recombinant proteins, virus-like particles and viral vectors. Recent work has generated molecular (systems level) characterisation of HEK293 variants that has enabled re-engineering of the cells towards enhanced use for manufacture-scale production of recombinant biopharmaceuticals (assessment of 'safe harbours' for gene insertion, engineering of new variants for stable, amplifiable expression). In parallel, there have been notable advances in the bioprocessing conditions (suspension adaptation, development of defined serum-free media) that offer the potential for large-scale manufacture, a feature especially important in the drive to produce viral vectors at large-scale and at commercially viable costs for gene therapy. The combination of cell-based and bioprocess-based modification of existing HEK293 cell processes, frequently informed by understandings transferred from developments with Chinese hamster ovary cell lines, seems destined to place the HEK293 cell systems firmly as a critical platform for production of future biologically based therapeutics. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • Molecular Dynamics of Janus Nanodimers Dispersed in Lamellar Phases of a Block Copolymer

      Burgos-Mármol, J. Javier; orcid: 0000-0003-1861-2657; email: J.J.Burgos-Marmol@liverpool.ac.uk; Patti, Alessandro; orcid: 0000-0002-7535-0000; email: alessandro.patti@manchester.ac.uk (MDPI, 2021-05-09)
      We investigate structural and dynamical properties of Janus nanodimers (NDs) dispersed in lamellar phases of a diblock copolymer. By performing molecular dynamics simulations, we show that an accurate tuning of the interactions between NDs and copolymer blocks can lead to a close control of NDs’ space distribution and orientation. In particular, NDs are preferentially found within the lamellae if enthalpy-driven forces offset their entropic counterpart. By contrast, when enthalpy-driven forces are not significant, the distribution of NDs, preferentially observed within the inter-lamellar spacing, is mostly driven by excluded-volume effects. Not only does the degree of affinity between host and guest species drive the NDs’ distribution in the polymer matrix, but it also determines their space orientation. In turn, these key structural properties influence the long-time dynamics and the ability of NDs to diffuse through the polymer matrix.
    • Monocytes/macrophages express CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation

      Schmutz, Caroline; Cartwright, Alison; Williams, Helen; Haworth, Oliver; Williams, John H. H.; Filer, Andrew; Salmon, Mike; Buckley, Christopher D.; Middleton, Jim F.; Keele University/University of Birmingham ; Keele University ; University of Chester ; University of Birmingham ; University of Chester ; University of Birmingham ; University of Birmingham ; University of Birmingham ; Keele University/University of Bristol (BioMed Central, 2010-08-05)
      Abstract Introduction Monocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers. Methods CCR9 expression on PB monocytes/macrophages was analysed by flow cytometry and in synovium by immunofluorescence. Chemokine receptor CCR9 mRNA expression was examined in RA and non-RA synovium, monocytes/macrophages from PB and synovial fluid (SF) of RA patients and PB of healthy donors using the reverse transcription polymerase chain reaction (RT-PCR). Monocyte differentiation and chemotaxis to chemokine ligand 25 (CCL25)/TECK were used to study CCR9 function. Results CCR9 was expressed by PB monocytes/macrophages in RA and healthy donors, and increased in RA. In RA and non-RA synovia, CCR9 co-localised with cluster of differentiation 14+ (CD14+) and cluster of differentiation 68+ (CD68+) macrophages, and was more abundant in RA synovium. CCR9 mRNA was detected in the synovia of all RA patients and in some non-RA controls, and monocytes/macrophages from PB and SF of RA and healthy controls. CCL25 was detected in RA and non-RA synovia where it co-localised with CD14+ and CD68+ cells. Tumour necrosis factor alpha (TNFα) increased CCR9 expression on human acute monocytic leukemia cell line THP-1 monocytic cells. CCL25 induced a stronger monocyte differentiation in RA compared to healthy donors. CCL25 induced significant chemotaxis of PB monocytes but not consistently among individuals. Conclusions CCR9 expression by monocytes is increased in RA. CCL25 may be involved in the differentiation of monocytes to macrophages particularly in RA.
    • Mononuclear Dysprosium Alkoxide and Aryloxide Single‐Molecule Magnets

