984 research outputs found
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Bicyclic RGD peptides enhance nerve growth in synthetic PEG-based Anisogels
Nerve regeneration scaffolds often consist of soft hydrogels modified with extracellular matrix (ECM) proteins or fragments, as well as linear and cyclic peptides. One of the commonly used integrin-mediated cell adhesive peptide sequences is Arg-Gly-Asp (RGD). Despite its straightforward coupling mechanisms to artificial extracellular matrix (aECM) constructs, linear RGD peptides suffer from low stability towards degradation and lack integrin selectivity. Cyclization of RGD improves the affinity towards integrin subtypes but lacks selectivity. In this study, a new class of short bicyclic peptides with RGD in a cyclic loop and 'random screened' tri-amino acid peptide sequences in the second loop is investigated as a biochemical cue for cell growth inside three-dimensional (3D) synthetic poly(ethylene glycol) (PEG)-based Anisogels. These peptides impart high integrin affinity and selectivity towards either αvβ3 or α5β1 integrin subunits. Enzymatic conjugation of such bicyclic peptides to the PEG backbone enables the formulation of an aECM hydrogel that supports nerve growth. Furthermore, different proteolytic cleavable moieties are incorporated and compared to promote cell migration and proliferation, resulting in enhanced cell growth with different degradable peptide crosslinkers. Mouse fibroblasts and primary nerve cells from embryonic chick dorsal root ganglions (DRGs) show superior growth in bicyclic RGD peptide conjugated gels selective towards αvβ3 or α5β1, compared to monocyclic or linear RGD peptides, with a slight preference to αvβ3 selective bicyclic peptides in the case of nerve growth. Synthetic Anisogels, modified with bicyclic RGD peptides and containing short aligned, magneto-responsive fibers, show oriented DRG outgrowth parallel to the fibers. This report shows the potential of PEG hydrogels coupled with bicyclic RGD peptides as an aECM model and paves the way for a new class of integrin selective biomolecules for cell growth and nerve regeneration
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Synthetic 3D PEG-Anisogel Tailored with Fibronectin Fragments Induce Aligned Nerve Extension
An enzymatically cross-linked polyethylene glycol (PEG)-based hydrogel was engineered to promote and align nerve cells in a three-dimensional manner. To render the injectable, otherwise bioinert, PEG-based material supportive for cell growth, its mechanical and biochemical properties were optimized. A recombinant fibronectin fragment (FNIII9*-10/12-14) was coupled to the PEG backbone during gelation to provide cell adhesive and growth factor binding domains in close vicinity. Compared to full-length fibronectin, FNIII9*-10/12-14 supports nerve growth at similar concentrations. In a 3D environment, only the ultrasoft 1 w/v% PEG hydrogels with a storage modulus of ∼10 Pa promoted neuronal growth. This gel was used to establish the first fully synthetic, injectable Anisogel by the addition of magnetically aligned microelements, such as rod-shaped microgels or short fibers. The Anisogel led to linear neurite extension and represents a large step in the direction of clinical translation with the opportunity to treat acute spinal cord injuries
AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis
Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle
Improving fleet solution – a case study
Transportation management is a logistical activity with a high impact on a company’s ability to compete in the market. Although the focus on cost reduction is the most usual concern with this activity, lead times and the quality of the service provided should also be considered depending on the market to be served. The goal of this research was to compare different fleet alternatives for a specific construction materials company and discuss which scenario is the most suited to fulfil the company’s customer service policy. A case study approach was developed, and four alternative scenarios were considered. These were compared both regarding the costs they involve, which was analysed using a vehicle routing problem heuristic, and the quality of the customer service they allow, which was assessed based on their ability to provide flexibility in the fleet occupancy rate to respond to unexpected orders. Evidence showed that the current fleet solution is not adequate and investment should be made only if the demand level increases, otherwise outsourcing should be considered along with a minimum level of the self-owned fleet.info:eu-repo/semantics/acceptedVersio
The properties of the first galaxies in the BlueTides simulation
We employ the very large cosmological hydrodynamical simulation BlueTides to investigate the predicted properties of the galaxy population during the epoch of reionization (z > 8). BlueTides has a resolution and volume ((400/h ≈ 577)3 cMpc3) providing a population of galaxies that is well matched to depth and area of current observational surveys targeting the high-redshift Universe. At z = 8, BlueTides includes almost 160 000 galaxies with stellar masses >108 M⊙. The population of galaxies predicted by BlueTides closely matches observational constraints on both the galaxy stellar mass function and far-UV (150 nm) luminosity function. Galaxies in BlueTides are characterized by rapidly increasing star formation histories. Specific star formation rates decrease with redshift though remain largely insensitive to stellar mass. As a result of the enhanced surface density of metals, more massive galaxies are predicted to have higher dust attenuation resulting in a significant steepening of the observed far-UV luminosity function at high luminosities. The contribution of active supermassive black holes (SMBHs) to the UV luminosities of galaxies with stellar masses 109–10 M⊙ is around 3 per cent on average. Approximately 25 per cent of galaxies with M∗ ≈ 1010 M⊙ are predicted to have active SMBHs that contribute >10 per cent of the total UV luminosity
