Is There a Role for Immunoregulatory and Antiviral Oligonucleotides Acting in the Extracellular Space? A Review and Hypothesis

Here, we link approved and emerging nucleic acid-based therapies with the expanding universe of small non-coding RNAs (sncRNAs) and the innate immune responses that sense oligonucleotides taken up into endosomes. The Toll-like receptors (TLRs) 3, 7, 8, and 9 are located in endosomes and can detect nucleic acids taken up through endocytic routes. These receptors are key triggers in the defense against viruses and/or bacterial infections, yet they also constitute an Achilles heel towards the discrimination between self- and pathogenic nucleic acids. The compartmentalization of nucleic acids and the activity of nucleases are key components in avoiding autoimmune reactions against nucleic acids, but we still lack knowledge on the plethora of nucleic acids that might be released into the extracellular space upon infections, inflammation, and other stress responses involving increased cell death. We review recent findings that a set of single-stranded oligonucleotides (length of 25–40 nucleotides (nt)) can temporarily block ligands destined for endosomes expressing TLRs in human monocyte-derived dendritic cells. We discuss knowledge gaps and highlight the existence of a pool of RNA with an approximate length of 30–40 nt that may still have unappreciated regulatory functions in physiology and in the defense against viruses as gatekeepers of endosomal uptake through certain routes.     

Ionic Transport Properties in Nanocrystalline Ce0.8A0.2O2-δ (with A = Eu,Gd, Dy,and Ho) Materials

The ionic transport properties of nanocrystalline 20 mol% Eu, Gd, Dy, and Ho doped cerias, with average grain size of around 14 nm were studied by correlating electrical, dielectric properties, and various dynamic parameters. Gd-doped nanocrystalline ceria shows higher value of conductivity (i.e., 1.8 × 10⁻⁴ S cm⁻¹ at 550°C) and a lower value of association energy of oxygen vacancies with trivalent dopants Gd³⁺ (i.e., 0.1 eV), compared to others. Mainly the lattice parameters and dielectric constants (ε_∞) are found to control the association energy of oxygen vacancies in these nanomaterials, which in turn resulted in the presence of grain and grain boundary conductivity in Gd- and Eu-doped cerias and only significant grain interior conductivity in Dy- and Ho-doped cerias.     

Investigation of Spectroscopic Properties and Spin-Orbit Splitting in the X(2)Π and A(2)Π Electronic States of the SO(+) Cation

The potential energy curves (PECs) of the X(2)Π and A(2)Π electronic states of the SO(+) ion are calculated using the complete active space self-consistent field method, which is followed by the internally contracted multireference configuration interaction (MRCI) approach for internuclear separations from 0.08 to 1.06 nm. The spin-orbit coupling effect on the spectroscopic parameters is included using the Breit-Pauli operator. To improve the quality of PECs and spin-orbit coupling constant (A(0)), core-valence correlation and scalar relativistic corrections are included. To obtain more reliable results, the PECs obtained by the MRCI calculations are corrected for size-extensivity errors by means of the Davidson modification (MRCI+Q). At the MRCI+Q/aug-cc-pV5Z+CV+DK level, the A(0) values of the SO(+)(X(2)Π(1/2, 3/2)) and SO(+)(A(2)Π(1/2, 3/2)) are 362.13 and 58.16 cm(-1) when the aug-cc-pCVTZ basis set is used to calculate the spin-orbit coupling splitting, and the A(0) of the SO(+)(X(2)Π(1/2, 3/2)) and SO(+)(A(2)Π(1/2, 3/2)) are 344.36 and 52.90 cm(-1) when the aug-cc-pVTZ basis set is used to calculate the spin-orbit coupling splitting. The conclusion is drawn that the core-valence correlations correction makes the A(0) slightly larger. The spectroscopic results are obtained and compared with those reported in the literature. Excellent agreement exists between the present results and the measurements. The vibrational manifolds are calculated, and those of the first 30 vibrational states are reported for the J = 0 case. Comparison with the measurements shows that the present vibrational manifolds are both reliable and accurate.     