      Parmar, Vijay S.; orcid: 0000-0002-7133-5532; Mills, David P.; orcid: 0000-0003-1575-7754; email: david.mills@manchester.ac.uk; Winpenny, Richard E. P.; orcid: 0000-0002-7101-3963; email: richard.winpenny@manchester.ac.uk (2021-03-24)
      Abstract: Recent studies have shown that mononuclear lanthanide (Ln) complexes can be high‐performing single‐molecule magnets (SMMs). Recently, there has been an influx of mononuclear Ln alkoxide and aryloxide SMMs, which have provided the necessary geometrical control to improve SMM properties and to allow the intricate relaxation dynamics of Ln SMMs to be studied in detail. Here non‐aqueous Ln alkoxide and aryloxide chemistry applied to the synthesis of low‐coordinate mononuclear Ln SMMs are reviewed. The focus is on mononuclear DyIII alkoxide and aryloxide SMMs with coordination numbers up to eight, covering synthesis, solid‐state structures and magnetic attributes. Brief overviews are also provided of mononuclear TbIII, HoIII, ErIII and YbIII alkoxide and aryloxide SMMs.
    • Monte Carlo Predictions of Aero-Engine Performance Degradation Due to Particle Ingestion

      Ellis, Matthew; orcid: 0000-0002-1337-3143; email: matthew.ellis@manchester.ac.uk; Bojdo, Nicholas; orcid: 0000-0001-8861-4231; email: nicholas.bojdo@manchester.ac.uk; Filippone, Antonio; orcid: 0000-0002-6512-6566; email: a.filippone@manchester.ac.uk; Clarkson, Rory; email: Rory.Clarkson@Rolls-Royce.com (MDPI, 2021-05-25)
      Aero-engines, which encounter clouds of airborne particulate, experience reduced performance due to the deposition of particles on their high-pressure turbine nozzle guide vanes. The rate of this degradation depends on particle properties, engine operating state and the duration of exposure to the particle cloud, variables that are often unknown or poorly constrained, leading to uncertainty in model predictions. A novel method coupling one-dimensional gas turbine performance analysis with generalised predictions of particle deposition is developed and applied through the use of Monte Carlo simulations to better predict high-pressure turbine degradation. This enables a statistical analysis of deterioration from which mean performance losses and confidence intervals can be defined, allowing reductions in engine life and increased operational risk to be quantified. The method is demonstrated by replicating two particle cloud encounter events for the Rolls-Royce RB211-524C engine and is used to predict empirical particle properties by correlating measured engine performance data with Monte Carlo model inputs. Potential improvements in the confidence of these predictions due to more tightly constrained input and validation data are also demonstrated. Finally, the potential combination of the Monte Carlo coupled degradation model with in-service engine performance data and particle properties determined through remote or in situ sensing is outlined and its role in a digital twin to enable a predictive approach to operational capability is discussed.
    • More that unites us than divides us? A qualitative study of integration of community health and social care services

      Mitchell, Claire; orcid: 0000-0002-2445-8468; email: Claire.mitchell@manchester.ac.uk; Tazzyman, Abigail; Howard, Susan J.; Hodgson, Damian (BioMed Central, 2020-05-29)
      Abstract: Background: The integration of community health and social care services has been widely promoted nationally as a vital step to improve patient centred care, reduce costs, reduce admissions to hospital and facilitate timely and effective discharge from hospital. The complexities of integration raise questions about the practical challenges of integrating health and care given embedded professional and organisational boundaries in both sectors. We describe how an English city created a single, integrated care partnership, to integrate community health and social care services. This led to the development of 12 integrated neighbourhood teams, combining and co-locating professionals across three separate localities. The aim of this research is to identify the context and the factors enabling and hindering integration from a qualitative process evaluation. Methods: Twenty-four semi-structured interviews were conducted with equal numbers of health and social care staff at strategic and operational level. The data was subjected to thematic analysis. Results: We describe three key themes: 1) shared vision and leadership; 2) organisational factors; 3) professional workforce factors. We found a clarity of vision and purpose of integration throughout the partnership, but there were challenges related to the introduction of devolved leadership. There were widespread concerns that the specified outcome measures did not capture the complexities of integration. Organisational challenges included a lack of detail around clinical and service delivery planning, tensions around variable human resource practices and barriers to data sharing. A lack of understanding and trust meant professional workforce integration remained a key challenge, although integration was also seen as a potential solution to engender relationship building. Conclusions: Given the long-term national policy focus on integration this ambitious approach to integrate community health and social care has highlighted implications for leadership, organisational design and inter-professional working. Given the ethos of valuing the local assets of individuals and networks within the new partnership we found the integrated neighbourhood teams could all learn from each other. Many of the challenges of integration could benefit from embracing the inherent capabilities across the integrated neighbourhood teams and localities of this city.
    • Morphological variability in the mucosal attachment site of Trichuris muris revealed by X-ray microcomputed tomography.

