Active State Research Articles

Validation of Analytical Methods for Quality Control of Gel for Dentin Remineralization

Introduction. As a result of a complex of scientific and experimental studies carried out at the Department of Pharmaceutical Technology of the State Pharmacy of Pharmaceuticals, a gel was developed for remineralization of dentin in order to carry out drug treatment of medium and deep caries. In the developed gel, along with the remineralizing effect, an antibacterial effect was achieved, which is necessary in the treatment of dentin caries due to the introduction of chlorhexidine bigluconate (CHB). The proposed composition simultaneously contains the main remineralizing ions – calcium, phosphate and fluoride in a free active state. Due to this, a significant increase in their penetration into the dentin is ensured. During the preparation of regulatory documentation for the gel for the treatment of dentine caries, validation of methods designed to control the quality of active substances was carried out.Aim. Validation of methods for testing the authenticity and quantification of active substances in the gel for dentine remineralization.Materials and methods. To achieve this goal, active pharmaceutical substances of pharmacopoeial quality are used. When developing test methods, pharmacopoeial and non-pharmacopoeial reactions to reacting cations and anions were used. For the quantitative determination of the chloride compound, the complexometric method, the back titration method is used, for potassium phosphate, the disubstituted acidimetric method, for sodium fluoride, the photoelectrocolorimetric method, for chlorhexidine bigluconate, the lauryl sulfate method. The objects of study were five serial samples of gels.Results and discussion. As a result of the studies, methods of testing for authenticity were developed, it was found that the proposed methods are characterized by a negative analytical signal on model mixtures free of the analyte and placebo, and a positive analytical signal on model mixtures of various compositions containing the analyte. The validation characteristics of methods for the quantitative determination of active substances in the gel were studied, positive results were obtained, the proposed methods can be used for inclusion in the regulatory documentation for the developed gel.Conclusion. When evaluating the validation characteristics of the proposed methods, it was found that the methods of testing for authenticity and quantitative determination of active substances in the gel are specific, the methods of quantitative determination are characterized by accuracy and repeatability, a linear dependence in the analytical region of ±20 % of the declared amount of active substances, which allows them to be used for reliable assessment of the quality of the developed gel.

Rapid and Nondestructive Evaluation of Platelet Function in Whole Blood by Microfluidic Deterministic Cytometry.

Platelet size is a determinant of platelet function. Here, a new microfluidic deterministic cytometry packed with S-shaped micropillars (S-MDC) was developed to rapidly and sensitively determine the apparent size (Dapp) of platelets, which was used to evaluate platelet function. The platelet Dapp in the diluted whole blood was rapidly and label-freely measured by S-MDC within 2 min under shear rates (0.4 mm/s) that mimicked physiological conditions. The level of CD62p on platelets scarcely changed before and after platelets went through the whole S-MDC, indicating that the platelet function was nondestructive. Notably, the human platelet Dapp determined before and after thrombin addition by S-MDC was highly coincident with the levels of CD62p on the platelet surface by flow cytometry (r = 0.819), revealing that the human platelet Dapp was available to assess the platelet activation state. In addition, the results of the rat platelet Dapp were consistent with myocardial injury of rats with myocardial ischemia before and after treatment with antiplatelet agents, suggesting that rat platelet Dapp can be used to reflect myocardial injury in vivo outcomes. These findings reveal that S-MDC is a promising technique for screening tests for a bleeding disorder, in addition to monitoring antiplatelet drugs.

Fecal Urgency in Ulcerative Colitis: Impact on Quality of Life and Psychological Well-Being in Active and Inactive Disease States

Ulcerative colitis (UC) is a chronic, relapsing-and-remitting, potentially progressive form of inflammatory bowel disease (IBD) with multidimensional and often negative effects on patients' lives. Fecal urgency, the sudden and compelling desire to defecate, often accompanied by impaired bowel control leading to frequent and urgent trips to the bathroom, is a distressing symptom, experienced by more than 50% of patients with UC.1 Physicians frequently underestimate the burden of fecal urgency on patients' lives, with ramifications ranging from disruption in daily activities, social interactions, and emotional distress with resultant impairment in quality of life (QoL).2,3.

