Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of ...zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.
In 2010, a tissue‐engineered trachea was transplanted into a 10‐year‐old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal ...stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti‐HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross‐sectional area analysis showed restriction of growth within an area of in‐stent stenosis. This report demonstrates the long‐term viability of a decellularized tissue‐engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.
This case presents a 4‐year follow‐up of a tissue‐engineered pediatric tracheal transplant and reports on the longterm viability of this approach and areas for further research.
•An up to date review with the latest scientific results of fractional calculus in both science and engineering fields.•The use of fractional calculus in modeling: respiratory tissue, bio-impedance ...and drug diffusion.•Fractional calculus offers parsimonious yet accurate models.
This review provides the latest developments and trends in the application of fractional calculus (FC) in biomedicine and biology. Nature has often showed to follow rather simple rules that lead to the emergence of complex phenomena as a result. Of these, the paper addresses the properties in respiratory lung tissue, whose natural solutions arise from the midst of FC in the form of non-integer differ-integral solutions and non-integer parametric models. Diffusion of substances in human body, e.g. drug diffusion, is also a phenomena well known to be captured with such mathematical models. FC has been employed in neuroscience to characterize the generation of action potentials and spiking patters but also in characterizing bio-systems (e.g. vegetable tissues). Despite the natural complexity, biological systems belong as well to this class of systems, where FC has offered parsimonious yet accurate models. This review paper is a collection of results and literature reports who are essential to any versed engineer with multidisciplinary applications and bio-medical in particular.
The risks to human populations in coastal areas are changing due to climate and socio-economic changes, and these trends are predicted to accelerate during the twenty-first century. To understand ...these changing risks, and the resulting choices and pathways to successful management and adaptation, broad-scale integrated assessment is essential. Due to their complexity the two risks of flooding and erosion are usually managed independently, yet frequently they are interconnected by longshore exchange of sediments and the resulting broad scale morphological system behaviour. In order to generate new insights into the effects of climate change and coastal management practises on coastal erosion and flood risk, we present an integrated assessment of 72 km of shoreline over the twenty-first century on the East Anglian coast of England which is a site of significant controversy about how to manage coastal flood and erosion risks over the twenty-first century. A coupled system of hydrodynamic, morphological, reliability and socio-economic models has been developed for the analysis, implemented under scenarios of coastal management, climate and socio-economic change. The study is unique in coastal management terms because of the large spatial scale and extended temporal scale over which the analysis is quantified. This study for the first time quantifies what has for some years been argued qualitatively: the role of sediments released from cliff erosion in protecting neighbouring low-lying land from flooding. The losses and benefits are expressed using the common currency of economic risk. The analysis demonstrates that over the twenty-first century, flood risk in the study area is expected to be an order of magnitude greater than erosion risk. Climate and socio-economic change and coastal management policy have a significant influence on flood risk. This study demonstrates that the choices concerning coastal management are profound, and there are clear tradeoffs between erosion and flood impacts.
Urban greening can potentially help mitigate heat-related mortality and flooding facing the >4 billion urban population worldwide. However, the geographical variation of the relative combined ...hydrological and thermal performance benefits of such interventions are unknown. Here we quantify globally, using a hydrological model, how climate-driven trade-offs exist between hydrological retention and cooling potential of urban greening such as green roofs and parks. Using a Budyko framework, we show that water retention generally increases with aridity in water-limited environments, while cooling potential favors energy-limited climates. Our models suggest that common urban greening strategies cannot yield high performance simultaneously for addressing both urban heat-island and urban flooding problems in most cities globally. Irrigation, if sustainable, may enhance cooling while maintaining retention performance in more arid locations. Increased precipitation variability with climate change may reduce performance of thinner green-infrastructure more quickly compared to greened areas with thicker soils and root systems. Our results provide a conceptual framework and first-order quantitative guide for urban development, renewal and policymaking.
The highly hydrated, petrologic type 1 CM and CI carbonaceous chondrites likely derived from primitive, water‐rich asteroids, two of which are the targets for JAXA's Hayabusa2 and NASA's OSIRIS‐REx ...missions. We have collected visible and near‐infrared (VNIR) and mid infrared (MIR) reflectance spectra from well‐characterized CM1/2, CM1, and CI1 chondrites and identified trends related to their mineralogy and degree of secondary processing. The spectral slope between 0.65 and 1.05 μm decreases with increasing total phyllosilicate abundance and increasing magnetite abundance, both of which are associated with more extensive aqueous alteration. Furthermore, features at ~3 μm shift from centers near 2.80 μm in the intermediately altered CM1/2 chondrites to near 2.73 μm in the highly altered CM1 chondrites. The Christiansen features (CF) and the transparency features shift to shorter wavelengths as the phyllosilicate composition of the meteorites becomes more Mg‐rich, which occurs as aqueous alteration proceeds. Spectra also show a feature near 6 μm, which is related to the presence of phyllosilicates, but is not a reliable parameter for estimating the degree of aqueous alteration. The observed trends can be used to estimate the surface mineralogy and the degree of aqueous alteration in remote observations of asteroids. For example, (1) Ceres has a sharp feature near 2.72 μm, which is similar in both position and shape to the same feature in the spectra of the highly altered CM1 MIL 05137, suggesting abundant Mg‐rich phyllosilicates on the surface. Notably, both OSIRIS‐REx and Hayabusa2 have onboard instruments which cover the VNIR and MIR wavelength ranges, so the results presented here will help in corroborating initial results from Bennu and Ryugu.
