A feasible approach to measure metal concentrations in drill hole waters on site for mineral exploration.

The new technologies used in the green transition towards carbon-free societies typically demand extensive use of metals. This leads to a heavily growing need for exploration and extraction of ore deposits. Exploration can be facilitated by measuring metal concentrations in ground and surface waters carrying trace concentrations of metals leached from nearby deposits. Currently, measuring metal concentrations in water is slow and expensive and it cannot be done on-site, which hinders the discovery of new ore deposits. To address this challenge, we have developed a method to collect and concentrate the dissolved metals in a solid filter and measure the metal concentrations directly from the filter with a portable X-ray fluorescence spectrometer. The permeable filter is made of mesoporous silicon modified with bisphosphonates. Two types of adsorbing materials for the filters were prepared based on scalable production methods: i) regenerative etching of metallurgical grade silicon powder, and ii) magnesiothermic reduction of silica from barley husks. Empirical calibrations were prepared in a concentration range of 10-200 µg/L for Mn, Co, Ni, Cu, Zn, and Pb using water samples prepared by spiking well water with standard metal solutions. Both filter types were tested for their ability to adsorb metals from the real water samples taken from drill holes. The developed system was able to detect metal concentrations down to 12 µg/L (ppb) showing its potential for on-site measurements of dissolved metals in water samples, which could be feasible in the discovery of new mineral deposits. This innovation enables smart sampling during exploration and provides real-time information on metal concentrations in water.

Approaches to improve the biocompatibility and systemic circulation of inorganic porous nanoparticles.

The exploitation of various inorganic nanoparticles as drug carriers and therapeutics is becoming increasingly common. The first issue to be considered with regard to the nanomaterials being utilized in medicine centers on their safety. The functionality of nanocarriers in real-life environments explains the enthusiasm for their use. Several functionalities are typically added onto nanocarriers but the most crucial feature of those carriers intended to be administered intravenously is that they should possess a long residence time in blood circulation. The present review focusses on the mesoporous nanoparticles due to their great promise in nanomedicine and concentrates on their coatings because it is the outmost layer which dictates their first interactions with the surroundings and often determines their biofate.

Biodegradation of inorganic drug delivery systems in subcutaneous conditions.

Despite extensive efforts to develop delivery systems for oral administration, subcutaneous (s.c.) injection remains the most common way to administer peptide drugs. To limit the number of frequent injections, sustained release systems that are easy to produce, suitable for various drugs, safe and biodegradable are urgently needed. Porous silicon (PSi) has been recognized to be one of the most promising materials for s.c. peptide delivery, but its biodegradation in s.c. tissue has not been studied in vivo, despite extensive in vitro research. In the present study, differently modified PSi microparticles were injected s.c. in mice, after which the morphology of the particles was thoroughly studied with transmission electron microscopy, micro-computed tomography and X-ray diffraction. Furthermore, histopathology of the s.c. tissue was analyzed to evaluate biocompatibility. To the best of our knowledge, this is the first systematic study which reveals the degradation behavior of various PSi materials in vivo. The PSi surface chemistry significantly affected the biodegradation rate of the s.c. injected microparticles. The most hydrophobic PSi microparticles with hydrocarbonized surface showed the lowest biodegradation rate while the hydrophilic microparticles, with oxide surface, degraded the fastest. The results from different empirical methods complemented each other to deduce the biodegradation mechanism of the inorganic delivery system, providing useful information for future development of s.c. carriers.

Electrochemically anodized porous silicon: Towards simple and affordable anode material for Li-ion batteries.

Silicon is being increasingly studied as the next-generation anode material for Li-ion batteries because of its ten times higher gravimetric capacity compared with the widely-used graphite. While nanoparticles and other nanostructured silicon materials often exhibit good cyclability, their volumetric capacity tends to be worse or similar than that of graphite. Furthermore, these materials are commonly complicated and expensive to produce. An effortless way to produce nanostructured silicon is electrochemical anodization. However, there is no systematic study how various material properties affect its performance in LIBs. In the present study, the effects of particle size, surface passivation and boron doping degree were evaluated for the mesoporous silicon with relatively low porosity of 50%. This porosity value was estimated to be the lowest value for the silicon material that still can accommodate the substantial volume change during the charge/discharge cycling. The optimal particle size was between 10-20 µm, the carbide layer enhanced the rate capability by improving the lithiation kinetics, and higher levels of boron doping were beneficial for obtaining higher specific capacity at lower rates. Comparison of pristine and cycled electrodes revealed the loss of electrical contact and electrolyte decay to be the major contributors to the capacity decay.

Development of a highly controlled gas-phase nanoparticle generator for inhalation exposure studies.