IL-13 expression by blood T cells and not eosinophils is increased in asthma compared to non-asthmatic eosinophilic bronchitis
<p>Abstract</p> <p>Background</p> <p>In asthma interleukin (IL)-13 is increased in the airway compared with non-asthmatic eosinophilic bronchitis. Whether this differential expression is specific to the airway or is more generalised is uncertain.</p> <p>Methods</p> <p>We sought to examine IL-13 expression in peripheral blood T-cells and eosinophils in asthma and non-asthmatic eosinophilic bronchitis. Peripheral blood CD3+ cell and eosinophil intracellular IL-13 expression from subjects with asthma, non-asthmatic eosinophilic bronchitis and healthy controls was assessed. The effect of priming by asthmatic serum on the release of IL-13 by peripheral blood mononuclear cells from healthy subjects was examined and the serum from these subjects was analysed for a range of chemokines and cytokines.</p> <p>Results</p> <p>The median (IQR)% intracellular IL-13 expression by CD3+ cells was increased in asthma [5.3 (2.7–9.8)%; n = 12] compared to non-asthmatic eosinophilic bronchitis [1.1 (0.5–3)%; n = 7] and healthy controls [1.7 (0.2–3%); n = 9] (p = 0.02), but was not significantly different in eosinophils across the groups. IL-13 released from healthy peripheral blood mononuclear cells (n = 10) was increased by asthmatic serum [117 (47.8–198)pg/ml] compared to control [78.5 (42.6–128)pg/ml; p = 0.02), but was not affected by non-asthmatic serum.</p> <p>Conclusion</p> <p>Our findings support the view that IL-13 expression is increased in peripheral blood-derived T cells in asthma and that asthmatic serum up-regulates IL-13 release from healthy peripheral blood mononuclear cells.</p
JWST-JADES. Possible Population III signatures at z=10.6 in the halo of GN-z11
Finding the first generation of stars formed out of pristine gas in the early
Universe, known as Population III (PopIII) stars, is one of the most important
goals of modern astrophysics. Recent models suggest that PopIII stars may form
in pockets of pristine gas in the halo of more evolved galaxies. Here we
present NIRSpec-IFU and NIRSpec-MSA observations of the region around GN-z11,
an exceptionally luminous galaxy at , which reveal a 5
detection of a feature consistent with being HeII1640 emission at the
redshift of GN-z11. The very high equivalent width of the putative HeII
emission in this clump (170 A), and the lack of metal lines, can be explained
in terms of photoionisation by PopIII stars, while photoionisation by PopII
stars is inconsistent with the data. It would also indicate that the putative
PopIII stars likely have a top-heavy initial mass function (IMF), with an upper
cutoff reaching at least 500 M. The PopIII bolometric luminosity
inferred from the HeII line would be , which
(with a top-heavy IMF) would imply a total stellar mass formed in the burst of
. We find that photoionisation by the Active
Galactic Nucleus (AGN) in GN-z11 cannot account for the HeII luminosity
observed in the clump, but can potentially be responsible for additional HeII
emission observed closer to GN-z11. We also consider the possibility of in-situ
photoionisation by an accreting Direct Collapse Black Hole (DCBH) hosted by the
HeII clump; we find that this scenario is less favoured, but it remains a
possible alternative interpretation. We also report the detection of a
Ly halo stemming out of GN-z11 and extending out to 2 kpc, as
well as resolved, funnel-shaped CIII] emission, likely tracing the ionisation
cone of the AGN.Comment: Submitted to A&A, 13 pages, 8 figures; some typos corrected and some
minor additional information added to match submitted versio
Differential Affinity and Catalytic Activity of CheZ in E. coli Chemotaxis
Push–pull networks, in which two antagonistic enzymes control the
activity of a messenger protein, are ubiquitous in signal transduction pathways.
A classical example is the chemotaxis system of the bacterium
Escherichia coli, in which the kinase CheA and the
phosphatase CheZ regulate the phosphorylation level of the messenger protein
CheY. Recent experiments suggest that both the kinase and the phosphatase are
localized at the receptor cluster, and Vaknin and Berg recently demonstrated
that the spatial distribution of the phosphatase can markedly affect the
dose–response curves. We argue, using mathematical modeling, that the
canonical model of the chemotaxis network cannot explain the experimental
observations of Vaknin and Berg. We present a new model, in which a small
fraction of the phosphatase is localized at the receptor cluster, while the
remainder freely diffuses in the cytoplasm; moreover, the phosphatase at the
cluster has a higher binding affinity for the messenger protein and a higher
catalytic activity than the phosphatase in the cytoplasm. This model is
consistent with a large body of experimental data and can explain many of the
experimental observations of Vaknin and Berg. More generally, the combination of
differential affinity and catalytic activity provides a generic mechanism for
amplifying signals that could be exploited in other two-component signaling
systems. If this model is correct, then a number of recent modeling studies,
which aim to explain the chemotactic gain in terms of the activity of the
receptor cluster, should be reconsidered
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