Are There Differences in Inflammatory and Fibrotic Pathways between IPAF,CTD-ILDs,and IIPs? A Single-Center Pilot Study

In this pilot study, we aim to determine differences in pathogenetic pathways between interstitial pneumonia with autoimmune features (IPAF), connective-tissue-disease-associated interstitial lung diseases (CTD-ILDs), and idiopathic interstitial pneumonias (IIPs). Forty participants were recruited: 9 with IPAF, 15 with CTD-ILDs, and 16 with IIPs. Concentration of transforming growth factor beta (TGF-β1), surfactant proteins A and D (SP-A, SP-D), interleukin 8 (IL-8), and chemokine 1 (CXCL1) were assessed with ELISA assay in bronchoalveolar lavage (BAL) fluid. We revealed that IL-8 and TGF-β1 concentrations were significantly lower in the IPAF group than in the CTD-ILD group (p = 0.008 and p = 0.019, respectively), but similar to the concentrations in the IIP group. There were significant correlations of IL-8 (rs = 0.46; p = 0.003) and CXCL1 (rs = 0.52; p = 0.001) and BAL total cell count (TCC). A multivariate regression model revealed that IL-8 (β = 0.32; p = 0.037) and CXCL1 (β = 0.45; p = 0.004) are significant predictors of BAL TCC. We revealed that IL-8 and TGF-β1 BAL concentrations vary in patients with different ILDs and found that IL-8 is a predictor of BAL TCC in IPAF. However, this needs to be confirmed in a multicenter cooperative study (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03870828","term_id":"NCT03870828"}}NCT03870828).     

A facile approach to synthesize SiO2?·?Re2O3 (Re?=?Y,Eu, La,Sm, Tb,Pr) hollow sphere and its application in drug release

Multifunctional SiO₂ · Re₂O₃ (Re = Y, Eu, La, Sm, Tb, Pr) hollow spheres (HSs) have been fabricated using an acidic Re³⁺ ion solution. Under ultraviolet radiation, functional HSs emit different colors of light according to the different rare-earth ions embedded into the shell of SiO₂ hollow spheres. The as-prepared hollow capsules were characterized by X-ray diffraction, transmission electron microscopy, high-resolution transmission electron microscopy, Brunauer-Emmett-Teller method, scanning electron microscopy, and energy-dispersive spectrometry. Drug loading and release experiments have been carried out using SiO₂ · Eu₂O₃ HSs that acted as drug carriers. The results demonstrate that the multifunctional HSs exhibit a high storage capacity and the ability of retaining drug stability and activity, which indicates that the as-synthesized fluorescent hollow capsules are a potential candidate as drug delivery materials.     

Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na⁺ voltage-operated channels (Na⁺VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na⁺/Ca²⁺ exchanger 2 (NCX2), resulting in toxic Ca²⁺ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.     

Nucleation and morphology of crystals in simple and complex silicate glasses R′2O-SiO2, R′2O-R″O-SiO2, (R′ = Li,Na, K; R″ = Ca,Mg) synthesized by the sol-gel method

Sol-gel technology is a promising method not only to obtain the batch of the main composition but also to include low additives in glass. In this work, the batches obtained via the sol-gel method have been used to synthesize silicate glass based on the Li₂O-SiO₂ system with the additives of R′₂O and R″O, (R′ = Na, K; R″ = Ca, Mg). The Li₂O-SiO₂ system without the additives R′ and R″ has been studied by us most completely. It has been determined that the main crystal phase in the glass of Li₂O-SiO₂ system with Li₂O content up to 33 mol % is lithium disilicate, Li₂O · 2SiO₂. In the range of compositions from 33.8 to 40.7 mol % Li₂O, solid solutions based on lithium disilicate are formed; and, starting from 40.7 mol % Li₂O, solid solutions based on lithium metasilicate. The kinetic dependences of the number of nucleating lithium disilicate crystals from the time of heat treatment have been obtained at various temperatures of heat treatment. The temperature dependences of the stationary rate of nucleation of crystals have been studied. The results have been compared for the glass prepared with the use of the conventional and sol-gel method. It has been determined that the complication of the composition of glass based on 26Li₂O · 74SiO₂ (mol %) by the addition of R′ = Na, K; R″ = Ca, Mg affects the morphology of lithium disilicate crystals. The use of the sol-gel method of synthesis of glass leads to a more homogeneous spatial arrangement of crystals in bulk glass, the measure of which (distribution) is the dispersion of the number of traces of crystals per unit area of the section.     

