Synthesis and structure of a dimeric scandium bis(μ-methoxy) complex

Reaction of hydrated scandium nitrate with 1,10-phenanthroline (phen) in methanol leads to formation of the unusual dimeric complex [(phen)(NO₃)₂Sc(μ-OMe)₂Sc(NO₃)₂(phen)], in which the scandium centres are eight co-ordinate. The complex features two bridging methoxy ligands, as well as bidentate nitrates and chelating 1,10-phenanthroline ligands.     

Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy

Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B₆-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.     

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.     

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI leads to a continuous cycle of altered muscle–bone crosstalk with weak muscles further compromising bone and vice versa. Currently, there is no cure for OI and understanding the pathogenesis of the skeletal muscle weakness in relation to the bone pathogenesis of OI in light of the critical role of muscle–bone crosstalk is essential to developing and identifying novel therapeutic targets and strategies for OI. This review will highlight how impaired skeletal muscle function contributes to the pathophysiology of OI and how this phenomenon further perpetuates bone fragility.     

Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.     

Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models

Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.     

Bioinformatic Tools for the Analysis and Prediction of ncRNA Interactions

Noncoding RNAs (ncRNAs) play prominent roles in the regulation of gene expression via their interactions with other biological molecules such as proteins and nucleic acids. Although much of our knowledge about how these ncRNAs operate in different biological processes has been obtained from experimental findings, computational biology can also clearly substantially boost this knowledge by suggesting possible novel interactions of these ncRNAs with other molecules. Computational predictions are thus used as an alternative source of new insights through a process of mutual enrichment because the information obtained through experiments continuously feeds through into computational methods. The results of these predictions in turn shed light on possible interactions that are subsequently validated experimentally. This review describes the latest advances in databases, bioinformatic tools, and new in silico strategies that allow the establishment or prediction of biological interactions of ncRNAs, particularly miRNAs and lncRNAs. The ncRNA species described in this work have a special emphasis on those found in humans, but information on ncRNA of other species is also included.     

Corrosion behavior of austenitic 304L and 316LN stainless steel clad reinforcing bars in cracked concrete

A study has been conducted on the chloride-induced corrosion behavior of 304L and 316LN stainless steel clad reinforcing bars (rebar) in concrete and in synthetic concrete pore solution. Metallographic examination of the as-received clad bars confirmed a strong metallurgical bond at the core/clad interface and some grain growth interdiffusion of species at the interface. Both bars showed a wide variation in coating thickness around the rebar circumference, from a minimum of 0.32 and 0.60 mm to a maximum of 1.4 and 2.8 mm in the 304L clad and 316LN clad, respectively. The electrochemical results and visual examination after autopsy showed that active corrosion was yet initiated on either the solid and clad stainless steel or carbon steel rebar in the sound noncracked concrete specimens. In contrast, corrosion had initiated in the bars embedded in cracked concrete at the base of the crack and extended along or around the bars. In the concrete and synthetic pore solution tests, the current densities of both solid and clad stainless steel rebar exposed to ∼21% chloride brine solution for days between 400 and 1,500 were similar. This was also the case for current densities of the straight and bent stainless steel bars tested in the synthetic pore solution test.     

Investigation of novel mixed metal ferrites for pure H2 and CO2 production using chemical looping

The mixed metal oxides NiFe₂O₄ and CoFe₂O₄ are candidate materials for the Chemical Looping Hydrogen (CLH) process, which produces pure and separate streams of H₂ and CO₂ without the use of complicated and expensive separations equipment. In the CLH process, syngas reduces a metal oxide, oxidizing the H₂ and CO in the syngas to H₂O and CO₂, and “stores” the chemical energy of the syngas in the reduced metal oxide. The reduced metal oxide is then oxidized in steam to regenerate the original metal oxide and produce H₂. In this study, we report thermodynamic modeling and experimental results regarding the syngas reduction and H₂O oxidation of NiFe₂O₄ and CoFe₂O₄ to determine the feasibility of their use in the CLH process. Modeling predicts the oxidation of nearly all the CO and H₂ in syngas to H₂O and CO₂ during the reduction step for both materials, and regeneration of the mixed metal spinel phase during oxidation with excess H₂O. Laboratory tests in a packed bed reactor confirmed over 99% conversion of H₂ and CO to H₂O and CO₂ during reduction of NiFe₂O₄ and CoFe₂O₄. Powder XRD analysis of the reduced materials showed, in accordance with thermodynamic predictions, the presence of a spinel phase and a metallic phase. High reactivity of the reduced NiFe₂O₄ and CoFe₂O₄ with H₂O was observed, and XRD analysis confirmed re-oxidation to NiFe₂O₄ and CoFe₂O₄ under the conditions tested. When compared with a conventional Fe-based CLH material, the mixed metal spinels showed a higher extent of reduction under the same conditions, and produced four times the H₂ per mass of active material than the Fe-based material. Analysis of the H₂ and CO consumed in the reduction and the H₂ produced during the oxidation showed over 90% conversion of the H₂ and CO in syngas back to H₂ during oxidation.