New Strontium-based Bioactive Glasses: Physicochemical Reactivity and Delivering Capability of Biologically Active Dissolution Products

International audienceThe development of bone tissue regeneration calls for biomaterials able to release biologically active substances in a controlled manner after implantation. In this context, strontium-doped bioactive glasses are of major interest; their key property relies on the increased kinetics of surface reactions, along with the release of critical concentrations of ionic dissolution products capable of stimulating cellular responses. In this paper, we report a complete evaluation of the in vitro reactivity of new SiO2–CaO–SrO and SiO2–CaO–P2O5–SrO bioactive glasses. In contact with simulated acellular physiological fluids, these materials induce the formation of a calcium phosphate surface layer that closely resembles to the biological apatite present in bones. Compared to strontium-free materials, the dissolution of SiO2–CaO–SrO and SiO2–CaO–P2O5–SrO glasses is reduced. However the surface layer is more quickly transformed into a bone-like apatite phase, according to the kinetics of evolution of the Ca/P atomic ratio. Evidences of the presence of Sr at the glass/biological fluids interface were obtained, along with the demonstration that this element is released in physiological concentrations into the biological environment. Knowing the well-recognized beneficial effects of strontium on cell activity and bone remodeling, this crucial result gives high hopes for the development of innovative applications based on Sr-doped glasses in treatment of osteoporosis and tissue engineering

Micro-PIXE-RBS methods highlighting the influence of phosphorus on the in vitro bioactivity of sol-gel derived glass particles in the SiO2-CaO-P2O5 system

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Influence of mesostructuration on the reactivity of bioactive glasses in biological medium: a PIXE-RBS study

Building mesostructured biomaterials is a challenging and exciting task that has attracted much attention because of their use as drug carriers or drug delivery systems. In the case of bioactive materials, the mesostructuration can also deeply impact their physico-chemical properties and the reactivity. In this study, we show how highly ordered mesoporosity influences the early steps of the biomineralization process and the reactivity in binary (SiO2–CaO) and ternary (SiO2–CaO–P2O5) bioactive glasses. Conventional porous sol–gel glasses were synthesized using a classical route, while mesostructured glasses were developed using a non-ionic surfactant. Textural properties of these materials have been characterized. The in vitro biomineralization process was followed, using Particle Induced X-ray Emission (PIXE) associated to Rutherford Backscattering Spectrometry (RBS), which are efficient methods for a highly sensitive multi-elemental analysis. Elemental maps of silicon, calcium and phosphorus were obtained at a micrometer scale and revealed for the first time a bulk reactivity for mesostructured glasses. This is a major advantage over conventional glasses, for which the first steps of biomineralization are limited to the periphery of the material. Their enhanced bioactivity combined with their possible use as drug-delivery systems make them promising candidates for bone regeneration

Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines.

In cancer, Transforming Growth Factor beta (TGFbeta) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma

Antihypertensive response to prolonged tempol in the spontaneously hypertensive rat

Antihypertensive response to prolonged tempol in the spontaneously hypertensive rat.IntroductionTempol is a permeant nitroxide superoxide dismutase (SOD) mimetic that lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHRs). We investigated the hypothesis that the antihypertensive response entails a negative salt balance, blunting of plasma renin activity (PRA), endothelin-1 (ET-1), or catecholamines or correction of oxidative stress as indexed by 8-isoprostane prostaglandin F2α (PGF2α) (8-Iso).MethodsGroups (N = 6 to 8) of SHRs were infused for 2 weeks with vehicle or tempol (200 nmol/kg/min) or given tempol (2 mmol/L) in drinking water.ResultsTempol infusion reduced the MAP of anesthetized SHRs (150 ± 5 vs. 126 ± 6mm Hg) (P < 0.005). Oral tempol did not change the heart rate but reduced the MAP of conscious SHRs (-23 ± 6mm Hg) (P < 0.01) but not Wistar-Kyoto (WKY) rats. Tempol infusion increased the PRA (2.2 ± 0.2 vs. 5.0 ± 0.9 ng/mL/hour) (P < 0.005), did not change excretion of nitric oxide (NO) [NO2 + NO3 (NOx)], ET-1, or catecholamines but reduced excretion of 8-Iso (13.2 ± 1.4 vs. 9.6 ± 0.9 ng/24 hours; P < 0.01). Cumulative Na+ balance and gain in body weight were unaltered by tempol infusion. Tempol prevented a rise in MAP with high salt intake.ConclusionTempol corrects hypertension without a compensatory sympathoadrenal activation or salt retention. The response is independent of nitric oxide, endothelin, or catecholamines and occurs despite increased PRA. It is accompanied by a reduction in oxidative stress and is maintained during increased salt intake