      O'Sullivan, James D B; Cruickshank, Sheena M; Withers, Philip J; Else, Kathryn J; email: kathryn.else@manchester.ac.uk (2021-06-30)
      Parasitic infections can be challenging to study because two dimensional light and electron microscopy are often limited in visualising complex and inaccessible attachment sites. Exemplifying this, Trichuris spp. inhabit a tunnel of epithelial cells within the host caecum and colon. A significant global burden of this infection persists, partly because available anthelminthics lack efficacy, although the mechanisms underlying this remain unknown. Consequently, there is a need to pioneer new approaches to better characterize the parasite niche within the host and investigate how variation in its morphology and integrity may contribute to resistance to therapeutic intervention. To address these aims, we exploited three-dimensional X-ray micro-computed tomography (microCT) to image the mouse whipworm, Trichuris muris, in caeca of wild-type C57BL/6 and SCID mice ex vivo. Using osmium tetroxide staining to effectively enhance the contrast of worms, we found that a subset exhibited preferential positioning towards the bases of the intestinal crypts. Moreover, in one rare event, we demonstrated whipworm traversal of the lamina propria. This morphological variability contradicts widely accepted conclusions from conventional microscopy of the parasite niche, showing Trichuris in close contact with the host proliferative and immune compartments that may facilitate immunomodulation. Furthermore, by using a skeletonization-based approach we demonstrate considerable variation in tunnel length and integrity. The qualitative and quantitative observations provide a new morphological point of reference for future in vitro study of host-Trichuris interactions, and highlight the potential of microCT to characterise enigmatic host-parasite interactions more accurately. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.]
    • Morphology and Mechanical Properties of Plantar Fascia in Flexible Flatfoot: A Noninvasive In Vivo Study

      Qian, Zhihui; Jiang, Zhende; Wu, Jianan; Chang, Fei; Liu, Jing; email: jingliu@jlu.edu.cn; Ren, Lei; email: lei.ren@manchester.ac.uk; Ren, Luquan (Frontiers Media S.A., 2021-09-15)
      Plantar fascia plays an important role in human foot biomechanics; however, the morphology and mechanical properties of plantar fascia in patients with flexible flatfoot are unknown. In this study, 15 flexible flatfeet were studied, each plantar fascia was divided into 12 positions, and the morphologies and mechanical properties in the 12 positions were measured in vivo with B-mode ultrasound and shear wave elastography (SWE). Peak pressures under the first to fifth metatarsal heads (MH) were measured with FreeStep. Statistical analysis included 95% confidence interval, intragroup correlation coefficient (ICC1,1), one-way analysis of variance (one-way ANOVA), and least significant difference. The results showed that thickness and Young’s modulus of plantar fascia were the largest at the proximal fascia (PF) and decreased gradually from the proximal end to the distal end. Among the five distal branches (DB) of the fascia, the thickness and Young’s modulus of the second and third DB were larger. The peak pressures were also higher under the second and third MH. This study found a gradient distribution in that the thickness and Young’s modulus gradient decreased from the proximal end to the distal end of plantar fascia in the longitudinal arch of flexible flatfeet. In the transverse arch, the thickness and Young’s modulus under the second and third DB were larger than those under the other three DB in flexible flatfoot, and the peak pressures under the second and third MH were also larger than those under the other three MH in patients with flexible flatfoot. These findings deepen our understanding of the changes of biomechanical properties and may be meaningful for the study of pathological mechanisms and therapy for flexible flatfoot.
    • Mortality in 98 type 1 diabetes mellitus and type 2 diabetes mellitus: Foot ulcer location is an independent risk determinant