Abstract The effort required to inhale a breath of air is a critically important measure in assessing airway function. Although the contribution of the trachea to the total flow resistance of the ...airways is generally modest, pathological alterations in tracheal geometry can have a significant negative effect. This study investigates the mechanisms of flow energy loss in a healthy trachea and in four geometries affected by retrosternal goitre which can cause significant distortions of tracheal geometry including constriction and deviation with abnormal curvature. By separating out the component of energy loss related to the wall shear (frictional loss), striking differences are found between the patterns of energy dissipation in the normal and pathological tracheas. Furthermore the ratio of frictional to total loss is dramatically reduced in the pathological geometries.
Glomerular-derived proteins may activate tubular cells to express the macrophage-directed chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Macrophages at interstitial sites have a central ...role in directing renal scarring. We have prospectively assessed the relationship between albuminuria, urinary MCP-1/CCL2, interstitial macrophage infiltration, in situ damage, and clinical outcomes in a large group of patients with chronic kidney disease. We studied 215 patients and quantified albumin–creatinine ratio (ACR), urinary MCP-1/CCL2, interstitial macrophage numbers, and in situ damage. ACR correlated with urinary MCP-1/CCL2 (correlation 0.499; P<0.001), interstitial macrophage numbers (correlation 0.481; P<0.001), and index of chronic damage (correlation 0.363; P<0.001). Macrophage numbers closely correlated with in situ damage (correlation 0.755; P<0.001). By multivariate analysis ACR, urinary MCP-1/CCL2, and interstitial macrophage numbers were interdependent. By Kaplan–Meier survival analysis albuminuria, urinary MCP-1/CCL2, interstitial macrophages, and chronic damage predict the outcome. ACR, macrophage numbers, chronic damage, and creatinine independently predicted renal survival. The association of ACR with other variables was strongest in patients with less advanced disease states. There is a close association between albuminuria, urinary MCP-1/CCL2, and interstitial macrophage infiltration with in situ damage and clinical outcomes. These findings support the hypothesis that albuminuria triggers tubular MCP-1/CCL2 expression with subsequent macrophage infiltration. These processes may represent the dominant pathway for the progression of renal injury before the establishment of advanced renal scarring
Life on the margin Andersson, Andreas J.; Mackenzie, Fred T.; Bates, Nicholas R.
Marine ecology. Progress series,
12/2008, Volume:
373
Journal Article
Peer reviewed
Open access
Future anthropogenic emissions of CO₂ and the resulting ocean acidification may have severe consequences for marine calcifying organisms and ecosystems. Marine calcifiers depositing calcitic hard ...parts that contain significant concentrations of magnesium, i.e. Mg-calcite, and calcifying organisms living in high latitude and/or cold-water environments are at immediate risk to ocean acidification and decreasing seawater carbonate saturation because they are currently immersed in seawater that is just slightly supersaturated with respect to the carbonate phases they secrete. Under the present rate of CO₂ emissions, model calculations show that high latitude ocean waters could reach undersaturation with respect to aragonite in just a few decades. Thus, before this happens these waters will be undersaturated with respect to Mg-calcite minerals of higher solubility than that of aragonite. Similarly, tropical surface seawater could become undersaturated with respect to Mgcalcite minerals containing ≥12 mole percent (mol%) MgCO₃ during this century. As a result of these changes in surface seawater chemistry and further penetration of anthropogenic CO₂ into the ocean interior, we suggest that (1) the magnesium content of calcitic hard parts will decrease in many ocean environments, (2) the relative proportion of calcifiers depositing stable carbonate minerals, such as calcite and low Mg-calcite, will increase and (3) the average magnesium content of carbonate sediments will decrease. Furthermore, the highest latitude and deepest depth at which cold-water corals and other calcifiers currently exist will move towards lower latitudes and shallower depth, respectively. These changes suggest that anthropogenic emissions of CO₂ may be currently pushing the oceans towards an episode characteristic of a ‘calcite sea.’
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