We have developed a gas-phase nanoparticle generator that produces stable and well-defined size distributions for TiO(2). The online analyses of the gas-phase compounds and total number concentration of the generated particles as well as the off-line analysis of the filter samples confirmed the stability of the production. The major advantage of this reactor is that the test substance is directly in the aerosol phase, and thus no preprocessing is needed. This eliminates the physicochemical changes between bulk and administrated material during storing or processing. This system is easy to adjust to different experimental setups and precursors. As a result, well-characterized nanomaterials for inhalation exposure studies can be produced. At mass concentration of 30 mg/Nm(3), the count mean diameter was 126 nm (geometric SD 1.6), mass mean diameter was 161 nm (2.0), mass median aerodynamic diameter was 125 nm, and the concentrations of harmful gas-phase by-products remained low. The produced powder consisted of crystals of anatase (77 vol%) and brookite (23 vol%), and its specific surface area was 69 m(2)/g.

In vivo delivery of a peptide, ghrelin antagonist, with mesoporous silicon microparticles.

Peptides may represent potential treatment options for many severe illnesses. However, they need an effective delivery system to overcome rapid degradation after their administration. One possible way to prolong peptide action is to use particulate drug delivery systems. In the present study, thermally hydrocarbonized mesoporous silicon (THCPSi) microparticles (38-53 microm) were studied as a peptide delivery system in vivo. D-lys-GHRP6 (ghrelin antagonist, GhA) was used as a model peptide. The effects of GhA-loaded THCPSi microparticles on food intake (s.c., GhA dose 14 mg/kg) and on blood pressure (s.c., GhA dose 4 mg/kg) were examined in mice and rats, respectively. In addition, the effects of THCPSi microparticles (2 mg) on cytokine secretion in mice after single s.c. administration were examined by determining several cytokine plasma concentrations. The present results demonstrate that GhA can be loaded into THCPSi microparticles with a high loading degree (20% w/w). GhA loaded THCPSi microparticles inhibited food intake for a prolonged time, and increased blood pressure more slowly than encountered with a GhA solution. Furthermore, THCPSi microparticles did not increase cytokine activity. The present results suggest that THCPSi might be used as a drug delivery system for peptides.

Evaluation of mesoporous TCPSi, MCM-41, SBA-15, and TUD-1 materials as API carriers for oral drug delivery.

The feasibility of four mesoporous materials composed of biocompatible Si (TCPSi) or SiO(2) (MCM-41, SBA-15, and TUD-1) were evaluated for oral drug delivery applications. The main focus was to study the effect of the materials different pore systems (unidirectional/2D/3D) and their pore diameters, pore size distributions, pore volumes on the maximal drug load capacity, and release profiles of a loaded active pharmaceutical ingredient. Ibuprofen was used as the model drug. The total pore volume of the mesoporous solid was the main factor limiting the maximum drug load capacity, with SBA-15 reaching a very high drug load of 1:1 in weight due to its high pore volume. Dissolution experiments were performed in HBSS buffers of pH 5.5, 6.8, and 7.4 to mimic the conditions in the small intestine. At pH 5.5 the dissolution rate of ibuprofen released from the mesoporous carriers was significantly faster compared with the standard bulk ibuprofen (86-63% versus 25% released at 45 min), with the fastest release observed from the 3D pore network of TUD-1 carrier. The utilization of mesoporous carriers diminished the pH dependency of ibuprofen dissolution (pK(a) = 4.42), providing an interesting prospect for the formulation of poorly soluble drug compounds.

Surface chemistry and pore size affect carrier properties of mesoporous silicon microparticles.

Six different types of mesoporous silicon microparticles were prepared to evaluate the effect of surface treatment and pore sizes on their properties as drug carriers. The studied porous silicon particles were as-anodized, thermally carbonized (TCPSi) and thermally oxidized (TOPSi) in addition to three novel ones: annealed TCPSi, annealed TOPSi and thermally hydrocarbonized porous silicon (THCPSi). Drug dissolution at pH 5.5 and physical and chemical stabilities after 3 months of storage were used as experimental models to investigate the loaded particles. Loading degrees of ibuprofen in the particles were determined by several methods before and after storage, and the results were in good agreement with each other. Loading improved the dissolution rate of ibuprofen in all the studied cases, while the hydrophilic TCPSi material resulted in the fastest dissolution and the most stable mesoporous microparticles. The release profiles of ibuprofen did not change markedly during storage. The effect of storage on the loading degrees of the other PSi microparticles than the unstable (easily oxidized) as-anodized porous silicon was not notable.

Mesoporous silica material TUD-1 as a drug delivery system.