      Schofield, Heather; Haycocks, Samantha; Robinson, Adam; Edmonds, Michael; Anderson, Simon G; Heald, Adrian H.; orcid: 0000-0002-9537-4050; email: adrian.heald@manchester.ac.uk (2021-06-14)
      Abstract: Introduction: We previously demonstrated in both a longitudinal study and in meta‐analysis (pooled relative‐risk RR, 2.45) that all‐cause mortality is significantly higher in people with diabetes foot ulceration (DFU) than with those without a foot ulcer. In this prospective study, we looked at the factors linked to mortality after presentation to podiatry with DFU. Methods: Ninety‐eight individuals recruited consecutively from the Salford Royal Hospital Multidisciplinary Foot Clinic in Spring 2016 were followed up for up to 48 months. Data concerning health outcomes were extracted from the electronic patient record (EPR). Results: Seventeen people (17) had type 1 diabetes mellitus, and 81 had type 2 diabetes mellitus. Thirty‐one were women. The mean age (range) was 63.6 (28–90) years with maximum diabetes duration 45 years. Mean HbA1c was 72 (95% CI: 67–77) mmol/mol; 97% had neuropathy (International Working Group on the Diabetic Foot (IWGDF) monofilament); 62% had vascular insufficiency (Doppler studies); 69% of ulcers were forefoot, and 23% of ulcers were hind foot in location. Forty of 98 (40%) patients died in follow‐up with 27% of death certificates including sepsis (not foot‐related) and 35% renal failure as cause of death. Multivariate regression analysis indicated a 6.3 (95% CI: 3.9–8.1) fold increased risk of death with hind foot ulcer, independent of age/BMI/gender/HbA1c/eGFR/total cholesterol level. Conclusion: This prospective study has indicated a very high long‐term mortality rate in individuals with DFU, greater for those with a hind foot ulcer and shown a close relation between risk of sepsis/renal failure and DFU mortality, highlighting again the importance of addressing all risk factors as soon as people present with a foot ulcer.
    • Motion artefact removal in electroencephalography and electrocardiography by using multichannel inertial measurement units and adaptive filtering

      Beach, Christopher; orcid: 0000-0003-4964-3173; email: christopher.beach@manchester.ac.uk; Li, Mingjie; Balaban, Ertan; orcid: 0000-0001-7904-6172; Casson, Alexander J.; orcid: 0000-0003-1408-1190 (2021-06-24)
      Abstract: This paper presents a new active electrode design for electroencephalogram (EEG) and electrocardiogram (ECG) sensors based on inertial measurement units to remove motion artefacts during signal acquisition. Rather than measuring motion data from a single source for the entire recording unit, inertial measurement units are attached to each individual EEG or ECG electrode to collect local movement data. This data is then used to remove the motion artefact by using normalised least mean square adaptive filtering. Results show that the proposed active electrode design can reduce motion contamination from EEG and ECG signals in chest movement and head swinging motion scenarios. However, it is found that the performance varies, necessitating the need for the algorithm to be paired with more sophisticated signal processing to identify scenarios where it is beneficial in terms of improving signal quality. The new instrumentation hardware allows data driven artefact removal to be performed, providing a new data driven approach compared to widely used blind‐source separation methods, and helps enable in the wild EEG recordings to be performed.
    • Mucus.

