Recent Submissions

  • Oncology Activity

    Gill, J.H.; Shnyder, Steven (Springer, 2015-01-15)
    The development of therapeutics to treat cancer is conceptually more difficult than for nonlife-threatening diseases for several reasons, including its complex pathophysiological nature, the molecular individuality of each tumor, and the robustness and predictability of preclinical models toward determining efficacy and safety. A major limitation to development of a “blockbuster” therapeutic strategy is the infinite combination of cellular and molecular perturbations and associated heterogeneity of causative genetic factors driving disease progression. Although challenging, the diversity of drug targets, coupled with the lethality of the disease, has encouraged studies of a vast array of approaches and opportunities for disease treatment over the years.
  • The 2021 Campus Dig

    George, Sarah; Jennings, Benjamin R. (Unknown, 2023-12)
  • Apigenin cocrystals: from computational pre-screening to physicochemical property characterisation

    Makadia, J.; Seaton, Colin C.; Li, M. (2023-05)
    Apigenin (4′,5,7-trihydroxyflavone, APG) has many potential therapeutic benefits; however, its poor aqueous solubility has limited its clinical applications. In this work, a large scale cocrystal screening has been conducted, aiming to discover potential APG cocrystals for enhancement of its solubility and dissolution rate. In order to reduce the number of the experimental screening tests, three computational prescreening tools, i.e., molecular complementarity (MC), hydrogen bond propensity (HBP), and hydrogen bond energy (HBE), were used to provide an initial selection of 47 coformer candidates, leading to the discovery of seven APG cocrystals. Among them, six APG cocrystal structures have been determined by successful growth of single crystals, i.e., apigenin-carbamazepine hydrate 1:1:1 cocrystal, apigenin-1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin-valerolactam 1:2 cocrystal, apigenin-(dl) proline 1:2 cocrystal, apigenin-(d) proline/(l) proline 1:1 cocrystal. All of the APG cocrystals showed improved dissolution performances with the potential to be formulated into drug products.
  • High-fat diet effects on contractile performance of isolated mouse soleus and extensor digitorum longus when supplemented with high dose vitamin D

    Shelley, S.P.; James, Rob S.; Eustace, S.J.; Eyre, E.L.J.; Tallis, J. (2024)
    Evidence suggests vitamin D3 (VD) supplementation can reduce accumulation of adipose tissue and inflammation and promote myogenesis in obese individuals, and thus could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. However, this is yet to be directly investigated. This study, using the work-loop technique, examined effects of VD (cholecalciferol) supplementation on isolated SkM contractility. Female mice (n = 37) consumed standard low-fat diet (SLD) or high-fat diet (HFD), with or without VD (20,000 IU/kg-1 ) for 12 weeks. Soleus and EDL (n = 8-10 per muscle per group) were isolated and absolute and normalized (to muscle size and body mass) isometric force and power output (PO) were measured, and fatigue resistance determined. Absolute and normalized isometric force and PO of soleus were unaffected by diet (P > 0.087). However, PO normalized to body mass was reduced in HFD groups (P  0.588). HFD reduced EDL isometric stress (P = 0.048) and absolute and normalized PO (P  0.493). Cumulative work during fatiguing contractions was lower in HFD groups (P  0.060). This study uniquely demonstrated that high-dose VD had limited effects on SkM contractility and did not offset demonstrated adverse effects of HFD. However, small and moderate effect sizes suggest improvement in EDL muscle performance and animal morphology in HFD VD groups. Given effect sizes observed, coupled with proposed inverted U-shaped dose-effect curve, future investigations are needed to determine dose/duration specific responses to VD, which may culminate in improved function of HFD SkM. NEW FINDINGS: What is the central question of this study? Can vitamin D supplementation alleviate detrimental effects of high-fat diet (HFD) consumption on contractile performance of isolated skeletal muscles? What is the main finding and its importance? The present study is the first to examine the synergistic effects of HFD consumption and vitamin D supplementation on the contractile performance of isolated skeletal muscle. These findings suggest high dose vitamin D has limited effects on force, power or fatigue resistance of isolated mouse soleus and extensor digitorum longus.
  • Evaluating the irritant factors of silicone and hydrocolloid skin contact adhesives using trans-epidermal water loss, protein stripping, erythema, and ease of removal

