99 research outputs found
Role of a functional polymorphism in the F2R gene promoter in sarcoidosis
Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by increased inflammation, and results from gene-environment interactions. Proteinase-activated receptor-1 mediates the interplay between coagulation and inflammation. The rs2227744G > A promoter single nucleotide polymorphism has been linked to inflammation, cardiovascular disease and chronic obstructive pulmonary disease exacerbations. Using a case-control study (184 cases with sarcoidosis and 368 controls), we show that the rs2227744A allele significantly associates with protection from sarcoidosis (P = 0.003, OR = 0.68 (0.52-0.88))
TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells.
The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.Medical Research Council UK (MRC) CASE studentship with Novartis awarded to RCC, MRC Centenary Award awarded to NS and RCC, and MRC Career Development Award G0800340 to CJS
Surface modification of a POSS-nanocomposite material to enhance cellular integration of a synthetic bioscaffold
AbstractPolyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) is a versatile nanocomposite biomaterial with growing applications as a bioscaffold for tissue engineering. Integration of synthetic implants with host tissue can be problematic but could be improved by topographical modifications. We describe optimization of POSS-PCU by dispersion of porogens (sodium bicarbonate (NaHCO3), sodium chloride (NaCl) and sucrose) onto the material surface, with the principle aim of increasing surface porosity, thus providing additional opportunities for improved cellular and vascular ingrowth. We assess the effect of the porogens on the material's mechanical strength, surface chemistry, wettability and cytocompatibilty. Surface porosity was characterized by scanning electron microscopy (SEM). There was no alteration in surface chemistry and wettability and only modest changes in mechanical properties were detected. The size of porogens correlated well with the porosity of the construct produced and larger porogens improved interconnectivity of spaces within constructs. Using primary human bronchial epithelial cells (HBECs) we demonstrate moderate in vitro cytocompatibility for all surface modifications; however, larger pores resulted in cellular aggregation. These cells were able to differentiate on POSS-PCU scaffolds. Implantation of the scaffold in vivo demonstrated that larger pore sizes favor cellular integration and vascular ingrowth. These experiments demonstrate that surface modification with large porogens can improve POSS-PCU nanocomposite scaffold integration and suggest the need to strike a balance between the non-porous surfaces required for epithelial coverage and the porous structure required for integration and vascularization of synthetic scaffolds in future construct design
Author Correction: The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
Correction to: Nature Communications https://doi.org/10.1038/s41467-018-07858-8, published online 2 January 2019
Vacuum-assisted decellularization: an accelerated protocol to generate tissue-engineered human tracheal scaffolds
Patients with large tracheal lesions unsuitable for conventional endoscopic or open operations may require a tracheal replacement but there is no present consensus of how this may be achieved. Tissue engineering using decellularized or synthetic tracheal scaffolds offers a new avenue for airway reconstruction. Decellularized human donor tracheal scaffolds have been applied in compassionate-use clinical cases but naturally derived extracellular matrix (ECM) scaffolds demand lengthy preparation times. Here, we compare a clinically applied detergent-enzymatic method (DEM) with an accelerated vacuum-assisted decellularization (VAD) protocol. We examined the histological appearance, DNA content and extracellular matrix composition of human donor tracheae decellularized using these techniques. Further, we performed scanning electron microscopy (SEM) and biomechanical testing to analyze decellularization performance. To assess the biocompatibility of scaffolds generated using VAD, we seeded scaffolds with primary human airway epithelial cells in vitro and performed in vivo chick chorioallantoic membrane (CAM) and subcutaneous implantation assays. Both DEM and VAD protocols produced well-decellularized tracheal scaffolds with no adverse mechanical effects and scaffolds retained the capacity for in vitro and in vivo cellular integration. We conclude that the substantial reduction in time required to produce scaffolds using VAD compared to DEM (approximately 9 days vs. 3–8 weeks) does not compromise the quality of human tracheal scaffold generated. These findings might inform clinical decellularization techniques as VAD offers accelerated scaffold production and reduces the associated costs
ARPES: A probe of electronic correlations
Angle-resolved photoemission spectroscopy (ARPES) is one of the most direct
methods of studying the electronic structure of solids. By measuring the
kinetic energy and angular distribution of the electrons photoemitted from a
sample illuminated with sufficiently high-energy radiation, one can gain
information on both the energy and momentum of the electrons propagating inside
a material. This is of vital importance in elucidating the connection between
electronic, magnetic, and chemical structure of solids, in particular for those
complex systems which cannot be appropriately described within the
independent-particle picture. Among the various classes of complex systems, of
great interest are the transition metal oxides, which have been at the center
stage in condensed matter physics for the last four decades. Following a
general introduction to the topic, we will lay the theoretical basis needed to
understand the pivotal role of ARPES in the study of such systems. After a
brief overview on the state-of-the-art capabilities of the technique, we will
review some of the most interesting and relevant case studies of the novel
physics revealed by ARPES in 3d-, 4d- and 5d-based oxides.Comment: Chapter to appear in "Strongly Correlated Systems: Experimental
Techniques", edited by A. Avella and F. Mancini, Springer Series in
Solid-State Sciences (2013). A high-resolution version can be found at:
http://www.phas.ubc.ca/~quantmat/ARPES/PUBLICATIONS/Reviews/ARPES_Springer.pdf.
