The regulation of nerve and blood vessel ingrowth in aneural and avascular intervertebral disc and articular cartilage

Introduction This review will discuss the regulatory mechanisms of both innervation and vascularisation within normally aneural and avascular tissues, and how they may become altered in degeneration enabling new nerve and blood vessel formation which is hypothesised to be a source of pain. Conclusion Normal intervertebral discs and articular cartilage are the largest aneural and avascular tissues in the human body yet during intervertebral disc degeneration and osteoarthritis these tissues become increasingly vascularised by small blood vessels and innervated by peptide containing sensory nerve fibres. The mechanism by which this process occurs remains largely unknown. Published data suggests that various factors present within the healthy tissues such as aggrecan, chondromodulin and semaphorins may act as repulsive barriers to neurite and endothelial cell invasion. During degeneration however, the synthesis of these molecules becomes disrupted, potentially leading to vascularisation and innervation of the tissue

Differential interactions of Falcarinol combined with anti-tumour agents on cellular proliferation and apoptosis in human lymphoid leukaemia cell lines

Leukaemia is the most common childhood cancer, and whilst recent advances in therapy have improved survival, current treatments are still limited by their side effects. Thus, new therapies are urgently needed, this study investigated the effects of Falcarinol, a polyacetylene isolated from carrots (Daucus carota) in combination with chemotherapy agents, anti-cancer agents and other apoptosis inducers. Inhibition of cellular proliferation and induction of apoptosis were investigated in three human lymphoid Leukaemia cell lines. Cellular proliferation was determined via ATP quantification using the Cell Titer Glo assay. Induction of apoptosis was investigated using caspase 3 activity assay and confirmed by nuclear morphology using Hoechst 33342. The study demonstrated that CCRF-CEM cells failed to induce synergistic response with any of the investigated chemotherapies, but importantly no inhibition was observed either. Jurkat cells showed a significant synergistic induction of apoptosis following joint treatment with Falcarinol and a Death Receptor 5 agonist (DR5), whereas CCRF-CEM cells showed only an additive response. Conversely within MOLT-3 cells Falcarinol partially inhibited the induction of apoptosis by DR5 agonist although this failed to reach significance. However MOLT-3 cells demonstrated synergistic induction of apoptosis when Falcarinol was combined with either Bortezomib (proteosome inhibitor), or Sulforaphane (histone deacetylase inhibitor). Identification of interactions between natural bioactive compounds with anti-cancer drugs may provide new pathways to target cancerous cells. Furthermore, since some combinations enhance apoptosis but some inhibit apoptosis it may be important to consider these interactions for dietary advice during therapy

Improving aircraft performance using machine learning: a review

This review covers the new developments in machine learning (ML) that are impacting the multi-disciplinary area of aerospace engineering, including fundamental fluid dynamics (experimental and numerical), aerodynamics, acoustics, combustion and structural health monitoring. We review the state of the art, gathering the advantages and challenges of ML methods across different aerospace disciplines and provide our view on future opportunities. The basic concepts and the most relevant strategies for ML are presented together with the most relevant applications in aerospace engineering, revealing that ML is improving aircraft performance and that these techniques will have a large impact in the near future

Guidance for researchers wanting to link NHS data using non-consent approaches: a thematic analysis of feedback from the Health Research Authority Confidentiality Advisory Group

Introduction: The use of linked data and non-consent methodologies is a rapidly growing area of health research due to the increasing detail, availability and scope of routinely collected electronic health records data. However, gaining the necessary legal and governance approvals to undertake data linkage is a complex process in England. / Objectives: We reflect on our own experience of establishing lawful basis for data linkage through Section 251 approval, with the intention to build a knowledgebase of practical advice for future applicants. / Methods: Thematic analysis was conducted on a corpus of Section 251 feedback reports from the NHS Health Research Authority Confidentiality Advisory Group. / Results: Four themes emerged from the feedback. These were: (a) Patient and Public Involvement, (b)~Establishing Rationale, (c) Data maintenance and contingency, and the need to gain (d) Further Permissions from external authorities prior to full approval. / Conclusions: Securing Section 251 approval poses ethical, practical and governance challenges. However, through a comprehensive, planned approach Section 251 approval is possible, enabling researchers to unlock the potential of linked data for the purposes of health research

Differential effects of polyphenols on proliferation and apoptosis in human myeloid and lymphoid leukemia cell lines.