التحليل الشبكي لدور القيادات النسائية في التمكين السياسي للمرأة السعودية عبر منصات التواصل الاجتماعي: (X) نموذجًا

The study aims to identify the number of tweets concerned with the political empowerment of Saudi women through the accounts of tweeters on the (x) platform, and the network analysis of the accounts of women leaders to monitor the number of nodes and links on political empowerment topics through the (x) platform. The study belongs to descriptive explanatory studies and relies on the network analysis methodology. The study used network analysis in data collection, analysis and interpretation, by applying to a sample of (5) accounts of women leaders in Saudi society through the (X) platform, namely: (Hala Al-Tuwaijri - Kawthar Al-Arbash - Haifa Mohammed Al Saud - Amal Yahya Al-Muallimi - Adwaa Abdul Rahman Al-Arifi) were withdrawn during October 2023, with a total of (1274) tweets, relying on the theory of network analysis as a theoretical framework for the study. The study reached a set of results, most notably: It was found that there is a large state of activity and interaction in the accounts of women leaders in the Kingdom of the study sample through the (X) platform, where the presence of tweets of a large number of users commenting on what is published during the study period, and this is clearly shown by the high number of tweets. The account of (Amal Yahya Al-Moallimi) was distinguished from the rest of the accounts of the study sample, in the emergence of words indicating the political empowerment of women, the most prominent of which came (ambassador), (diplomacy), and (leadership). With regard to the most prominent forms of interaction with tweets on the accounts of women leaders, the form of interaction (showing likes) came at the forefront of the forms of interaction between the five accounts of the study sample. The study recommends the need to increase attention to the political empowerment of Saudi women, by opening more areas of discussion on topics of political empowerment through various media, especially through social networking sites and applications, in light of the Kingdom's direction in its ambitious Vision 2030.

The Combination of Bioavailable Concentrations of Curcumin and Resveratrol Shapes Immune Responses While Retaining the Ability to Reduce Cancer Cell Survival.

The polyphenols Curcumin (CUR) and Resveratrol (RES) are widely described for their antitumoral effects. However, their low bioavailability is a drawback for their use in therapy. The aim of this study was to explore whether CUR and RES, used at a bioavailable concentration, could modulate immune responses while retaining antitumor activity and to determine whether CUR and RES effects on the immune responses of peripheral blood mononuclear cells (PBMCs) and tumor growth inhibition could be improved by their combination. We demonstrate that the low-dose combination of CUR and RES reduced the survival of cancer cell lines but had no effect on the viability of PBMCs. Although following CUR + RES treatment T lymphocytes showed an enhanced activated state, RES counteracted the increased IFN-γ expression induced by CUR in T cells and the polyphenol combination increased IL-10 production by T regulatory cells. On the other hand, the combined treatment enhanced NK cell activity through the up- and downregulation of activating and inhibitory receptors and increased CD68 expression levels on monocytes/macrophages. Overall, our results indicate that the combination of CUR and RES at low doses differentially shapes immune cells while retaining antitumor activity, support the use of this polyphenol combinations in anticancer therapy and suggest its possible application as adjuvant for NK cell-based immunotherapies.

Rapid and high accurate identification of Escherichia coli active and inactivated state by hyperspectral microscope imaging combing with machine learning algorithm

Rapid identification of the active state of foodborne bacteria is crucial for ensuring the safety and quality control of food or pharmaceutical products. In this study, a combination of hyperspectral microscope imaging (HMI) and machine learning algorithm is employed for the identification of active state of Escherichia coli (E. coli). Hyperspectral microscope images of live, 100 ℃ heat inactivation and 121 ℃ high-pressure inactivation of E. coli are collected in wavelength range of 370–1060 nm. Savitzky-Golay (SG) smoothing combing with normalization is used for spectra preprocessing. And principal component analysis (PCA) is employed for spectral dimension reduction. Four different regions of interest (ROIs), including the entire bacterial cell ROI (cell), the outer cell wall ROI (cell_r), the membrane structure ROI (cell_w) formed by the cell wall and cell membrane, and the central of the cell ROI (cell_cy), are extracted and used as model input variables to investigate the influence on the modeling results. Five model algorithms, support vector machines (SVM), random forests (RF), k-nearest neighbors (KNN) algorithms, discriminant analysis (DA) classifiers, and long short-term memory (LSTM) neural networks are used and compared. Modeling results with spectral data of cell_r perform better than those with other ROIs. Accuracy of the models with data of the cell_r ROI are as follows: 79.78% for SVM, 95.11% for RF, 91.33% for KNN, 98.22% for DA, and 93.78% for LSTM. DA achieves the highest classification accuracy. The results show that high-temperature inactivation induces changes in bacterial tissue and morphology, resulting in certain spectral differences among bacteria in three different states. The combination of hyperspectral microscope imaging and machine learning algorithm can provide an effective method for identification of active and inactive states of E. coli. Furthermore, the model, constructed with the data of cell_r ROI, exhibits the best performance in identification.