For the first time the feasibility of siliceous mesoporous material TUD-1 (Technische Universiteit Delft) for drug delivery was studied. Model drug, ibuprofen, was adsorbed into TUD-1 mesopores via a soaking procedure. Characterizations with nitrogen adsorption, XRD, TG, HPLC and DSC demonstrated the successful inclusion of ibuprofen into TUD-1 host. The amount of ibuprofen adsorbed into the nanoreservoir of TUD-1 material was higher than reported for other mesoporous silica drug carriers (drug/carrier 49.5 wt.%). Drug release studies in vitro (HBSS buffer pH 5.5) demonstrated a fast and unrestricted liberation of ibuprofen, with 96% released at 210 min of the dissolution assay. The drug dissolution profile of TUD-1 material with the random, foam-like three-dimensional mesopore network and high accessibility to the dissolution medium was found to be much faster (kinetic constant k = 10.7) and more diffusion based (release constant n = 0.64) compared to a mesoporous MCM-41 material with smaller, unidirectional mesopore channels (k = 4.7, n = 0.71). Also, the mesoporous carriers were found to significantly increase the dissolution rate of ibuprofen, when compared to the pure crystalline form of the drug (k = 0.6, n = 0.96). TUD-1 was constituted as a potential drug delivery device with fast release property, with prospective applications in the formulation of poorly soluble drug compounds.

Mesoporous silicon microparticles for oral drug delivery: loading and release of five model drugs.

Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

Progression of malignancy in clear cell renal cell carcinomas.

Much progress has recently been obtained in the classification and characterization of RCC by using cytogenetic, gene microarray and proteomic techniques. Pivotal for the understanding of the progression of malignancy of clear cell renal cell carcinomas are findings connecting its biology to inactivation of the von Hippel-Lindau tumour suppressor gene product (VHLp), found in most CC-RCCs. Disruption of VHLp function appears to be involved in altered cell cycle control, resistance to hypoxia, hyperangiogenesis and changes in the organization of cytoskeletal and extracellular matrix proteins in RCC. These changes are reflected in the overexpression of the vascular endothelial growth factor (VEGF) and the subunits of hypoxia-inducible factor (HIF), and other angiogenetic and metastasis-promoting factors. Other changes related to progression of malignancy in RCC are the upregulation of proinflammatory cytokines and changes in cell adhesion proteins.

Involvement of the subacromial bursa in impingement syndrome of the shoulder as judged by expression of tenascin-C and histopathology.

Our aim was to evaluate bursal involvement at different stages of the impingement syndrome as judged by conventional histopathological examination and expression of tenascin-C, which is known to reflect active reparative processes in different tissues and disorders. Samples of subacromial bursa were taken from 33 patients with tendinitis, 11 with a partial tear and 18 with a complete tear of the rotator cuff, and from 24 control shoulders. We assessed the expression of tenascin-C, the thickness of the bursa, and the occurrence and degree of fibrosis, vascularity, haemorrhage and inflammatory cells. The expression of tenascin-C was significantly more pronounced in the complete tear group (p < 0.001) than in the partial tear, tendinitis or control groups. It was more pronounced in the tendinitis group than in the control group (p = 0.06), and there was more fibrosis in all the study groups than in the control group. The changes in the other parameters were not equally distinctive. Expression of tenascin-C did not correlate with the conventional histopathological parameters, suggesting that these markers reflect different phases of the bursal reaction. Tenascin-C seems to be a general indicator of bursal reaction, being especially pronounced at the more advanced stages of impingement and this reaction seems to be an essential part of the pathology of impingement at all its stages.

STAM/EAST/Hbp adapter proteins--integrators of signalling pathways.

STAM/EAST/Hbp family of proteins consists of eight members well conserved from yeast to mammals. The basic domain architecture is comprised of an N-terminal Vps27, Hrs and STAM homology domain, a ubiquitin-interacting motif and a central Src homology-3 domain. Vertebrate members also carry an immunoreceptor tyrosine-based activation motif. STAM/EAST/Hbp proteins become tyrosine-phosphorylated by a variety of cytokines and growth factors. STAM 1 and STAM 2A are involved in cytokine-mediated signalling for DNA synthesis and c-myc induction. EAST and STAM 2A/Hbp play a role in receptor-mediated endo- and exocytosis and probably also in the regulation of actin cytoskeleton. Knockout experiments implicate a role for STAM 1 in neural cell survival. A picture is emerging of STAM/EAST/Hbp proteins acting as integrators of thus far mechanistically disparate cellular signalling events.

Podocyte-specific expression of a novel trans-Golgi protein Vear in human kidney.

