Associations between the Nutrient Profiling System Underlying the Nutri-Score Nutrition Label and Biomarkers of Chronic Low-Grade Inflammation: A Cross-Sectional Analysis of a Middle- to Older-Aged Population

Low-grade systemic inflammation is associated with a range of conditions. Diet may modulate inflammation and public health strategies are needed to guide consumers’ dietary choices and help prevent diet-related disease. The Food Standards Agency nutrient profiling system (FSAm-NPS) constitutes the basis of the five-colour front-of-pack Nutri-Score labelling system. No study to date has examined FSAm-NPS dietary index associations with biomarkers of inflammation. Therefore, our objective was to test relationships between the FSAm-NPS and a range of inflammatory biomarkers in a cross-sectional sample of 2006 men and women aged 46–73 years. Individual participant FSAm-NPS scores were derived from food frequency questionnaires. Pro-inflammatory cytokine, adipocytokine, acute-phase response protein, coagulation factor and white blood cell count concentrations were determined. Correlation and linear regression analyses were used to examine FSAm-NPS relationships with biomarker levels. In crude and adjusted analyses, higher FSAm-NPS scores, reflecting poorer nutritional quality, were consistently and positively associated with biomarkers. In fully adjusted models, significant associations with concentrations of complement component 3, c-reactive protein, interleukin 6, tumour necrosis factor alpha, resistin, white blood cell count, neutrophils, eosinophils and the neutrophil-to-lymphocyte ratio persisted. These results suggest that dietary quality, determined by Nutri-Score rating, is associated with inflammatory biomarkers related to health.     

Retinal Layers Measurements following Silicone Oil Tamponade for Retinal Detachment Surgery

This study aimed to investigate the influence of silicone oil on the retinal nerve fiber layer (RNFL) thickness in patients with primary rhegmatogenous retinal detachment who underwent vitreoretinal surgery. The study included 47 patients (eyes), who underwent a pars plana vitrectomy with the silicone oil tamponade. The control group included unoperated eye of all participants. Spectral-domain optical coherence tomography (SD-OCT) was used for the measurements of peripapilar and macular RNFL thickness. The average peripapillary RNFL thickness was significantly higher in the silicone oil filled eyes during endotamponade and after its removal. The eyes with elevated IOP had less thickening of the RNFL in comparison to the eyes with normal IOP. Central macular thickness and macular volume were decreased in the silicone oil filled eyes in comparison to the control eyes. In conclusion, silicone oil caused peripapilar RNFL thickening in the vitrectomized eyes during endotamponade and after silicone oil removal.     

2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxyadenosine adducts resulting from the reaction of tetrahydrofuran with DNA bases

A recent study showed that tetrahydrofuran (THF), a widely used solvent, is carcinogenic in experimental animals. Despite its carcinogenic activity, there is a paucity of information regarding cellular toxicity, biomolecular damage, and genotoxicity induced by THF. We describe here the structural characterization of adducts produced by the reaction of oxidized THF with 2'-deoxyguanosine (dGuo-THF 1 and dGuo-THF 2), 2'-deoxyadenosine (dAdo-THF), and 2'-deoxycytidine (dCyd-THF). Adducts were isolated from in vitro reactions by reverse-phase HPLC and fully characterized on the basis of spectroscopic measurements. The stable derivatives obtained by the reduction of adducts with NaBH(4) (the case of dGuo-THF 1, dCyd-THF, and dAdo-THF) and the stable adduct dGuo-THF 2 were used as standards for optimization of chromatographic separations for adduct detection in DNA through HPLC/ESI/MS-MS. Using this methodology, we successfully detected the four adducts in calf thymus DNA reacted with oxidized THF. The present study also provides evidence that rat liver microsomal monooxigenases oxidize THF to the reactive electrophilic compounds that are able to damage the DNA molecule, as indicated by a significant increase in adduct dGuo-THF 1 level when NADPH was added to the THF/microsomes/dGuo incubation mixtures. Our data point to DNA-THF adducts as possible contributing factors to the toxicological effects of THF exposure.     