Background: Mortality rates for leukemia are high despite considerable improvements in treatment. Since polyphenols exert pro-apoptotic effects in solid tumors, our study investigated the effects of polyphenols in haematological malignancies. The effect of eight polyphenols (quercetin, chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene and trans-stilbene) were studied on cell proliferation, cell cycle and apoptosis in four lymphoid and four myeloid leukemic cells lines, together with normal haematopoietic control cells. Methods: Cellular proliferation was measured by CellTiter-Glo® luminescent assay; and cell cycle arrest was assessed using flow cytometry of propidium iodide stained cells. Apoptosis was investigated by caspase-3 activity assay using flow cytometry and apoptotic morphology was confirmed by Hoescht 33342 staining. Results: Emodin, quercetin, and cis-stilbene were the most effective polyphenols at decreasing cell viability (IC50 values of 5-22 µM, 8-33 µM, and 25-85 µM respectively) and inducing apoptosis (AP50 values (the concentration which 50% of cells undergo apoptosis) of 2-27 µM, 19-50 µM, and 8-50 µM respectively). Generally, lymphoid cell lines were more sensitive to polyphenol treatment compared to myeloid cell lines, however the most resistant myeloid (KG-1a and K562) cell lines were still found to respond to emodin and quercetin treatment at low micromolar levels. Non-tumor cells were less sensitive to all polyphenols compared to the leukemia cells. Conclusions: These findings suggest that polyphenols have anti-tumor activity against leukemia cells with differential effects. Importantly, the differential sensitivity of emodin, quercetin, and cis-stilbene between leukemia and normal cells suggests that polyphenols are potential therapeutic agents for leukemia

Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration

Introduction : The degenerate intervertebral disc (IVD) becomes innervated by sensory nerve fibres, and vascularised by blood vessels. This study aimed to identify neurotrophins, neuropeptides and angiogenic factors within native IVD tissue and to further investigate whether pro-inflammatory cytokines are involved in the regulation of expression levels within nucleus pulposus (NP) cells, nerve and endothelial cells. Methods : Quantitative real-time PCR (qRT-PCR) was performed on 53 human IVDs from 52 individuals to investigate native gene expression of neurotrophic factors and their receptors, neuropeptides and angiogenic factors. The regulation of these factors by cytokines was investigated in NP cells in alginate culture, and nerve and endothelial cells in monolayer using RT-PCR and substance P (SP) protein expression in interleukin-1 (IL-1ß) stimulated NP cells. Results : Initial investigation on uncultured NP cells identified expression of all neurotrophins by native NP cells, whilst the nerve growth factor (NGF) receptor was only identified in severely degenerate and infiltrated discs, and brain derived neurotrophic factor (BDNF) receptor expressed by more degenerate discs. BDNF expression was significantly increased in infiltrated and degenerate samples. SP and vascular endothelial growth factor (VEGF) were higher in infiltrated samples. In vitro stimulation by IL-1ß induced NGF in NP cells. Neurotropin-3 was induced by tumour necrosis factor alpha in human dermal microvascular endothelial cells (HDMECs). SP gene and protein expression was increased in NP cells by IL-1ß. Calcitonin gene related peptide was increased in SH-SY5Y cells upon cytokine stimulation. VEGF was induced by IL-1ß and interleukin-6 in NP cells, whilst pleiotrophin was decreased by IL-1ß. VEGF and pleiotrophin were expressed by SH-SY5Y cells, and VEGF by HDMECs, but were not modulated by cytokines. Conclusions : The release of cytokines, in particular IL-1ß during IVD degeneration, induced significant increases in NGF and VEGF which could promote neuronal and vascular ingrowth. SP which is released into the matrix could potentially up regulate the production of matrix degrading enzymes and also sensitise nerves, resulting in nociceptive transmission and chronic low back pain. This suggests that IL-1ß is a key regulatory cytokine, involved in the up regulation of factors involved in innervation and vascularisation of tissues.</p

