Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier—the glomerular basement membrane (GBM)—can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities)

Do young people stand alone in their demand to live alone? The intergenerational conflict hypothesis put to test in the housing sector

The housing sector is currently under pressure: demographic shifts, urbanisation as well as the availability and costs of housing have led to increasing prices. Concerns are being raised that these rising housing costs could lead to intergenerational conflicts. While older generations often live in their privatelyowned dwellings, younger cohorts struggle to become homeowners, moving the field of housing into the spotlight of national debates. We analyse the importance of housing for Europeans using data from Eurobarometer. Results show that the relevance of housing increased between 2008 and 2018. However, generational differences were found: while older and younger people see housing as an important topic at the country level, only the younger generation seems to be affected personally

Coccolithophore fluxes in the open tropical North Atlantic: influence of thermocline depth, Amazon water, and Saharan dust

Coccolithophores are calcifying phytoplankton and major contributors to both the organic and inorganic oceanic carbon pumps. Their export fluxes, species composition, and seasonal patterns were determined in two sediment trap moorings (M4 at 12 degrees N, 49 degrees W and M2 at 14 degrees N, 37 degrees W) collecting settling particles synchronously from October 2012 to November 2013 at 1200 m of water depth in the open equatorial North Atlantic. The two trap locations showed a similar seasonal pattern in total coccolith export fluxes and a predominantly tropical coccolithophore settling assemblage. Species fluxes were dominated throughout the year by lower photic zone (LPZ) taxa (Florisphaera profunda, Gladiolithus flabellatus) but also included upper photic zone (UPZ) taxa (Umbellosphaera spp., Rhabdosphaera spp., Umbilicosphaera spp., Helicosphaera spp.). The LPZ flora was most abundant during fall 2012, whereas the UPZ flora was more important during summer. In spite of these similarities, the western part of the study area produced persistently higher fluxes, averaging 241 x 10(7) +/- 76 x 10(7) coccoliths m(-2) d(-1) at station M4 compared to only 66 x 10(7) +/- 31 x 10(7) coccoliths m(-2) d(-1) at station M2. Higher fluxes at M4 were mainly produced by the LPZ species, favoured by the westward deepening of the thermocline and nutricline. Still, most UPZ species also contributed to higher fluxes, reflecting enhanced productivity in the western equatorial North Atlantic. Such was the case of two marked flux peaks of the more opportunistic species Gephyrocapsa muellerae and Emiliania huxleyi in January and April 2013 at M4, indicating a fast response to the nutrient enrichment of the UPZ, probably by wind-forced mixing. Later, increased fluxes of G. oceanica and E. huxleyi in October-November 2013 coincided with the occurrence of Amazon-River-affected surface waters. Since the spring and fall events of 2013 were also accompanied by two dust flux peaks, we propose a scenario in which atmospheric dust also provided fertilizing nutrients to this area. Enhanced surface buoyancy associated with the river plume indicates that the Amazon acted not only as a nutrient source, but also as a surface density retainer for nutrients supplied from the atmosphere. Nevertheless, lower total coccolith fluxes during these events compared to the maxima recorded in November 2012 and July 2013 indicate that transient productivity by opportunistic species was less important than "background" tropical productivity in the equatorial North Atlantic. This study illustrates how two apparently similar sites in the tropical open ocean actually differ greatly in ecological and oceanographic terms. The results presented here provide valuable insights into the processes governing the ecological dynamics and the downward export of coccolithophores in the tropical North Atlantic.Netherlands Organization for Scientific Research (NWO) [822.01.008]; European Research Council (ERC) [311152]; University of Bremen; European Union [600411]info:eu-repo/semantics/publishedVersio

Nanoscale Topography and Poroelastic Properties of Model Tissue Breast Gland Basement Membranes

Basement membranes (BMs) are thin layers of condensed extracellular matrix proteins serving as permeability filters, cellular anchoring sites, and barriers against cancer cell invasion. It is believed that their biomechanical properties play a crucial role in determining cellular behavior and response, especially in mechanically active tissues like breast glands. Despite this, so far, relatively little attention has been dedicated to their analysis because of the difficulty of isolating and handling such thin layers of material. Here, we isolated BMs derived from MCF10A spheroids—three-dimensional breast gland model systems mimicking in vitro the most relevant phenotypic characteristics of human breast lobules—and characterized them by atomic force microscopy, enhanced resolution confocal microscopy, and scanning electron microscopy. By performing atomic force microscopy height-clamp experiments, we obtained force-relaxation curves that offered the first biomechanical data on isolated breast gland BMs to our knowledge. Based on enhanced resolution confocal microscopy and scanning electron microscopy imaging data, we modeled the system as a polymer network immersed in liquid and described it as a poroelastic material. Finite-element simulations matching the experimental force-relaxation curves allowed for the first quantification, to our knowledge, of the bulk and shear moduli of the membrane as well as its water permeability. These results represent a first step toward a deeper understanding of the mechanism of tensional homeostasis regulating mammary gland activity as well as its disruption during processes of membrane breaching and metastatic invasion