    Dyson, Edward; Sikkink, Stephen; Nocita, Davide; Twigg, Peter C.; Westgate, Gillian E.; Swift, Thomas (ACS, 2024-01)
    A composite silicone skin adhesive material was designed to improve its water vapor permeability to offer advantages to wearer comfort compared to existing skin adhesive dressings available (including perforated silicone and hydrocolloid products). The chemical and mechanical properties of this novel dressing were analyzed to show that it has a high creep compliance, offering anisotropic elasticity that is likely to place less stress on the skin. A participant study was carried out in which 31 participants wore a novel silicone skin adhesive (Sil2) and a hydrocolloid competitor and were monitored for physiological response to the dressings. Trans-epidermal water loss (TEWL) was measured pre- and postwear to determine impairment of skin barrier function. Sil2 exhibited a higher vapor permeability than the hydrocolloid dressings during wear. Peel strength measurements and dye counter staining of the removed dressings showed that the hydrocolloid had a higher adhesion to the participants’ skin, resulting in a greater removal of proteins from the stratum corneum and a higher pain rating from participants on removal. Once the dressings were removed, TEWL of the participants skin beneath the Sil2 was close to normal in comparison to the hydrocolloid dressings that showed an increase in skin TEWL, indicating that the skin had been highly occluded. Analysis of the skin immediately after removal showed a higher incidence of erythema following application of hydrocolloid dressings (>60%) compared to Sil2, (
  • Germ cell determination and the developmental origin of germ cell tumors

    Nicholls, Peter; Page, D.C. (2021-04)
    In each generation, the germline is tasked with producing somatic lineages that form the body, and segregating a population of cells for gametogenesis. During animal development, when do cells of the germline irreversibly commit to producing gametes? Integrating findings from diverse species, we conclude that the final commitment of the germline to gametogenesis - the process of germ cell determination - occurs after primordial germ cells (PGCs) colonize the gonads. Combining this understanding with medical findings, we present a model whereby germ cell tumors arise from cells that failed to undertake germ cell determination, regardless of their having colonized the gonads. We propose that the diversity of cell types present in these tumors reflects the broad developmental potential of migratory PGCs.
  • Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium

    Fonseca, A.; Lobo, J.; Hazard, F.K.; Gell, J.; Nicholls, Peter; Weiss, R.S.; Klosterkemper, L.; Volchenboum, S.L.; Nicholson, J.C.; Frazier, A.L.; et al. (2022-11)
    Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes.
  • Effect of myopia management contact lens design on accommodative microfluctuations and eye movements during reading