      McShane, Abigail; Bath, Jade; Jaramillo, Ana M; Ridley, Caroline; Walsh, Agnes A; Evans, Christopher M; email: christopher.evans@cuanschutz.edu; Thornton, David J; email: dave.thornton@manchester.ac.uk; Ribbeck, Katharina; email: ribbeck@mit.edu (2021-08-09)
      Mucus is a slimy hydrogel that lines the mucosal surfaces in our body, including the intestines, stomach, eyes, lungs and urogenital tract. This glycoprotein-rich network is truly the jack of all trades. As a barrier, it lubricates surfaces, protects our cells from physical stress, and selectively allows the passage of nutrients while clearing out pathogens and debris. As a home to our microbiota, it supports a level of microbial diversity that is unattainable with most culture methods. As a reservoir of complex carbohydrate structures called glycans, it plays critical roles in controlling cell adhesion and signaling, and it alters the behavior and spatial distribution of microbes. On top of all this, mucus regulates the passage of sperm during fertilization, heals wounds, helps us smell, and prevents the stomach from digesting itself, to name just a few of its functions. Given these impressive features, it is no wonder that mucus crosses boundaries of species and kingdoms - mucus gels are made by organisms ranging from the simplest metazoans to corals, snails, fish, and frogs. It is also no surprise that mucus is exploited in everyday applications, including foods, cosmetics, and other products relevant to medicine and industry. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases

      Rabbie, Roy; orcid: 0000-0002-9195-5659; Ansari-Pour, Naser; Cast, Oliver; orcid: 0000-0002-5880-7726; Lau, Doreen; orcid: 0000-0002-7623-2401; Scott, Francis; Welsh, Sarah J.; Parkinson, Christine; Khoja, Leila; Moore, Luiza; orcid: 0000-0001-5315-516X; Tullett, Mark; et al. (Nature Publishing Group UK, 2020-08-27)
      Abstract: Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
    • Multiple imputation with missing indicators as proxies for unmeasured variables: simulation study

      Sperrin, Matthew; orcid: 0000-0002-5351-9960; email: matthew.sperrin@manchester.ac.uk; Martin, Glen P. (BioMed Central, 2020-07-08)
      Abstract: Background: Within routinely collected health data, missing data for an individual might provide useful information in itself. This occurs, for example, in the case of electronic health records, where the presence or absence of data is informative. While the naive use of missing indicators to try to exploit such information can introduce bias, its use in conjunction with multiple imputation may unlock the potential value of missingness to reduce bias in causal effect estimation, particularly in missing not at random scenarios and where missingness might be associated with unmeasured confounders. Methods: We conducted a simulation study to determine when the use of a missing indicator, combined with multiple imputation, would reduce bias for causal effect estimation, under a range of scenarios including unmeasured variables, missing not at random, and missing at random mechanisms. We use directed acyclic graphs and structural models to elucidate a variety of causal structures of interest. We handled missing data using complete case analysis, and multiple imputation with and without missing indicator terms. Results: We find that multiple imputation combined with a missing indicator gives minimal bias for causal effect estimation in most scenarios. In particular the approach: 1) does not introduce bias in missing (completely) at random scenarios; 2) reduces bias in missing not at random scenarios where the missing mechanism depends on the missing variable itself; and 3) may reduce or increase bias when unmeasured confounding is present. Conclusion: In the presence of missing data, careful use of missing indicators, combined with multiple imputation, can improve causal effect estimation when missingness is informative, and is not detrimental when missingness is at random.
    • Multiplicities of sandscapes and granular geographies

      Kothari, Uma; email: uma.kothari@manchester.ac.uk (SAGE Publications, 2021-03-30)
      This commentary on William Jamieson’s article, ‘For Granular Geography’, which illuminates the granular relations of sand as it is transformed by capitalist urbanism, suggests that understanding what might constitute granular geographies requires further consideration of the multiplicities of granular material. It considers the manifold values of sand beyond its worth as an economic resource and explores the temporalities associated with the movement and fixity of sand. It goes on to argue that there is a need for renewed focus on the impacts of sand extraction for local communities and landscapes as well as for more substantive accounts of the myriad mobile choreographies of sand in processes of place-making.
    • Multiscale understanding of electric polarization in poly(vinylidene fluoride)-based ferroelectric polymers

