Bending creep performance of modified timber

The present study is a supplement to Epmeier and Kliger (2005), which investigated the effect of three different modification methods (acetylation, modification with methylated melamine resin and heat treatment in vegetable oil) on four material properties (density, modulus of elasticity (MOE), creep deflection and relative creep) and their inter-relations. In this study, another modification method (furfurylation) and four additional material parameters (“relative stiffness”, i.e. MOE/density, moisture content, change in moisture content and anti-creep efficiency) and their correlations are included. In addition, the creep curves were analysed to assess the development of bending creep performance. The properties were assessed by experimental work on 132 specimens of Scots pine sapwood with dimensions of 45×70×1100 mm³. It was found that modification leads to significant changes in material properties. Furfurylation increases density and reduces creep deflection, relative creep and moisture content. Modified timber tends to deflect and creep significantly less than untreated timber. However, the extent of reduction in relative creep appears not to be related to the extent of reduction in creep deflection. Initial deflection and/or modulus of elasticity are suitable for predicting the creep deflection of untreated and modified timber.     

Getting Drugs Across Biological Barriers

The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.     

Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study

Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.     

Tissue Sampling and Homogenization with NIRL Enables Spatially Resolved Cell Layer Specific Proteomic Analysis of the Murine Intestine

For investigating the molecular physiology and pathophysiology in organs, the most exact data should be obtained; if not, organ-specific cell lines are analyzed, or the whole organ is homogenized, followed by the analysis of its biomolecules. However, if the morphological organization of the organ can be addressed, then, in the best case, the composition of molecules in single cells of the target organ can be analyzed. Laser capture microdissection (LCM) is a technique which enables the selection of specific cells of a tissue for further analysis of their molecules. However, LCM is a time-consuming two-dimensional technique, and optimal results are only obtained if the tissue is fixed, e.g., by formalin. Especially for proteome analysis, formalin fixation reduced the number of identifiable proteins, and this is an additional drawback. Recently, it was demonstrated that sampling of fresh-frozen (non-fixed) tissue with an infrared-laser is giving higher yields with respect to the absolute protein amount and number of identifiable proteins than conventional mechanical homogenization of tissues. In this study, the applicability of the infrared laser tissue sampling for the proteome analysis of different cell layers of murine intestine was investigated, using LC–MS/MS-based differential quantitative bottom-up proteomics. By laser ablation, eight consecutive layers of colon tissue were obtained and analyzed. However, a clear distinguishability of protein profiles between ascending, descending, and transversal colon was made, and we identified the different intestinal-cell-layer proteins, which are cell-specific, as confirmed by data from the Human Protein Atlas. Thus, for the first time, sampling directly from intact fresh-frozen tissue with three-dimensional resolution is giving access to the different proteomes of different cell layers of colon tissue.     

18F Site-Specific Labelling of a Single-Chain Antibody against Activated Platelets for the Detection of Acute Thrombosis in Positron Emission Tomography

Positron emission tomography is the imaging modality of choice when it comes to the high sensitivity detection of key markers of thrombosis and inflammation, such as activated platelets. We, previously, generated a fluorine-18 labelled single-chain antibody (scFv) against ligand-induced binding sites (LIBS) on activated platelets, binding it to the highly abundant platelet glycoprotein integrin receptor IIb/IIIa. We used a non-site-specific bio conjugation approach with N-succinimidyl-4-[¹⁸F]fluorobenzoate (S[¹⁸F]FB), leading to a mixture of products with reduced antigen binding. In the present study, we have developed and characterised a novel fluorine-18 PET radiotracer, based on this antibody, using site-specific bio conjugation to engineer cysteine residues with N-[2-(4-[¹⁸F]fluorobenzamido)ethyl]maleimide ([¹⁸F]FBEM). ScFv_anti-LIBS and control antibody mut-scFv, with engineered C-terminal cysteine, were reduced, and then, they reacted with N-[2-(4-[¹⁸F]fluorobenzamido)ethyl]maleimide ([¹⁸F]FBEM). Radiolabelled scFv was injected into mice with FeCl₃-induced thrombus in the left carotid artery. Clots were imaged in a PET MR imaging system, and the amount of radioactivity in major organs was measured using an ionisation chamber and image analysis. Assessment of vessel injury, as well as the biodistribution of the radiolabelled scFv, was studied. In the in vivo experiments, we found uptake of the targeted tracer in the injured vessel, compared with the non-injured vessel, as well as a high uptake of both tracers in the kidney, lung, and muscle. As expected, both tracers cleared rapidly via the kidney. Surprisingly, a large quantity of both tracers was taken up by organs with a high glutathione content, such as the muscle and lung, due to the instability of the maleimide cysteine bond in vivo, which warrants further investigations. This limits the ability of the novel antibody radiotracer ¹⁸F-scFv_anti-LIBS to bind to the target in vivo and, therefore, as a useful agent for the sensitive detection of activated platelets. We describe the first fluorine-18 variant of the scFv_anti-LIBS against activated platelets using site-specific bio conjugation.     

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.     

Retraction Note: Tolerance rough set firefly-based quick reduct

Neural Computing and Applications -     

Examination of Secondary Metabolite Biosynthesis in Apicomplexa

Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists represent an underexplored kingdom for specialized metabolite searches despite bioinformatic analysis that suggests they harbor distinct biologically active small molecules. Specifically, pathogenic apicomplexan parasites, responsible for billions of global infections, have been found to possess multiple biosynthetic gene clusters, which hints at their capacity to produce polyketide metabolites. Biochemical studies have revealed unique features of apicomplexan polyketide synthases, but to date, the identity and function of the polyketides synthesized by these megaenzymes remains unknown. Herein, we discuss the potential for specialized metabolite production in protists and the possible evolution of polyketide biosynthetic gene clusters in apicomplexan parasites. We then focus on a polyketide synthase from the apicomplexan Toxoplasma gondii to discuss the unique domain architecture and properties of these proteins when compared to previously characterized systems, and further speculate on the possible functions for polyketides in these pathogenic parasites.     

Conductive Polymer-Coated 3D Printed Microneedles: Biocompatible Platforms for Minimally Invasive Biosensing Interfaces

Conductive polymeric microneedle (MN) arrays as biointerface materials show promise for the minimally invasive monitoring of analytes in biodevices and wearables. There is increasing interest in microneedles as electrodes for biosensing, but efforts have been limited to metallic substrates, which lack biological stability and are associated with high manufacturing costs and laborious fabrication methods, which create translational barriers. In this work, additive manufacturing, which provides the user with design flexibility and upscale manufacturing, is employed to fabricate acrylic-based microneedle devices. These microneedle devices are used as platforms to produce intrinsically-conductive, polymer-based surfaces based on polypyrrole (PPy) and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS). These entirely polymer-based solid microneedle arrays act as dry conductive electrodes while omitting the requirement of a metallic seed layer. Two distinct coating methods of 3D-printed solid microneedles, in situ polymerization and drop casting, enable conductive functionality. The microneedle arrays penetrate ex vivo porcine skin grafts without compromising conductivity or microneedle morphology and demonstrate coating durability over multiple penetration cycles. The non-cytotoxic nature of the conductive microneedles is evaluated using human fibroblast cells. The proposed fabrication strategy offers a compelling approach to manufacturing polymer-based conductive microneedle surfaces that can be further exploited as platforms for biosensing.     

6,5-Fused Ring,C2-Salvinorin Ester,Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects**

Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.