    Ghorbani Mojarrad, Neema; Hussain, M.; Mankowska, Aleksandra; Mallen, Edward A.H.; Cufflin, Matthew P. (2024-02)
    Background: Soft contact lenses have been developed and licensed for reducing myopia progression. These lenses have different designs, such as extended depth of focus (EDOF) and dual focus (DF). In this prospective, doublemasked, cross-over study, different lens designs were investigated to see whether these had impact on accommodative microfluctuations and eye movements during reading. Methods: Participants were fitted with three lenses in a randomised order; a single vision (SV) design (Omafilcon A2; Proclear), a DF design (Omafilcon A2; MiSight), and an EDOF lens design (Etafilcon A; NaturalVue),. Accommodative microfluctuations were measured at 25 cm for at least 60s in each lens, using a Shin-Nippon SRW-5000 autorefractor adapted to continuously record accommodation at 22Hz. Eye movement data was collected with the Thomson Clinical Eye Tracker incorporating a Tobii Eye bar. Eye movements include fixations per row, fixations per minute, mean regressions per row, total number of regressions, and total rightward saccades. Accommodation data was analysed using power spectrum analysis. Differences between the lenses were compared using a related sample two-way Friedman test. Results: Twenty-three participants (18–29 years) were recruited to take part. The average mean spherical error was − 2.65D ± 1.42DS, with an average age of 23.4 ± 3.5 years. No significant difference for accommodative microfluctuations was found. Significant differences were found for fixations per row (P = 0.03), fixations per minute (P = 0.008), mean regressions per row (P = 0.002), and total number of regressions (P = 0.002), but not total rightward saccades (P = 0.10). Post-hoc analysis indicated the EDOF lens results were significantly different from the other lenses, with more regressive eye movements observed. Conclusions: Regressive saccades appear to increase when wearing EDOF lens designs, which may impact visual comfort. Further studies in children, over a longer period of adaptation are necessary to assess the potential impact of this finding on daily reading activities in children.
  • Adiponectin negatively regulates pigmentation, Wnt/β-catenin and HGF/c-Met signalling within human scalp hair follicles ex vivo

    Nicu, C.; Jackson, J.; Shahmalak, A.; Pople, J.; Ansell, David; Paus, R. (2023-04)
    Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated microdissected, organ-cultured HFs in the presence or absence of dWAT with a recombinant human adiponectin oligomer mix, or inhibited dWAT-derived adiponectin using a neutralizing antibody. Multiplex qPCR (Fluidigm) revealed that adiponectin oligomers downregulated pigmentation genes KITLG, PMEL and TYRP1 and Wnt genes AXIN2, LEF1 and WNT10B. In situ hybridization showed that adiponectin downregulated AXIN2 and LEF1, and up-regulated DKK1 within the dermal papilla (DP), a highly unusual transcriptional profile for a putative hair growth-promoting agent. Adiponectin oligomers also downregulated protein expression of the HGF receptor c-Met within the matrix and DP. However, adiponectin did not alter hair matrix keratinocyte proliferation within 48 h ex vivo, irrespective of the presence/absence of dWAT; HF pigmentation (Masson-Fontana histochemistry, tyrosinase activity) was also unchanged. In contrast, neutralizing adiponectin isoforms within HF + dWAT increased proliferation, melanin content and tyrosinase activity but resulted in fewer melanocytes and melanocytic dendrites, as assessed by gp100 immunostaining. These seemingly contradictory effects suggest that adiponectin exerts complex effects upon human HF biology, likely in parallel with the pro-pigmentation effects of dWAT- and DP-derived HGF. Our data suggest that dWAT-derived ratios of adiponectin isoforms and the cleaved, globular version of adiponectin may in fact determine how adiponectin impacts upon follicular pigmentation and growth.
  • Supramolecular chemistry enables vat photopolymerization 3D printing of novel water-soluble tablets

    Ong, J.J.; Chow, Y.L.; Gaisford, S.; Cook, M.T.; Swift, Thomas; Telford, Richard; Rimmer, Stephen; Qin, Y.; Mai, Y.; Goyanes, A.; et al. (2023-08-25)
    Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate …
  • Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer

    Presa, Daniela; Khurram, S.A.; Zubir, A.Z.A.; Swaroop, Sneha; Cooper, Patricia A.; Morais, Goreti R.; Sadiq, Maria; Sutherland, Mark; Loadman, Paul; McCaul, Jim; et al. (2021-09)
    Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.
  • Exploring Radio Frequency Techniques for Bone Fracture Detection: A Comprehensive Review of Low Frequency and Microwave Approaches