Metastable Ni(I)-TiO2-X Photocatalyst: Self-Amplifying H2 Evolution from Plain Water without Noble Metal Co-Catalyst and Sacrificial Agent

This contribution describes the self-assembling and self-activating nature of a TiO2 photocatalyst that generates hydrogen from water in the absence of sacrificial species or noble metal co-catalysts [1]. Such system forms when nanoparticles of reduced anatase TiO2 are illuminated in an aqueous Ni2+ solution [2,3]. UV illumination creates in-situ a Ni+/TiO2/Ti3+ photocatalyst that over time produces H2 at a higher rate. Thus, UV light is both the synthesis tool that forms this active metastable photocatalytic entity and the energy provider for this entity to enable H2 evolution from water.Operando X-ray absorption (XAS) and electron paramagnetic (EPR) spectroscopies show that key to self-assembly and self-activation is the light-induced formation of defects in the semiconductor [4], which enables the formation of monovalent Ni+ surface states. Metallic nickel states, i.e., Ni0, do not form, neither in the dark (resting state) nor under illumination (active state). Once the catalyst is assembled, the Ni+ surface states act as electron relay for electron transfer to form H2 from water.Self-amplifying reaction schemes of this type entail considerable potential for developing a new generation of photocatalysts via simple one-pot synthesis routes.

Relationship between Surface States of Carbon Support and Electrode Reaction Activity in Cathode Catalyst Layer Toward High Power Output of Polymer Electrolyte Fuel Cells by Large-Scale Reactive Molecular Dynamics Simulations