BACKGROUND: Vear is a recently identified Golgi apparatus-associated protein. It has been suggested to be involved in vesicular trafficking between the Golgi and the vacuolar/lysosomal system. Proteins similar to Vear have also been shown to interact with activated ARF proteins (ADP ribosylation factor), and they are probably involved in membrane trafficking from the trans-Golgi network (TGN). We have previously shown that Vear is widely distributed in human tissues, with an especially high level of mRNA in the kidney. This study further characterizes the distribution and subcellular localization of Vear in normal adult kidney and shows its association with glomerulogenesis in fetal kidney. METHODS: Immunofluorescence and immunoelectron microscopy were used to study the expression of Vear in fetal and adult kidney. The expression of Vear in isolated glomeruli was shown by immunoblotting. The distribution of its mRNA was analyzed by using in situ and Northern hybridization. RESULTS: In situ hybridization and immunofluorescence microscopy showed that in the kidney, Vear is present in glomerular structures. By fluorescence microscopy, the immunoreactivity for Vear was found only in podocytes, as judged by its distinct colocalization with podocalyxin and vimentin, well-established marker proteins of podocytes. Its specific expression in the glomeruli versus other compartments of the kidney was also verified by Western blotting. By using immunogold electron microscopy, Vear was seen in the Golgi apparatus, tubulovesicular structures, and membranes adjacent to the Golgi complex. In fetal kidney, expression of Vear coincided with the formation of segmental structures of the glomeruli. It was first seen close to the undifferentiated luminal cells at the vesicular stage and increasingly in the differentiating podocytes at the more advanced stages of glomerulogenesis. CONCLUSIONS: In the kidney, Vear shows a distinct, specific, and developmentally regulated expression in glomerular podocytes. This suggests that Vear has a specific function in podocytes. It could be associated with the known high secretory and synthetic activity of the podocytes, especially the production of the basement membrane components, which are critically involved in the glomerulogenesis and the maintenance of the glomerular function.

Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor.

The GGAs are a multidomain protein family implicated in protein trafficking between the Golgi and endosomes. Here, the VHS domain of GGA2 was shown to bind to the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR). Receptors with mutations in this motif were defective in lysosomal enzyme sorting. The hinge domain of GGA2 bound clathrin, suggesting that GGA2 could be a link between cargo molecules and clathrin-coated vesicle assembly. Thus, GGA2 binding to the CI-MPR is important for lysosomal enzyme targeting.

Dynamic solid-state and tableting properties of four theophylline forms.

Relationships between solid-state, densification and compact properties of theophylline monohydrate (TMO), a mixture of forms (TMIX), and anhydrous polymorphs I (TA-I) and II (TA-II) were evaluated. Solid-state identification of powders and compacts was accomplished by powder X-ray diffraction. A compaction simulator was used to assess deformation behaviour of the powders and to prepare compacts. Porosity and tensile strength of the compacts were determined after 1,24, and 168 h of storage at 22% relative humidity. TA-II was stable, whereas TA-I, TMIX and TMO partially transformed to the TA-II form during storage. All theophylline modifications primarily deformed by plastic flow. Increased water content decreased resistance towards densification and deformation of TMIX and TMO when compared to TA-II or TA-I, demonstrating viscoelasticity. Permanent densification behaviours of TMIX and TMO approached to that of TA-II during storage. Tensile strength of the different theophylline forms were practically equal after 1 h of storage. Tensile strength and porosity of TMIX and TMO compacts increased during the storage. Dynamic solid-state transformations from TMO, TMIX and TA-I to TA-II were associated with parallel changes in their densification and compact properties. The extent of these changes was also dependent on the materials' water content.

The small myelin-associated glycoprotein binds to tubulin and microtubules.

The myelin-associated glycoprotein (MAG) exists as two isoforms, differing only by their respective cytoplasmic domains, that have been suggested to function in the formation and maintenance of myelin. In the present study, a 50 kDa protein binding directly to the small MAG (S-MAG) cytoplasmic domain was detected and identified as tubulin, the core component of the microtubular cytoskeleton. In vitro, the S-MAG cytoplasmic domain slowed the polymerization rate of tubulin and co-purified with assembled microtubules. A significant sequence homology was found between the tau family tubulin-binding repeats and the carboxy-terminus of S-MAG. Our results indicate that S-MAG is the first member of the Ig superfamily that can be classified as a microtubule-associated protein, and place S-MAG in a dynamic structural complex that could participate in linking the axonal surface and the myelinating Schwann cell cytoskeleton.

Vear, a novel Golgi-associated protein, is preferentially expressed in type I cells in skeletal muscle.

Vear is a novel Golgi-associated protein with a domain structure characteristic of many vesicular transport-associated proteins. It has been suggested that Vear is involved in vesicle transport through trans-Golgi. In this study, we have determined the localization of Vear in skeletal muscle. The staining for Vear in normal human muscle revealed a distribution pattern similar to that of type I fibers. We conclude that Vear is preferentially expressed in type I fibers in human muscle, presumably indicative of a specific function that remains to be identified.