DNA as a programmable viscoelastic nanoelement

The two strands of a DNA molecule with a repetitive sequence can pair into many different basepairing patterns. For perfectly periodic sequences, early bulk experiments of Poerschke indicate the existence of a sliding process, permitting the rapid transition between different relative strand positions [Biophys. Chem. 2 (1974) 83]. Here, we use a detailed theoretical model to study the basepairing dynamics of periodic and nearly periodic DNA. As suggested by Poerschke, DNA sliding is mediated by basepairing defects (bulge loops), which can diffuse along the DNA. Moreover, a shear force f on opposite ends of the two strands yields a characteristic dynamic response: An outward average sliding velocity v~1/N is induced in a double strand of length N, provided f is larger than a threshold f_c. Conversely, if the strands are initially misaligned, they realign even against an external force less than f_c. These dynamics effectively result in a viscoelastic behavior of DNA under shear forces, with properties that are programmable through the choice of the DNA sequence. We find that a small number of mutations in periodic sequences does not prevent DNA sliding, but introduces a time delay in the dynamic response. We clarify the mechanism for the time delay and describe it quantitatively within a phenomenological model. Based on our findings, we suggest new dynamical roles for DNA in artificial nanoscale devices. The basepairing dynamics described here is also relevant for the extension of repetitive sequences inside genomic DNA.Comment: 10 pages, 7 figures; final version to appear in Biophysical Journa

Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary

High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package 'conumee', to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as 'conumee-KCN', improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity

'Hollow promises?' Critical materialism and the contradictions of the Democratic Peace

© Cambridge University PressThe Democratic Peace research programme explicitly and implicitly presents its claims in terms of their potential to underpin a universal world peace. Yet whilst the Democratic Peace appears robust in its geographical heartlands it appears weaker at the edges of the democratic world, where the spread of democracy and the depth of democratic political development is often limited and where historically many of the purported exceptions to the Democratic Peace are found. Whereas Democratic Peace scholarship has tended to overlook or downplay these phenomena, from a critical materialist perspective they are indicative of a fundamental contradiction within the Democratic Peace whereby its universalistic aspirations are thwarted by its material grounding in a hierarchical capitalist world economy. This, in turn, raises the question of whether liberal arguments for a universal Democratic Peace are in fact hollow promises. The article explores these concerns and argues that those interested in democracy and peace should pay more attention to the critical materialist tradition, which in the discussion below is represented principally by the world-system approach

Assessment of health‐related quality of life as an outcome measure in granulomatosis with polyangiitis (Wegener's)

Objective To assess a generic measure of health‐related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's) (GPA). Methods Subjects were participants in the Wegener's Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC‐LS). HRQOL was assessed with the Short Form 36 (SF‐36) health survey that includes physical and mental component summary scores (PCS and MCS, respectively). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG). Results The data from 180 subjects in the WGET (median followup 2.3 years, mean number of visits 10) and 237 subjects in the VCRC‐LS (median followup 2.0 years, mean number of visits 8) were analyzed. A 1 unit increase in the BVAS/WG corresponded to a 1.15 unit (95% confidence interval [95% CI] 1.02, 1.29) decrease for the PCS and a 0.93 (95% CI 0.78, 1.07) decrease for the MCS in the WGET, and to a 1.16 unit decrease for the PCS (95% CI 0.94, 1.39) and a 0.79 unit decrease for the MCS (95% CI 0.51, 1.39) in the VCRC‐LS. In both arms of the WGET study, SF‐36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per 3 months), but worsened slightly (0.03 decrease in PCS every 3 months) among patients not achieving sustained remission ( P = 0.005). Conclusion HRQOL, as measured by the SF‐36, is reduced among patients with GPA. SF‐36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90377/1/20649_ftp.pd

Towards an eficient atomic frequency comb quantum memory

We present an efficient photon-echo experiment based on atomic frequency combs [Phys. Rev. A 79, 052329 (2009)]. Echoes containing an energy of up to 35% of that of the input pulse are observed in a Pr3+-doped Y2SiO5 crystal. This material allows for the precise spectral holeburning needed to make a sharp and highly absorbing comb structure. We compare our results with a simple theoretical model with satisfactory agreement. Our results show that atomic frequency combs has the potential for high-efficiency storage of single photons as required in future long-distance communication based on quantum repeaters.Comment: 10 pages, 5 figure

North Atlantic forcing of tropical Indian Ocean climate

Author Posting. © The Author(s), 2014. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 509 (2014): 76-80, doi:10.1038/nature13196.The response of the tropical climate in the Indian Ocean realm to abrupt climate change events in the North Atlantic Ocean is contentious. Repositioning of the intertropical convergence zone is thought to have been responsible for changes in tropical hydroclimate during North Atlantic cold spells1–5, but the dearth of high-resolution records outside the monsoon realm in the Indian Ocean precludes a full understanding of this remote relationship and its underlying mechanisms. Here we show that slowdowns of the Atlantic meridional overturning circulation during Heinrich stadials and the Younger Dryas stadial affected the tropical Indian Ocean hydroclimate through changes to the Hadley circulation including a southward shift in the rising branch (the intertropical convergence zone) and an overall weakening over the southern Indian Ocean. Our results are based on new, high-resolution sea surface temperature and seawater oxygen isotope records of well dated sedimentary archives from the tropical eastern Indian Ocean for the past 45,000 years, combined with climate model simulations of Atlantic circulation slowdown under Marine Isotope Stages 2 and 3 boundary conditions. Similar conditions in the east and west of the basin rule out a zonal dipole structure as the dominant forcing of the tropical Indian Ocean hydroclimate of millennial-scale events. Results from our simulations and proxy data suggest dry conditions in the northern Indian Ocean realm and wet and warm conditions in the southern realm during North Atlantic cold spells.This study was funded by the German Bundesministerium für Bildung und Forschung (grant 03G0189A) and the Deutsche Forschungsgemeinschaft (DFG grants HE3412/15-1 and STE1044/4-1, and the DFG Research Centre/Cluster of Excellence ‘The Ocean in the Earth System’). D.W.O. is funded by the US NSF, R.D.P.-H. is supported by Chilean FONDAP 15110009/ICM Nucleus NC120066.2014-10-3