Higher output of polymer electrolyte fuel cells (PEFC) is required for use in many industrial fields such as the transport industry. PEFCs consist of a gas diffusion layer, a catalyst layer (CL), and a polymer electrolyte membrane. The output of PEFCs depends on the electrode reaction activity of the CL consisting of the carbon support, ionomer, water, and Pt nanoparticles (NPs). For high electrode reaction activity, the optimization of the CL structures such as Pt alloy, pore structures of the carbon support, and I/C (Ionomer carbon ratio), are key factors. To optimize the CL structures, computational simulation, which can propose theoretical design principles, is a promising method. Thus, many researchers have investigated the CL structures with high electrode reaction activity by computational simulation to propose design principles. For example, first-principles calculation can optimize highly active Pt catalysts by considering activation barriers, molecular adsorption structures and surface electronic states, which involves the behavior of atoms and molecules. However, this method cannot consider the effects of carbon support, ionomer, and water because of the limitation in computational costs. On the other hand, macro-scale approach using differential equations can discuss the highly active CL structures since this method can consider multiple structures such as carbon support, ionomer distribution, water content, and Pt loading. However, this approach cannot consider the behavior of atoms and molecules. Therefore, large-scale molecular simulations which, can simultaneously consider the behavior of atoms and molecules, and the CL structures are required. Here, reactive molecular dynamics (RMD) simulation is a practical approach to deal with the behavior of atoms and the chemical reactions in the CL. By using RMD method, we successfully constructed large-scale CL structures and established the CL design methodology both including atomic and molecular effects and clarifying the effect of the pore size of carbon support on the electrode reaction activity [1]. In order to design the higher-performance CL structures, we focused on the distribution of water which mediates proton transfer process. Improving the wettability of carbon support by termination of hydroxyl groups to the carbon support surface can alter the water distribution. Therefore, by large-scale RMD simulations, we investigated the effect of the ratio of the hydroxyl groups on the carbon support surface on water distribution to propose design principles for higher-performance cathode CL structures.A CL structures model consisting of 1 million atoms was constructed by modeling carbon support, Pt NPs, ionomer, and water. We selected the carbon support, where there were six meso pores on an amorphous carbon sphere. The ratios of hydroxyl groups to the carbon surface atoms were set to 10 and 32% to control the water distribution on the carbon surface. In addition, Pt NPs were put on the carbon support outer surface and interior of the pores. The water film whose thickness is 0.7 nm and ionomer are coated on Pt-supported carbon. Hereafter, we call this structure catalyst particle (CP) model (Fig. 1).To clarify the effect of the ratio of hydroxyl groups on the carbons support surface, the morphology of the water film was compared in the CP models with different hydroxyl ratios. At the exterior of the pores, the water film was peeled off from the carbon support surface regardless of the ratio of hydroxyl groups. At the interior of the pores, when the ratio of hydroxyl groups was 10%, the water film was peeling from the carbon support surface（Fig. 2(a), (b)). On the other hand, when the ratio of hydroxyl groups was 32%, the water film did not peel off from the carbon support surface, and the structure of the water film was maintained (Fig. 2(c), (d)). Next, to clarify the effect of the water film morphology on the proton conduction to the Pt NPs, the water clusters as proton conduction paths were analyzed. Water clusters were defined as a group of water molecules whose inter-molecular distance is less than 3.5Å. The amount of proton conduction paths to the Pt NPs at the exterior of the pores did not change regardless of the ratio of hydroxyl groups. On the other hand, the amount of proton conduction path to the Pt NPs at the interior of the pores was increased by increasing the ratio of hydroxyl groups (Fig. 3). These results indicate that the increasing the ratio of hydroxyl groups on the carbon support surface to improve the proton conduction path is an effective approach for the design of the higher-performance cathode CL.[1] T. NAKAMURA, M. KUBO et al. J. Comput. Chem. Jpn., 20,150-154, (2021). Figure 1

Preventing Pt Catalysts in PEM Fuel Cells from CO Poisoning by Getting COPROX to Work

Proton-exchange membrane fuel cells still require CO-scrubbed H2 feedstreams to sustain long-duration performance. Sufficiently CO-free H2 costs an order of magnitude more than steam refining fossil fuels to generate H2—and until green processes produce the bulk of H2, preferential oxidation of CO from H2-rich feedstreams, also known as COPROX, is a necessity. We design architected catalytic platforms as ultraporous metal nanoparticle–modified oxide aerogels in which a covalently bonded oxide nanoparticulate network (NPs) supports comparably sized catalytic nanoparticles (NPs). The degree of physical and chemical interfacial intimacy stabilizes the more catalytically active low valent state of Cu and the ultraporous catalytic platform demonstrates high activity and on-stream durability for thermal catalysis of CO [1]. We then evaluate the selectivity and activity of this architected catalyst and a related aerogel, Cu/GdxCe1–xO2, for preferential oxidation of CO (COPROX) in H2 feedstreams. The catalysts convert >95% of CO at temperatures that prevent oxidation (consumption) of the H2 fuel (a purification reaction necessary to prevent poisoning of the anode catalysts in H2 fuel cells). The architected Cu/ceria catalysts achieve >95% selectivity vs. H2 and maintain this unprecedented activity for >16 h at 100°C in dry or humidified feedstreams [2,3]. The ability to purify H2 from steam-reformed fuels for use in proton-exchange membrane fuel cells increases power source flexibility as the world transitions to more sustainable, carbon-neutral routes to highly purified H2.[1] Stabilization of reduced copper on ceria aerogels for CO oxidation. C. L. Pitman, A. M. Pennington, T. H. Brintlinger, D. E. Barlow, L. F. Esparraguera, R. M. Stroud, J. J. Pietron, P. A. DeSario, D. R. Rolison, Nanoscale Adv. 2020, 2, 4547–4556 (10.1039/D0NA00594K).[2] Preferential oxidation of CO in H2-containing gas. T.G. Novak, D.R. Rolison, P.A. DeSario, US Patent Application, filed Jan 27, 2023 [Navy Case #210,945].[3] Cu/CeO2 and Cu/Gd-substituted CeO2 aerogels for active, selective, and stable COPROX catalysis. T.G. Novak, P.A. DeSario, T.H. Brintlinger, R.H. DeBlock, J.W. Long, and D.R. Rolison, ACS Sus. Chem. Eng. 2023, 11, 2853–2860 (10.1021/acssuschemeng.2c06158).