Scalable Multi-Agent Reinforcement Learning for Warehouse Logistics with Robotic and Human Co-Workers

We envision a warehouse in which dozens of mobile robots and human pickers work together to collect and deliver items within the warehouse. The fundamental problem we tackle, called the order-picking problem, is how these worker agents must coordinate their movement and actions in the warehouse to maximise performance (e.g. order throughput). Established industry methods using heuristic approaches require large engineering efforts to optimise for innately variable warehouse configurations. In contrast, multi-agent reinforcement learning (MARL) can be flexibly applied to diverse warehouse configurations (e.g. size, layout, number/types of workers, item replenishment frequency), as the agents learn through experience how to optimally cooperate with one another. We develop hierarchical MARL algorithms in which a manager assigns goals to worker agents, and the policies of the manager and workers are co-trained toward maximising a global objective (e.g. pick rate). Our hierarchical algorithms achieve significant gains in sample efficiency and overall pick rates over baseline MARL algorithms in diverse warehouse configurations, and substantially outperform two established industry heuristics for order-picking systems

Mechanism of Calcium Incorporation Inside Sol–Gel Silicate Bioactive Glass and the Advantage of Using Ca(OH)2 over Other Calcium Sources

Calcium is an essential component of osteogenesis and is often required for imparting significant bioactivity to synthetic bone substitutes and, in particular, silicate-based materials. However, the mechanism of calcium incorporation inside sol–gel silicates is poorly understood. In this work, we shed light on the determinant parameters for incorporation of calcium into acid–base-catalyzed sol–gel silicates at ambient temperature: increasing the pH above the isoelectric point of silicic acid and the nature of the calcium counterion in the calcium precursor are found to be the key. Based on our proposed reaction sequence, we were able to compare calcium precursors and select an ideal candidate compound for the synthesis of bioactive glasses (BG) and organic–inorganic hybrids at ambient temperature. Reproducible syntheses and gel times of SiO2–CaO BG were obtained using calcium hydroxide (CH), and we demonstrate its usability in the synthesis of promising BG–polycaprolactone hybrid scaffolds. BG and hybrids prepared with CH were able to form nanocrystalline nonstoichiometric apatite in simulated body fluid. The increased reliability of low-temperature syntheses associated with the use of a stable and inexpensive alkaline-earth precursor are major steps toward the translation of calcium silicate hybrids or other alkaline-earth silicates from bench to clinic

DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation

An engineered gastrointestinally stable microbial leucine decarboxylase for potential treatment of maple syrup urine disease

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Initial spacing of teak (Tectona grandis) in northern Lao PDR: Impacts on the growth of teak and companion crops

Teak (Tectona grandis) has been planted extensively by smallholder farmers in Luang Prabang province of northern Laos, primarily in small woodlots established at high initial stocking rates with little/no management until the largest trees are harvested selectively, commencing at 15–20 years after planting. This study used a Nelder wheel experiment planted in 2008, and measured annually after the end of the first 10 growing seasons, to evaluate the effects of the initial planting density on the growth of teak. The potential for intercropping established teak was also evaluated using this Nelder wheel, when the trees were 5–6 years of age, to emulate what might be achievable from companion cropping under an agroforestry system with teak. Individual tree diameter was maximised at the lowest initial stocking, but tree height showed optimum development between 637 and 1020 trees ha−1. While standing volume (m3 ha−1) was maximised at the highest initial stocking (2424 trees ha−1), merchantable volume maximised at initial stocking rates between 423 and 637 trees ha−1. Companion cropping demonstrated that modest yields of maize, cassava and pigeon pea are possible under established teak, where the spacing between trees exceeds 8 m. Both maize and cassava achieved yields of over 2 t ha−1 with a spacing of 8 m between trees, while pigeon pea achieved 3 t ha−1 at 10 m spacing between trees. These results demonstrate that the adoption of reduced initial stocking rates for teak (i.e. below 1000 trees ha−1) can significantly increase the growth rates of teak, improving individual tree volumes, and potentially reducing time to commercial harvest. Further, where row spacing is at least 8–10 m, these results suggest that extended periods of companion cropping (2–6 years after planting) may be possible. Finally, given that Lao farmers are reluctant to adopt pre-commercial thinning, serious consideration should be given to the promotion of simple, regimes for teak woodlots using an initial stocking rate of around 600 trees ha−1. Alleys widths of 10 m are recommended for farmers wishing to establish grow teak in an agroforestry system and extend the period for companion cropping. Nevertheless, revision of Government of Lao policy frameworks are required to support the adoption of more appropriate initial spacing in teak woodlots and agroforestry systems by smallholders