    Ahmad, Aldelemy; Ebenezer, Adjei; Prince, Siaw; Buckley, John; Hardy, Maryann; Qahwaji, Rami S.R.; Abd-Alhameed, Raed; Bastos, J.; Barbosa, C.; Elfergani, I.; et al. (2023-09-13)
    This comprehensive review paper examines bone fracture detection techniques based on time-domain low-frequency and microwave radiofrequency (RF). Early and accurate diagnosis of bone fractures remains critical in healthcare, as it can significantly improve patient outcomes. This review focuses on the potential of low-frequency and microwave RF methods, particularly their combination and application of time-domain analysis for enhanced fracture detection. We begin by providing an overview of the fundamental concepts of RF techniques and then by examining biological tissues' dielectric properties. We then compare the advantages and limitations of various bone fracture detection techniques, such as low-frequency RF methods, microwave RF methods, ultrasonography, X-ray, and CT scans. The discussion then shifts to hybrid approaches that combine low-frequency and microwave techniques, emphasising the advantages of such combinations in fracture detection. Machine learning techniques, their applications in bone fracture detection, and the role of time-domain analysis in hybrid approaches are also investigated. Finally, we examine the accuracy and reliability of simulated models for bone fracture detection. We discuss recent advancements and future directions, such as novel sensor technologies, improved signal processing techniques, integration with medical imaging modalities, and personalised fracture detection approaches. This review aims to comprehensively understand the landscape and future potential of time-domain analysis in low-frequency and microwave RF techniques for bone fracture detection.
  • Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol

    Hull, M.A.; Ow, P.L.; Ruddock, S.; Brend, T.; Smith, A.F.; Marshall, H.; Song, M.; Chan, A.T.; Garrett, W.S.; Yilmaz, O.; et al. (BMJ, 2023-11)
    There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. Ethics and dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. Trial registration number NCT03428477.
  • Current approaches to soft contact lens handling training - Global perspectives

    Vianya-Estopa, M.; Ghorbani Mojarrad, Neema; Huntjens, B.; Garcia-Porta, N.; Pinero, D.P.; Nagra, M.; Terry, L.; Dutta, D.; Wolffsohn, J.; Joshi, M.; et al. (2023-12)
    All neophyte contact lens wearers require training on how to handle contact lenses. Currently, almost no published information exists describing the most common approaches used by those involved in such training in soft contact lens wearers. This study aimed to gather information on the approaches taken by those conducting this training worldwide. An online survey was created in English and translated to Spanish and distributed internationally via social media, conference attendees, and professional contacts. The anonymous survey included information on workplace setting of respondents, information about the typical approaches used for application and removal of soft contact lenses, length of the appointment, and success rate with their approach. Survey responses were received between May 2021 and April 2022. A total of 511 individuals completed the survey and responses were received from 31 countries with 48.7% from the UK. The most common approach taught for application was to have the patient hold the upper eyelashes (84.7%) and to hold the lower eyelid with the same hand as the lens (89.4%). Lenses were applied directly to the cornea by 57.7% of the respondents. The most common approach taught for lens removal was to drag the lens inferiorly from the cornea prior to removal (49.3%). Most respondents did not use videos to aid the teaching appointment (62.0%); however, they felt that their approach was successful in most cases (90). Application and removal training sessions lasted a median of 30 min and contact lenses were typically dispensed after the instructor witnessing successful application and removal three times. Various methods are adopted globally for training of application and removal of soft contact lenses, with many advising a patient-specific approach is required for success. The results of this survey provide novel insights into soft contact lens handling training in clinical practice.
  • Clinical investigation of flat pack toric contact lenses and wearer attitudes to environmental impact