Hyperandrogenism? Increased 17, 20-Lyase Activity? A Metanalysis and Systematic Review of Altered Androgens in Boys and Girls with Autism

Introduction: There is increasing evidence that steroid hormone levels and, especially, androgen levels are elevated in autism. An overactivity of 17, 20-lyase with a higher production of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione/androstenediol seems especially present in autism. Methods: An encompassing literature analysis was performed, searching for altered androgens in children with autism and using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Included were all studies published before 31 March 2021 found using the following electronic databases: PubMed, Google Scholar, Cochrane Library, Scopus, and TRIP. Eight studies with boys and three studies with girls where steroid hormone measurements were performed from either plasma, urine, or saliva were found and analyzed. Analyses were performed for DHEA(-S/-C), androstenedione/androstenediol, and testosterone. Effect sizes were calculated for each parameter between mean concentrations for children with autism versus healthy controls. Results: Higher levels of androgens in autism were detected, with the majority of calculated effect sizes being larger than one. Conclusions: We found higher levels of the main testosterone precursors DHEA, androstenedione, and androstenediol, likely causing an additionally higher level of testosterone, and an increased 17, 20-lyase activity is therefore implied. Medications already used in PCOS such as metformin might be considered to treat hyperandrogenism in autism following further research.     

Synthesis and Crystal Structure of Novel Hollandite Compounds AxMgx/2Sn8 − x/2O16 (A = K, Rb, and Cs)

We have prepared novel hollandite compounds AxMgx/2Sn8–x/2O16 (A = K, Rb, and Cs) by solid state reaction, using A2CO3 (A = K, Rb, and Cs), Mg(NO3)2 ·6H2O and SnO2 in the molar ratio 1 : 1 : 3, at 1500°C for 5 hours in air. All compounds crystallize in the monoclinic space group C2/m. Their crystal structures and compositions were determined by the Rietveld analysis using X-ray powder diffraction data. K2MgSn7O16: a = 14.837(3) Å, b = 3.1667(1) Å, c = 10.490(2) Å, = 134.919(8) Å, and Z = 1, RI = 7.32%. Rb2MgSn7O16: a = 14.890(4) Å, b = 3.1706(1) Å, c = 10.514(3) Å, = 134.989(13) Å, and Z = 1, RI = 8.97%. Cs1.26Mg0.63Sn7.37O16: a = 15.015(3) Å, b = 3.1656(1) Å, c = 10.621(3) Å, = 135.061(11) Å, and Z = 1, RI = 9.24%. Sn and Mg octahedra form the hollandite framework, and alkali ions are located in the hollandite tunnels. The Cs ion only partially occupies the tunnel, because the length of b-axis is shorter than Cs ion size. As a result, Cs hollandite only has the non-stoichiometric composition.     

Theoretical exploration of the abnormal trend in lattice thermal conductivity for monosilicates RE2SiO5 (RE = Dy,Ho, Er,Tm, Yb and Lu)

Rare earth monosilicates RE₂SiO₅ have been considered as promising environmental barrier coating materials for silicon-based ceramics due to their low thermal conductivity and good high-temperature stability. We herein performed a systematic study of the lattice dynamics for RE₂SiO₅ (RE?=?Dy, Ho, Er, Tm, Yb and Lu) using first-principles calculations. The loosely bound rare earth atoms provide large Grüneisen parameters and low phonon group velocities, both of which determine the low thermal conductivity. Theoretical exploration predicts an anomalous increase of lattice thermal conductivity with increment of RE atomic number and the mechanism is explained by the stronger atomic bonding and weaker phonon anharmonicity. Although incorporating heavier atoms has long been considered as an effective way to reduce lattice thermal conductivity, this work addresses the importance of bonding heterogeneity and anharmonicity rather than atomic mass variation. This theoretical study suggests an alternative approach towards the design of new thermal insulating materials.     