Influence of long-range dipolar interactions on the phase stability and hysteresis shapes of ferroelectric and antiferroelectric multilayers

Phase transition and field driven hysteresis evolution of a two-dimensional Ising grid consisting of ferroelectric-antiferroelectric multilayers that take into account the long range dipolar interactions were simulated by a Monte-Carlo method. Simulations were carried out for a 1+1 bilayer and a 5+5 superlattice. Phase stabilities of components comprising the structures with an electrostatic-like coupling term were also studied. An electrostatic-like coupling, in the absence of an applied field, can drive the ferroelectric layers towards 180º domains with very flat domain interfaces mainly due to the competition between this term and the dipole-dipole interaction. The antiferroelectric layers do not undergo an antiferroelectric-to-ferroelectric transition under the influence of an electrostatic-like coupling between layers as the ferroelectric layer splits into periodic domains at the expense of the domain wall energy. The long-range interactions become significant near the interfaces. For high periodicity structures with several interfaces, the interlayer long-range interactions substantially impact the configuration of the ferroelectric layers while the antiferroelectric layers remain quite stable unless these layers are near the Neel temperature. In systems investigated with several interfaces, the hysteresis loops do not exhibit a clear presence of antiferroelectricity that could be expected in the presence of anti-parallel dipoles, i. e., the switching takes place abruptly. Some recent experimental observations in ferroelectric-antiferroelectric multilayers are discussed where we conclude that the different electrical properties of bilayers and superlattices are not only due to strain effects alone but also long-range interactions. The latter manifests itself particularly in superlattices where layers are periodically exposed to each other at the interfaces

Universality of the Gunn effect: self-sustained oscillations mediated by solitary waves

The Gunn effect consists of time-periodic oscillations of the current flowing through an external purely resistive circuit mediated by solitary wave dynamics of the electric field on an attached appropriate semiconductor. By means of a new asymptotic analysis, it is argued that Gunn-like behavior occurs in specific classes of model equations. As an illustration, an example related to the constrained Cahn-Allen equation is analyzed.Comment: 4 pages,3 Post-Script figure

Ion induced solid flow

Amorphous solids can flow over very long periods of time. Solid flow can also be artificially enhanced by creating defects, as by Ion Beam Sputtering (IBS) in which collimated ions with energies in the 0.1 to 10 keV range impact a solid target, eroding its surface and inducing formation of nanometric structures. Recent experiments have challenged knowledge accumulated during the last two decades so that a basic understanding of self-organized nano-pattern formation under IBS is still lacking. We show that considering the irradiated solid to flow like a highly viscous liquids can account for the complex IBS morphological phase diagram, relegating erosion to a subsidiary role and demonstrating a controllable instance of solid flow at the nanoscale. This new perspective can allow for a full harnessing of this bottom-up route to nanostructuring.Comment: 17 pages, 5 figure

Nerves are more abundant than blood vessels in the degenerate human intervertebral disc

Chronic low back pain (LBP) is the most common cause of disability worldwide. New ideas surrounding LBP are emerging that are based on interactions between mechanical, biological and chemical influences on the human IVD. The degenerate IVD is proposed to be innervated by sensory nerve fibres and vascularised by blood vessels, and it is speculated to contribute to pain sensation. However, the incidence of nerve and blood vessel ingrowth, as well as whether these features are always associated, is unknown. We investigated the presence of nerves and blood vessels in the nucleus pulposus (NP) of the IVD in a large population of human discs