159 research outputs found
Extracellular matrix stiffness controls cardiac fibroblast proliferation via the nuclear factor-Y (NF-Y) transcription factor
The proliferative expansion of cardiac fibroblasts (CF) contributes towards cardiac fibrosis, which results in myocardial stiffening, cardiac dysfunction, and heart failure. CF sense and respond to increased stiffness of their local extracellular matrix, modulating their phenotype towards increased collagen synthesis and higher proliferation, leading potentially to a vicious circle of positive feedback. Here we describe a novel mechanism that mediates increased CF proliferation in response to a pathologically stiff Exteracellular matrix (ECM). The mechanism we describe is independent of the well-characterised mechano-sensitive transcript factors, YAP-TEAD and MKL1-SRF, which our data indicate are only responsible for part of the genes induced by stiffened ECM. Instead, our data identify Nuclear Factor-Y (NF-Y) as a novel mechanosensitive transcription factor, which mediates enhanced CF proliferation in response to a stiff ECM. We show that levels of NF-YA protein, the major regulatory subunit of NF-Y, and NF-Y transcriptional activity, are increased by a stiff ECM. Indeed, NF-Y activity drives the expression of multiple cell-cycle genes. Furthermore, NF-YA protein levels are dependent on FAK signalling suggesting a mechanistic link to ECM composition. Consistent with its role as a mechano-sensor, inhibition of NF-Y using siRNA or dominant negative mutant blocks CF proliferation on plastic in vitro, which models a stiff ECM, whereas ectopic expression of NF-YA increases the proliferation of cells interacting under conditions that model a physiologically soft ECM. In summary, our data demonstrate that NF-Y is a biomechanically sensitive transcription factor that promotes CF proliferation in a model of pathologically stiffened ECM
International Educatorsβ Perspectives on the Purpose of Science Education and the Relationship between School Science and Creativity
This is the author accepted manuscript. The final version is available from Taylor & Francis (Routledge) via the DOI in this record.Background: Creativity across all disciplines is increasingly viewed as a fundamental
educational capability. Science can play a potentially important role in the nurturing of
creativity. Research also suggests that creative pedagogy, including interdisciplinary
teaching with Science and the Arts, can engage students with science. Previous studies
into teachersβ attitudes to the relationship between science and creativity have been
largely situated within national educational contexts.
Purpose: This study, part of the large EU funded CREATIONs project, explores
educatorsβ perspectives on the relationship between Science and Creativity across
national contexts drawn from Europe and beyond.
Sample and Methods: 270 educators, broadly defined to include primary (age 4-11) and
secondary (age 11-18) teachers and trainee teachers, informal educators and teacher
educators, responded to a survey designed to explore perceptions of the relationship
between science and creativity. Respondents were a convenience sample recruited by
project partners and through online media. The elements of the survey reported here
included Likert-scale questions, open response questions, and ranking questions in the
form of an electronic self-administered questionnaire. Exploratory factor analysis was
used to develop a combined attitude scale labelled βscience is creativeβ, with results
compared across nationalities and phases of education. Open question responses were
analysed thematically to allow more nuanced interpretation of the descriptive statistical
findings.
Results: The findings show broad agreement internationally and across phases that
science is a creative endeavour, with a small number of educators disagreeing about the
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relationship between science and creativity in the context of school science. Those who
disagreed were usually secondary science teachers, from England, Malta or outside
Europe (primarily from the United States). The role of scientific knowledge within
creativity in science education was found to be contentious.
Conclusions: That educators broadly see science as creative is unsurprising, but initial
exploration of educatorsβ perspectives internationally shows some areas of difference.
These were especially apparent for educators working in formal education, particularly
relating to the role of knowledge with respect to creativity in science. With current
interest in STEAM education, further investigation to understand potential mediating
factors of national educational contexts on teachersβ perspectives with respect to the
role of disciplinary knowledge(s) in creativity and their interaction in interdisciplinary
teaching and learning, is recommended.European Commissio
Substrate stiffness promotes vascular smooth muscle cell calcification by reducing levels of nuclear actin monomers:Mechanical regulation of VSMC calcification
Background:Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood.Methods:Using hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo, we investigated the role of substrate stiffness in the regulation of VSMC calcification.Results:We demonstrate that increased substrate stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of substrate stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft substrate, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2). Conclusion:This work highlights for the first time the role of nuclear actin in mediating substrate stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes.<br/
Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis
The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1mg) or saline, and weight bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic)+capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314+capsaicin signfcantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and refex excitability measured using electromyography. DAMGO (3ng) had a signifcantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints
Stroking modulates noxious-evoked brain activity in human infants
A subclass of C fibre sensory neurons found in hairy skin are activated by gentle touch [1] and respond optimally to stroking at βΌ1β10 cm/s, serving a protective function by promoting affiliative behaviours. In adult humans, stimulation of these C-tactile (CT) afferents is pleasant, and can reduce pain perception [2]. Touch-based techniques, such as infant massage and kangaroo care, are designed to comfort infants during procedures, and a modest reduction in pain-related behavioural and physiological responses has been observed in some studies [3]. Here, we investigated whether touch can reduce noxious-evoked brain activity. We demonstrate that stroking (at 3 cm/s) prior to an experimental noxious stimulus or clinical heel lance can attenuate noxious-evoked brain activity in infants. CT fibres may represent a biological target for non-pharmacological interventions that modulate pain in early life
Overcoming the barriers to greater public engagement
Integrating science communication training into an undergraduate research project encourages greater academic involvement in public engagement, maximizes audience size, and provides high-quality research data
Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain
Objectives Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia.
Methods The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12- ydroxyeicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LCMS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied.
Results We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical
stimulation of the knee. Local administration of JNJ- 17203212 reversed this sensitisation of joint afferents
and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ-
17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for
increased TRPV1 function in the spinal cord in this model of OA pain.
Conclusions Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain
Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience
The importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood
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