Applicability of the Demirjian,Willems and Haavikko methods in Croatian children

Age estimation is an inescapable part of every identification process. During growth and development, it is possible to estimate age based on the developmental stages of teeth. The aim of this study was to evaluate three frequently used methods for dental age estimation on a broad sample of Croatian children. The sample comprised 1996 digital, standardized orthopantomograms of children (1121 boys and 875 girls) aged 5 to 16, collected in four major Croatian cities. Age was estimated according to the Demirjian, Willems and Haavikko methods and the accuracy of the estimation was evaluated. The Kappa for intra-examiner agreement was 0.83 for the Haavikko stages and 0.92 for the Demirjian stages. Using the Demirjian method, the average overestimation of age was 0.80 years for boys and 0.84 years for girls. The Willems method overestimated the mean age by 0.41 years in boys and 0.22 years in girls. The Haavikko method underestimated the mean age by 0.60 years in boys and 0.80 years in girls. The Willems method proved to be the most accurate and can be used for dental age estimation among Croatian children. The Demirjian and Haavikko methods showed greater deviation between dental and chronological age and require adaptation when used in the Croatian population.     

Silicone Materials for Flexible Optoelectronic Devices

Polysiloxanes and materials based on them (silicone materials) are of great interest in optoelectronics due to their high flexibility, good film-forming ability, and optical transparency. According to the literature, polysiloxanes are suggested to be very promising in the field of optoelectronics and could be employed in the composition of liquid crystal devices, computer memory drives organic light emitting diodes (OLED), and organic photovoltaic devices, including dye synthesized solar cells (DSSC). Polysiloxanes are also a promising material for novel optoectronic devices, such as LEDs based on arrays of III–V nanowires (NWs). In this review, we analyze the currently existing types of silicone materials and their main properties, which are used in optoelectronic device development.     

Substrate mediated properties of gold monolayers on SiC

In light of their unique physicochemical properties two-dimensional metals are of interest in the development of next-generation sustainable sensing and catalytic applications. Here we showcase results of the investigation of the substrate effect on the formation and the catalytic activity of representative 2D gold layers supported by non-graphenized and graphenized SiC substrates. By performing comprehensive density functional theory (DFT) calculations, we revealed the epitaxial alignment of gold monolayer with the underlying SiC substrate, regardless of the presence of zero-layer graphene or epitaxial graphene. This is explained by a strong binding energy (∼4.7 eV) of 2D Au/SiC and a pronounced charge transfer at the interface, which create preconditions for the penetration of the related electric attraction through graphene layers. We then link the changes in catalytic activity of substrate-supported 2D Au layer in hydrogen evolution reaction to the formation of a charge accumulation region above graphenized layers. Gold intercalation beneath zero-layer graphene followed by its transformation to quasi-free-standing epitaxial graphene is found to be an effective approach to tune the interfacial charge transfer and catalytic activity of 2D Au. The sensing potential of substrate-supported 2D Au was also tested through exploring the adsorption behaviour of NH₃, NO₂ and NO gas molecules. The present results can be helpful for the experimental design of substrate-supported 2D Au layers with targeted catalytic activity and sensing performance.

In light of their unique physicochemical properties two-dimensional metals are of interest in the development of next-generation sustainable sensing and catalytic applications.     

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.