      Meng, Nan; orcid: 0000-0002-7609-0407; Ren, Xintong; orcid: 0000-0003-2472-4866; Zhu, Xiaojing; orcid: 0000-0001-8947-1658; Wu, Jiyue; orcid: 0000-0002-0827-2831; Yang, Bin; orcid: 0000-0001-5620-9506; Gao, Feng; orcid: 0000-0002-5075-4076; Zhang, Han; orcid: 0000-0002-0479-224X; Liao, Yaozu; orcid: 0000-0001-9263-6281; Bilotti, Emiliano; orcid: 0000-0003-3952-1148; Reece, Michael J.; et al. (Royal Society of Chemistry (RSC), 2020)
      The electric polarization of ferroelectric polymers with tailored structures was studied using the terahertz time-domain spectroscopy technique combined with impedance analysis.
    • Multiscale understanding of electric polarization in poly(vinylidene fluoride)-based ferroelectric polymers

      Meng, Nan; orcid: 0000-0002-7609-0407; Ren, Xintong; orcid: 0000-0003-2472-4866; Zhu, Xiaojing; orcid: 0000-0001-8947-1658; Wu, Jiyue; orcid: 0000-0002-0827-2831; Yang, Bin; orcid: 0000-0001-5620-9506; Gao, Feng; orcid: 0000-0002-5075-4076; Zhang, Han; orcid: 0000-0002-0479-224X; Liao, Yaozu; orcid: 0000-0001-9263-6281; Bilotti, Emiliano; orcid: 0000-0003-3952-1148; Reece, Michael J.; et al. (Royal Society of Chemistry (RSC), 2020)
      The electric polarization of ferroelectric polymers with tailored structures was studied using the terahertz time-domain spectroscopy technique combined with impedance analysis.
    • Multivariate statistical data analysis of cell‐free protein synthesis toward monitoring and control

      Duran‐Villalobos, Carlos A.; orcid: 0000-0002-5350-761X; email: carlos.duran@manchester.ac.uk; Ogonah, Olotu; Melinek, Beatrice; Bracewell, Daniel G.; Hallam, Trevor; Lennox, Barry (John Wiley & Sons, Inc., 2021-03-23)
      Abstract: The optimization and control of cell free protein synthesis (CFPS) presents an ongoing challenge due to the complex synergies and nonlinearities that cannot be fully explained in first principle models. This article explores the use of multivariate statistical tools for analyzing data sets collected from the CFPS of Cereulide monoclonal antibodies. During the collection of these data sets, several of the process parameters were modified to investigate their effect on the end‐point product (yield). Through the application of principal component analysis and partial least squares (PLS), important correlations in the process could be identified. For example, yield had a positive correlation with pH and NH3 and a negative correlation with CO2 and dissolved oxygen. It was also found that PLS was able to provide a long‐term prediction of product yield. The presented work illustrates that multivariate statistical techniques provide important insights that can help support the operation and control of CFPS processes.
    • Museum collections: Management, conservation and presentation

      Peters, Lisa; McKay, Ian S. H.; University of Chester (2011-09-21)
    • Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development

      Millán-Esteban, David; orcid: 0000-0002-8066-1444; email: david.millan@ucv.es; Peña-Chilet, María; orcid: 0000-0002-6445-9617; email: maria.pena.chilet.ext@juntadeandalucia.es; García-Casado, Zaida; email: zgarcia@fivo.org; Manrique-Silva, Esperanza; email: emanrique@fivo.org; Requena, Celia; email: crequena@fivo.org; Bañuls, José; orcid: 0000-0002-0990-7608; email: banuls_jos@gva.es; López-Guerrero, Jose Antonio; orcid: 0000-0002-7369-8388; email: jalopez@fivo.org; Rodríguez-Hernández, Aranzazu; email: arodriguezh@fivo.org; Traves, Víctor; email: vtraves@fivo.org; Dopazo, Joaquín; orcid: 0000-0003-3318-120X; email: joaquin.dopazo@juntadeandalucia.es; et al. (MDPI, 2021-10-18)
      According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.