arXiv admin note: text overlap with arXiv:cond-mat/0307085,
arXiv:cond-mat/020850
Quantum oscillations and the Fermi surface in an underdoped high-Tc superconductor
Despite twenty years of research, the phase diagram of high transition-
temperature superconductors remains enigmatic. A central issue is the origin of
the differences in the physical properties of these copper oxides doped to
opposite sides of the superconducting region. In the overdoped regime, the
material behaves as a reasonably conventional metal, with a large Fermi
surface. The underdoped regime, however, is highly anomalous and appears to
have no coherent Fermi surface, but only disconnected "Fermi arcs". The
fundamental question, then, is whether underdoped copper oxides have a Fermi
surface, and if so, whether it is topologically different from that seen in the
overdoped regime. Here we report the observation of quantum oscillations in the
electrical resistance of the oxygen-ordered copper oxide YBa2Cu3O6.5,
establishing the existence of a well-defined Fermi surface in the ground state
of underdoped copper oxides, once superconductivity is suppressed by a magnetic
field. The low oscillation frequency reveals a Fermi surface made of small
pockets, in contrast to the large cylinder characteristic of the overdoped
regime. Two possible interpretations are discussed: either a small pocket is
part of the band structure specific to YBa2Cu3O6.5 or small pockets arise from
a topological change at a critical point in the phase diagram. Our
understanding of high-transition temperature (high-Tc) superconductors will
depend critically on which of these two interpretations proves to be correct
Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)
Introduction
The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD).
Methods and analysis
The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment.
Ethics and dissemination
All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals.
Conclusion
This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD
Lifshitz quantum phase transitions and Fermi surface transformation with hole doping in high- superconductors
We study the doping evolution of the electronic structure in the normal phase
of high- cuprates. Electronic structure and Fermi surface of cuprates with
single CuO layer in the unit cell like LaSrCuO have been
calculated by the LDA+GTB method in the regime of strong electron correlations
(SEC) and compared to ARPES and quantum oscillations data. We have found two
critical concentrations, and , where the Fermi surface
topology changes. Following I.M. Lifshitz ideas of the quantum phase
transitions (QPT) of the 2.5-order we discuss the concentration dependence of
the low temperature thermodynamics. The behavior of the electronic specific
heat is similar to the Loram and Cooper
experimental data in the vicinity of .Comment: 8 pages, 4 figure
Universal quantum oscillations in the underdoped cuprate superconductors
The metallic state of the underdoped high-Tc cuprates has remained an enigma:
How may seemingly disconnected Fermi surface segments, observed in zero
magnetic field as a result of the opening of a partial gap (the pseudogap),
possess conventional quasiparticle properties? How do the small Fermi-surface
pockets evidenced by the observation of quantum oscillations (QO) emerge as
superconductivity is suppressed in high magnetic fields? Such QO, discovered in
underdoped YBa2Cu3O6.5 (Y123) and YBa2Cu4O8 (Y124), signify the existence of a
conventional Fermi surface (FS). However, due to the complexity of the crystal
structures of Y123 and Y124 (CuO2 double-layers, CuO chains, low structural
symmetry), it has remained unclear if the QO are specific to this particular
family of cuprates. Numerous theoretical proposals have been put forward to
explain the route toward QO, including materials-specific scenarios involving
CuO chains and scenarios involving the quintessential CuO2 planes. Here we
report the observation of QO in underdoped HgBa2CuO4+{\delta} (Hg1201), a model
cuprate superconductor with individual CuO2 layers, high tetragonal symmetry,
and no CuO chains. This observation proves that QO are a universal property of
the underdoped CuO2 planes, and it opens the door to quantitative future
studies of the metallic state and of the Fermi-surface reconstruction
phenomenon in this structurally simplest cuprate.Comment: 17 pages, 5 figure
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