Palladium Nanoparticles in Glycerol: A Versatile Catalytic System for C?X Bond Formation and Hydrogenation Processes

Palladium nanoparticles stabilised by tris(3‐sulfophenyl)phosphine trisodium salt in neat glycerol have been synthesised and fully characterised, starting from both Pd(II) and Pd(0) species. The versatility of this innovative catalytic colloidal solution has been proved by its efficient application in C X bond formation processes (X=C, N, P, S) and C C multiple bond hydrogenation reactions. The catalytic glycerol phase could be recycled more than ten times, preserving its activity and selectivity. The scope of each of these processes has demonstrated the power of the as‐prepared catalyst, isolating the corresponding expected products in yields higher than 90%. The dual catalytic behaviour of this glycerol phase, associated to the metallic nanocatalysts used in wet medium (molecular‐ and surface‐like behaviour), has allowed attractive applications in one‐pot multi‐step transformations catalysed by palladium, such as C C coupling followed by hydrogenation, without isolation of intermediates using only one catalytic precursor.

     

Transparent Photochromic Glasses in the BaO–R2O3–SiO2 (R = Al, B, and La) System for Applications in Fiber Optics

Photochromic glasses of new compositions in the BaO–R ₂O₃–SiO₂ (R = Al, B, and La) system are synthesized. The glasses prepared are characterized by the additional optical density of saturation D _s (for 5-mm-thick samples, D _s = 0.1–0.9), the relaxation criterion after dark bleaching for 3 min (K _{r, 3} = 35–90%), the optical transmission in the visible range (73–96%), and the softening temperature (650–710°C). These glasses can be used both for preparing an optical fiber core in photochromic glass fiber products of different types with an enhanced resolution and as a recording medium for random-access memory in optoelectronics.     

Parasite Survival and Disease Persistence in Cystic Fibrosis,Schistosomiasis and Pathogenic Bacterial Diseases: A Role for Universal Stress Proteins?

Universal stress proteins (USPs) were originally discovered in Escherichia coli over two decades ago and since then their presence has been detected in various organisms that include plants, archaea, metazoans, and bacteria. As their name suggests, they function in a series of various cellular responses in both abiotic and biotic stressful conditions such as oxidative stress, exposure to DNA damaging agents, nutrient starvation, high temperature and acidic stress, among others. Although a highly conserved group of proteins, the molecular and biochemical aspects of their functions are largely evasive. This is concerning, as it was observed that USPs act as essential contributors to the survival/persistence of various infectious pathogens. Their ubiquitous nature in various organisms, as well as their augmentation during conditions of stress, is a clear indication of their direct or indirect importance in providing resilience against such conditions. This paper seeks to clarify what has already been reported in the literature on the proposed mechanism of action of USPs in pathogenic organisms.     

Copper‐Catalyzed C?NH2 Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

A copper(II)‐catalyzed selective C NH₂ arylation of 2‐aminobenzimidazoles and related C‐amino‐NH‐azoles was achieved in presence of 2,2′‐bipyridine and cesium carbonate at 60 °C under open air conditions and this is first method for the copper‐catalyzed selective C NH₂ arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the C NH₂ position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important C NH(aryl) derivatives of aminoazoles without any protection/deprotection of ring N H bonds. It is first example for the selective C NH₂ arylation of 5‐aminoindazole, 4‐aminopyrazole, 5‐aminopyrazole, 9H‐purine‐6‐amine, and 1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine derivatives.

