Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.     

Extraction and characterization of hydroxyapatite-based materials from grey triggerfish skin and black scabbardfish bones

The conversion of food industry by-products to compounds with high added value is nowadays a significant topic, for social, environmental, and economic reasons. In this paper, calcium phosphate-based materials were obtained from black scabbardfish (Aphanopus carbo) bones and grey triggerfish (Balistes capriscus) skin, which are two of the most abundant fish by-products of Madeira Island. Different calcination temperatures between 400 and 1000°C were employed. Materials obtained from calcination of bones of black scabbard fish were composed by homogeneous mixtures of hydroxyapatite (Ca₁₀(PO4)₆(OH)₂, HAp) and β-tricalcium phosphate (β-Ca₃(PO₄)₂, β-TCP). Because of the high biocompatibility of HAp and the good resorbability of β-TCP, these natural biphasic materials could be very relevant in the field of biomaterials, as bone grafts. The ratio between HAp and β-TCP in the biphasic compound was dependent on the calcination temperature. Differently, the material obtained from skin of grey triggerfish contained HAp as the main phase, together with small amounts of other mineral phases, such as halite and rhenanite, which are known to enhance osteogenesis when used as bone substitutes. In both cases, the increase of calcination temperature led to an increase in the particles size with a consequent decrease in their specific surface area. These results demonstrate that from the fish by-products of the most consumed fishes in Madeira Island it is possible to obtain bioceramic materials with tunable composition and particle morphology, which could be promising materials for the biomedical field.     

Synthesis,Structural and Biomedical Characterization of Hydroxyapatite/Borosilicate Bioactive Glass Nanocomposites

Journal of Inorganic and Organometallic Polymers and Materials - In this work, a borosilicate glass sample (5SiO2–45B2O3–20Na2O–25CaO–5Ag2O) was added to nano-sized...     

Multicriteria Minimax Problems: Localization of the Pareto Set and Suboptimal Control Design

Automation and Remote Control - We consider multicriteria minimax optimization problems with criteria in the form of the maxima of functionals given by the induced norms of linear operators taking...     

Reusable Polyacrylonitrile-Sulfur Extractor of Heavy Metal Ions from Wastewater

Mercury, lead, and cadmium are among the most toxic and carcinogenic heavy metal ions (HMIs), posing serious threats to the sustainability of aquatic ecosystems and public health. There is an urgent need to remove these ions from water by a cheap but green process. Traditional methods have insufficient removal efficiency and reusability. Structurally robust, large surface-area adsorbents functionalized with high-selectivity affinity to HMIs are attractive filter materials. Here, an adsorbent prepared by vulcanization of polyacrylonitrile (PAN), a nitrogen-rich polymer, is reported, giving rise to PAN-S nanoparticles with cyclic π-conjugated backbone and electronic conductivity. PAN-S can be coated on ultra-robust melamine (ML) foam by simple dipping and drying. In agreement with hard/soft acid/base theory, N- and S-containing soft Lewis bases have strong binding to Hg²⁺, Pb²⁺, Cu²⁺, and Cd²⁺, with extraordinary capture efficiency and performance stability. Furthermore, the used filters, when collected and electrochemically biased in a recycling bath, can release the HMIs into the bath and electrodeposit on the counter-electrode as metallic Hg⁰, Pb⁰, Cu⁰, and Cd⁰, and the PAN-S@ML filter can then be reused at least 6 times as new. The electronically conductive PAN-S@ML filter can be fabricated cheaply and holds promise for scale-up applications.     

Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Evaluation of direct light processing for the fabrication of bioactive ceramic scaffolds: Effect of pore/strut size on manufacturability and mechanical performance

Bioactive ceramic scaffolds for bone regeneration consisting of a three-dimensional mesh of interpenetrating struts with square section were fabricated via Digital Light Processing (DLP). The ability of the technique to manufacture 3D porous structures from β-tricalcium phosphate (β-TCP) powders with different dimensions of struts and pores was evaluated, identifying the possibilities and limitations of the manufacturing process. Small pore sizes were found to seriously complicate the elimination of excess slurry from the scaffold’s innermost pores. The effect of the strut/pore size on the mechanical performance of the scaffolds under compressive stresses was also evaluated, but no significant influence was found. Under compressive stresses, the structures resulted weaker when tested perpendicularly to the printing plane due to interlayer shear failure. Interlayer superficial grooves are proposed as potential failure-controlling defects, which could also explain the lack of a Weibull size effect on the mechanical strength of the fabricated DLP scaffolds.     

Facile synthesis of MgO–Mg2SiO4 composite ceramics with high strength and low thermal conductivity

The recycling of solid waste is a win-win solution for humans and nature. For this purpose, magnesite tailings and silicon kerf waste were employed to prepare MgO–Mg₂SiO₄ composite ceramics by solid-state reaction synthesis in the present work. Then, effects of sintering temperature and raw material ratio on as-prepared ceramics were systematically studied. As-prepared ceramics showed improvement in their relative density (from 47.55%–68.12% to 90.96%–95.25%) and cold compressive strength (from 7.34–118.66 MPa to 303.39–546.65 MPa) with the increase in sintering temperature from 1300 to 1600 °C. In addition, it was found that Si promoted synthesis process of Mg₂SiO₄ phase through transient liquid phase sintering and Fe₂O₃ accelerated sintering process through activation sintering. Consequently, the presence of Mg₂SiO₄ phase effectively improved the density and strength of MgO–Mg₂SiO₄ composite ceramic, while reducing its thermal conductivity. This work provides a potential reutilization strategy for magnesite tailings, and as-prepared products are expected to be applied in fields of construction, metallurgy, and chemical industry.     

Ratiometric Detection of Glutathione Based on Disulfide Linkage Rupture between a FRET Coumarin Donor and a Rhodamine Acceptor

Abnormal levels of glutathione, a cellular antioxidant, can lead to a variety of diseases. We have constructed a near-infrared ratiometric fluorescent probe to detect glutathione concentrations in biological samples. The probe consists of a coumarin donor, which is connected through a disulfide-tethered linker to a rhodamine acceptor. Under the excitation of the coumarin donor at 405 nm, the probe shows weak visible fluorescence of the coumarin donor at 470 nm and strong near-infrared fluorescence of the rhodamine acceptor at 652 nm due to efficient Forster resonance energy transfer (FRET) from the donor to the acceptor. Glutathione breaks the disulfide bond through reduction, which results in a dramatic increase in coumarin fluorescence and a corresponding decrease in rhodamine fluorescence. The probe possesses excellent cell permeability, biocompatibility, and good ratiometric fluorescence responses to glutathione and cysteine with a self-calibration capability. The probe was utilized to ratiometrically visualize glutathione concentration alterations in HeLa cells and Drosophila melanogaster larvae.