    Ghorbani Mojarrad, Neema; Rountree, L.; Terry, L.; Bruce, Heather; Hallam, Emily; Jolly, Louise; Retallic, N.; Evans, K. (2023-11)
    Objectives: To investigate the performance of a novel flat pack toric daily disposable contact lens compared with traditionally packaged toric lenses in a randomized, crossover study. Environmental attitudes to contact lens wear were also explored. Methods: Habitual contact lens wearers were recruited to wear a hioxifilcon A (Miru 1 day Flat Pack Toric, Menicon, Nagoya, Japan) test lens and a control lens: either nelfilcon A (Dailies AquaComfort Plus, Alcon, Geneva, Switzerland) or etafilcon A (1-Day Acuvue Moist, Johnson & Johnson, New Brunswick, NJ). Objective lens performance was assessed at fitting, and participants wore lenses in a randomized order for three consecutive days. Subjective measures of lens performance (comfort, vision, and handling) were then assessed by a questionnaire, with further questions on overall lens preference and environmental perceptions. Results: Objective measures of lens fit were similar for the test and control lenses, except for distance VA which was better with the control lenses (P<0.05; difference of two logMAR letters). End of day comfort was greater with the test lens, but this did not reach significance. Both lenses demonstrated similar scores for overall satisfaction. 87.5% of participants indicated the environmental impact of contact lenses to be important/extremely important to them, with 100% of participants identifying the flat pack packaging as having a smaller environmental impact. Conclusion: Overall, the lenses used in the study performed to similar levels. Environmental credentials are important to contact lens wearers, which may contribute to overall lens preference.
  • Myokines, Measurement, and Technical Considerations

    Willis, Craig R.G.; Deane, C.S.; Etheridge, T. (Humana, 2023-07-31)
    Skeletal muscle has long been established as a highly multifunctional organ, playing a vital role in locomotion, whole-body metabolic and energy homeostasis, and thermoregulation. More recently, emergent evidence has highlighted a potent secretory role for muscle, producing and releasing “myokine” molecules that act in autocrine, paracrine, or endocrine fashion to govern muscle physiology and regulate whole-body homeostasis via multi-tissue cross talk mechanisms. Myokines represent promising therapeutic targets in health and disease, with their discovery, measurement, and functional importance being a hotbed of research across numerous physiological contexts. Here, we provide an overview of myokines and summarize current understanding of their biological role(s). We also outline primary approaches for myokine analysis, including detailed methodology for performing omics-driven myokine prediction, while further appraising both method-specific and general technical considerations to provide an evidence-based approach for designing and conducting myokine experiments.
  • Spaceflight Induces Strength Decline in Caenorhabditis elegans

    Soni, P.; Edwards, H.; Anupom, T.; Rahman, M.; Lesanpezeshki, L.; Blawzdziewicz, J.; Cope, H.; Gharahdaghi, N.; Scott, D.; Toh, L.S.; et al. (2023-10-17)
    Background: Understanding and countering the well-established negative health consequences of spaceflight remains a primary challenge preventing safe deep space exploration. Targeted/personalized therapeutics are at the forefront of space medicine strategies, and cross-species molecular signatures now define the 'typical' spaceflight response. However, a lack of direct genotype-phenotype associations currently limits the robustness and, therefore, the therapeutic utility of putative mechanisms underpinning pathological changes in flight. Methods: We employed the worm Caenorhabditis elegans as a validated model of space biology, combined with 'NemaFlex-S' microfluidic devices for assessing animal strength production as one of the most reproducible physiological responses to spaceflight. Wild-type and dys-1 (BZ33) strains (a Duchenne muscular dystrophy (DMD) model for comparing predisposed muscle weak animals) were cultured on the International Space Station in chemically defined media before loading second-generation gravid adults into NemaFlex-S devices to assess individual animal strength. These same cultures were then frozen on orbit before returning to Earth for next-generation sequencing transcriptomic analysis. Results: Neuromuscular strength was lower in flight versus ground controls (16.6% decline, p
  • Adaptability to eccentric exercise training is diminished with age in female mice