The macrodomain of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nonstructural protein 3 (NSP3) (Mac1) presents an intriguing target for drug discovery (1–5). Upon viral infection, host cells initiate an innate interferon-mediated immune response leading to the expression of poly-(ADP-ribose)-polymerases (PARPs), which catalyze the antiviral posttranslational addition of ADP-ribose (ADPr) to a large range of target proteins (6). Mac1 enzymatically reverses this mono-ADP-ribosylation, counteracting immune signaling (7). Promisingly, inactivation of Mac1 by single-point mutations in the ADPr-binding site significantly reduced lethality and pathogenicity in mice after SARS-CoV infection (8). Small-molecule inhibitors of SARS-CoV-2 Mac1 should therefore offer novel therapeutics to mitigate COVID-19 (9, 10).A challenge for the development of such inhibitors has been the lack of small-molecule modulators of macrodomain activity, other than ADPr; indeed, only recently have quantitative assays been developed (10, 11). This is true not only for Mac1 from SARS-CoV-2, but also for the overall family of enzymes, which lack good chemical matter by which their activity can be probed, despite their importance in several areas of health and diseases. Accordingly, to map the recognition determinants of Mac1, we adopted a biophysical approach, screening for fragment ligands using protein crystallography, molecular docking, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and a binding assay based on homogeneous time-resolved fluorescence (HTRF) (12). Mac1 proved to be unusually amenable to structure determination, enabling us to determine the structures of over 230 fragment complexes, typically to ultra-high resolution (often better than 1.1 Å), affording us a detailed map of enzyme hot spots with chemical matter of sufficient potency with which to optimize a quantitative assay (12, 13).Nevertheless, our best fragments remained of modest potency, with none more potent than 180 µM. Here, we describe the discovery and optimization of potent macrodomain ligands using two strategies (Fig. 1). In the first, we sought to link and merge pairs of fragments to create larger molecules that exploited multiple hot spots, so reaching higher affinities. This used a fragment-linking method (12), adapted to explore a virtual library of 22 billion readily synthesizable molecules (14). In the second approach, we exploited the hot spots revealed by the initial fragments to guide computational docking of ultra-large chemical libraries of lead-like molecules, potentially more potent than the fragments docked in our original study (12). Both approaches ultimately led to compounds with IC₅₀ values as low as 0.4 µM for the merged fragments and as low as 1.7 µM for the docking hits (Fig. 1). These represent the most potent inhibitors reported for any member of the broad family of macrodomains. Furthermore, the many X-ray crystal structures determined here provide an extensive resource for drug development campaigns against this promising antiviral target.Open in a separate windowFig. 1.Overview of the structure-based strategies used to discover ligands that bind to the NSP3 macrodomain of SARS-CoV-2 (Mac1).     

Settlement of Soil Reinforced with Vertical Fiberglass Micro-Piles

This article is dedicated to investigating the properties of soil after its reinforcement with fiberglass elements through large-scale laboratory plate-load tests of various samples that varied in the numbers and lengths of the reinforcing elements. The investigation of the vertical elements considered the diameter increase at the bottom toe by using widening washers. The results were compared relative to each other and to the theoretical calculation results. The theoretical calculations for the settlements were undertaken based on the authors’ proposed method. The method considers the number, shape, area and material of the strengthening elements using a pre-proposed reinforcement area factor µ. This pre-established factor was calculated with reference to the elements’ geometry—the diameter of the vertical elements and the bottom’s washer diameter—which determined the reinforcement area. A comparison between the reinforced and reference soft sandy soil samples indicated a 25% increase in the deformation modulus after the reinforcement process at a pressure of 25 kPa. Samples with µ ranging from 1.20 to 1.43 were 55–65% stiffer than samples with µ equal to 0.69 at a pressure of 100 kPa. The comparative analysis of the calculated results and the actual laboratory PLT test results was adequate for use for further development.     

Optimization of the Clinical Effectiveness of Radioembolization in Hepatocellular Carcinoma with Dosimetry and Patient-Selection Criteria

Selective internal radiation therapy (SIRT) is part of the treatment strategy for hepatocellular carcinoma (HCC). Strong clinical data demonstrated the effectiveness of this therapy in HCC with a significant improvement in patient outcomes. Recent studies demonstrated a strong correlation between the tumor response and the patient outcome when the tumor-absorbed dose was assessed by nuclear medicine imaging. Dosimetry plays a key role in predicting the clinical response and can be optimized using a personalized method of activity planning (multi-compartmental dosimetry). This paper reviews the main clinical results of SIRT in HCC and emphasizes the central role of dosimetry for improving it effectiveness. Moreover, some patient and tumor characteristics predict a worse outcome, and toxicity related to SIRT treatment of advanced HCC patient selection based on the performance status, liver function, tumor characteristics, and tumor targeting using technetium-99m macro-aggregated albumin scintigraphy can significantly improve the clinical performance of SIRT.