     

Genistein Induces Increase in Fluid pH,Na+ and HCO3? Concentration,SLC26A6 and SLC4A4 (NBCe1)-B Expression in the Uteri of Ovariectomized Rats

Genistein has been reported to stimulate luminal HCO₃⁻ secretion. We hypothesized that genistein mediates this effect via SLC26A6 and SLC4A4 (NBCe1) transporters. Our study aimed to: investigate changes in uterine fluid pH, Na⁺ and HCO₃⁻ concentration and expression of uterine SLC26A6 and NBCe1 under genistein effect. Ovariectomized adult female rats received 25, 50 and 100 mg/kg/day genistein for a week with and without ICI 182780. A day after the last injection, in vivo uterine perfusion was performed to collect uterine fluid for Na⁺, HCO₃⁻ and pH determination. The animals were then sacrificed and uteri were removed for mRNA and protein expression analyses. SLC26A6 and NBCe1-A and NBCe1-B distribution were visualized by immunohistochemistry (IHC). Genistein at 50 and 100 mg/kg/day stimulates uterine fluid pH, Na⁺ and HCO₃⁻ concentration increase. Genistein at 100 mg/kg/day up-regulates the expression of SLC26A6 and SLC4A4 mRNA, which were reduced following concomitant ICI 182780 administration. In parallel, SLC26A6 and NBCe1-B protein expression were also increased following high dose genistein treatment and were localized mainly at the apical membrane of the luminal epithelia. SLC26A6 and NBCe1-B up-regulation by genistein could be responsible for the observed increase in the uterine fluid pH, Na⁺ and HCO₃⁻ concentration under this condition.     

Degradation of surfactant used in iron mining by oxidation technique: Fenton,photo-Fenton,and H2O2/UV—A comparative study

Reuse of water in mining helps reduce the volume of tailings directed to dams, avoiding overloads and ruptures, as occurred in Brumadinho, Brazil. Water reuse in mining requires treatment mainly for removing the surfactant substances used. Photo-Fenton and UV/H₂O₂ showed 96% to 98% degradation results of anionic surfactants within 5 minutes, suggesting this technique is faster than biological systems that can take days. This paper aims to study the degradation of a surfactant used in the flotation process by UV/H₂O₂, Fenton, and photo-Fenton oxidation techniques. The compound was characterized by FTIR and MALDI-TOF. In degradation experiments, the variation in reactants concentrations was evaluated with hydrogen peroxide, iron sulphate heptahydrate, and oxalic acid. We used a synthetic solution of surfactant in the reverse flotation of ore with 180 mg/L. The reaction was monitored with TOC analysis and a spectrophotometer throughout the reaction. The UV/H₂O₂ and Fenton system were studied by varying peroxide and iron concentrations, with 120 minute tests. Additionally, photo-Fenton concentrations, the pH variation (1.5-8.0), temperature (15°C, 21°C, and 60°C), and time were evaluated. The results showed the most efficient degradation was that using photo-Fenton, which achieved total TOC removal using 4500 mg/L of peroxide and 364 mg/L of iron for 330 minutes, while the UV/H₂O₂ system achieved 29% and 49% TOC removal of the Fenton. It is verified that the oxidative processes can be applied to degrade the surfactants present in the water recovered from the flotation processes.     

New Pyridine ONN‐Pincer Gold and Palladium Complexes: Synthesis,Characterization and Catalysis in Hydrogenation,Hydrosilylation and C?C Cross‐Coupling Reactions

The ONN‐tridentate unsymmetrical pincer 2‐[6‐(pyrrolidin‐1‐ylmethyl)pyridin‐2‐yl]phenol and N‐tert‐butyl‐1‐{[6‐(2‐hydroxyphenyl)pyridin‐2‐yl]methyl}pyrrolidine‐2‐carboxamide ligands were synthesized by an easy method in high purity and good yields. All the organic compounds were characterized by elemental analysis, mass spectrometry, IR and ¹H and ¹³C NMR spectroscopy. Palladium(II) and gold(III) complexes have been prepared as air‐stable solids, with the ONN‐tridentate ligand after deprotonation of the hydroxy group, the coordination of the metal ion is completely stereospecific and gives rise to only one diastereoisomer. These complexes were shown to be very active catalysts in the hydrogenation (80 % ee was achieved with the chiral gold complex), hydrosilylation and C C coupling, Suzuki and Heck, reactions, under mild conditions.