    Baumann, C.W.; Deane, C.S.; Etheridge, T.; Szewczyk, N.J.; Willis, Craig R.G.; Lowe, D.A. (2023-11-01)
    The ability of skeletal muscle to adapt to eccentric contractions has been suggested to be blunted in older muscle. If eccentric exercise is to be a safe and efficient training mode for older adults, preclinical studies need to establish if older muscle can effectively adapt and if not, determine the molecular signatures that are causing this impairment. The purpose of this study was to quantify the extent age impacts functional adaptations of muscle and identify genetic signatures associated with adaptation (or lack thereof). The anterior crural muscles of young (4 mo) and older (28 mo) female mice performed repeated bouts of eccentric contractions in vivo (50 contractions/wk for 5 wk) and isometric torque was measured across the initial and final bouts. Transcriptomics was completed by RNA-sequencing 1 wk following the fifth bout to identify common and differentially regulated genes. When torques post eccentric contractions were compared after the first and fifth bouts, young muscle exhibited a robust ability to adapt, increasing isometric torque 20%-36%, whereas isometric torque of older muscle decreased up to 18% (P ≤ 0.047). Using differential gene expression, young and older muscles shared some common transcriptional changes in response to eccentric exercise training, whereas other transcripts appeared to be age dependent. That is, the ability to express particular genes after repeated bouts of eccentric contractions was not the same between ages. These molecular signatures may reveal, in part, why older muscles do not appear to be as adaptive to exercise training as young muscles.NEW & NOTEWORTHY The ability to adapt to exercise training may help prevent and combat sarcopenia. Here, we demonstrate young mouse muscles get stronger whereas older mouse muscles become weaker after repeated bouts of eccentric contractions, and that numerous genes were differentially expressed between age groups following training. These results highlight that molecular and functional plasticity is not fixed in skeletal muscle with advancing age, and the ability to handle or cope with physical stress may be impaired.
  • VEGF stimulates activation of ERK5 in the absence of C-terminal phosphorylation preventing nuclear localization and facilitating AKT activation in endothelial cells

    Mondru, A.K.; Aljasir, M.A.; Alrumayh, A.; Nithianandarajah, G.N.; Ahmed, K.; Muller, Jurgen; Goldring, C.E.P.; Wilm, B.; Cross, M.J. (2023-03)
    Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.
  • Talking about falls: a qualitative exploration of spoken communication of patients' fall risks in hospitals and implications for multifactorial approaches to fall prevention.

    McVey, Lynn; Alvarado, Natasha; Healey, F.; Montague, Jane; Todd, C.; Zaman, Hadar; Dowding, D.; Lynch, A.; Issa, B.; Randell, Rebecca (2023-11)
    Inpatient falls are the most common safety incident reported by hospitals worldwide. Traditionally, responses have been guided by categorising patients' levels of fall risk, but multifactorial approaches are now recommended. These target individual, modifiable fall risk factors, requiring clear communication between multidisciplinary team members. Spoken communication is an important channel, but little is known about its form in this context. We aim to address this by exploring spoken communication between hospital staff about fall prevention and how this supports multifactorial fall prevention practice. Data were collected through semistructured qualitative interviews with 50 staff and ethnographic observations of fall prevention practices (251.25 hours) on orthopaedic and older person wards in four English hospitals. Findings were analysed using a framework approach. We observed staff engaging in 'multifactorial talk' to address patients' modifiable risk factors, especially during multidisciplinary meetings which were patient focused rather than risk type focused. Such communication coexisted with 'categorisation talk', which focused on patients' levels of fall risk and allocating nursing supervision to 'high risk' patients. Staff negotiated tensions between these different approaches through frequent 'hybrid talk', where, as well as categorising risks, they also discussed how to modify them. To support hospitals in implementing multifactorial, multidisciplinary fall prevention, we recommend: (1) focusing on patients' individual risk factors and actions to address them (a 'why?' rather than a 'who' approach); (2) where not possible to avoid 'high risk' categorisations, employing 'hybrid' communication which emphasises actions to modify individual risk factors, as well as risk level; (3) challenging assumptions about generic interventions to identify what individual patients need; and (4) timing meetings to enable staff from different disciplines to participate.

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