Microglial-specific knockdown of iron import gene, Slc11a2, blunts LPS-induced neuroinflammatory responses in a sex-specific manner

Neuroinflammation and microglial iron load are significant hallmarks found in several neurodegenerative diseases. In in vitro systems, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and it has been shown that iron can augment cellular inflammation, suggesting a feed-forward loop between mechanisms involved in iron import and inflammatory signaling. However, it is not understood how microglial iron import mechanisms contribute to inflammation in vivo, or whether altering a microglial iron-related gene affects the inflammatory response. These studies aimed to determine the effect of knocking down microglial iron import gene Slc11a2 on the inflammatory response in vivo. We generated a novel model of tamoxifen-inducible, microglial-specific Slc11a2 knockdown using Cx3cr1Cre-ERT2 mice. Transgenic male and female mice were administered intraperitoneal saline or lipopolysaccharide (LPS) and assessed for sickness behavior post-injection. Plasma cytokines and microglial bulk RNA sequencing (RNASeq) analyses were performed at 4 h post-LPS, and microglia were collected for gene expression analysis after 24 h. A subset of mice was assessed in a behavioral test battery following LPS-induced sickness recovery. Control male, but not female, mice significantly upregulated microglial Slc11a2 at 4 and 24 h following LPS. In Slc11a2 knockdown mice, we observed an improvement in the acute behavioral sickness response post-LPS in male, but not female, animals. Microglia from male, but not female, knockdown animals exhibited a significant decrease in LPS-provoked pro-inflammatory cytokine expression after 24 h. RNASeq data from male knockdown microglia 4 h post-LPS revealed a robust downregulation in inflammatory genes including Il6, Tnfα, and Il1β, and an increase in anti-inflammatory and homeostatic markers (e.g., Tgfbr1, Cx3cr1, and Trem2). This corresponded with a profound decrease in plasma pro-inflammatory cytokines 4 h post-LPS. At 4 h, male knockdown microglia also upregulated expression of markers of iron export, iron recycling, and iron homeostasis and decreased iron storage and import genes, along with pro-oxidant markers such as Cybb, Nos2, and Hif1α. Overall, this work elucidates how manipulating a specific gene involved in iron import in microglia alters acute inflammatory signaling and overall cell activation state in male mice. These data highlight a sex-specific link between a microglial iron import gene and the pro-inflammatory response to LPS in vivo, providing further insight into the mechanisms driving neuroinflammatory disease.

EEG Signal Analysis for Monitoring Concentration of Operators

Often, operators of machines, including unmanned ground vehicles (UGVs) or working machines, are forced to work in unfavourable conditions, e.g. high temperatures continuously for a long period of time. This has a huge impact on their concentration, which usually determines the success of many tasks entrusted to them. Electroencephalography (EEG) allows the study of the electrical activity of the brain. It allows determining, for example, whether the operator is able to focus on the realization of his tasks. The main goal of the article was to develop an algorithm for determining the state of brain activity by analysing the EEG signal. For this purpose, methods of EEG signal acquisition were described, basic types of brain waves were discussed, and exemplary states of brain activity were recorded. Particular attention was paid to technical aspects related to signal analysis. The LabVIEW environment was used to implement the created algorithm. The results of the research showing the operation of the developed EEG signal analyser were also presented.

EEG Signal Analysis for Monitoring Concentration of Operators

Often, operators of machines, including unmanned ground vehicles (UGVs) or working machines, are forced to work in unfavourable conditions, e.g. high temperatures continuously for a long period of time. This has a huge impact on their concentration, which usually determines the success of many tasks entrusted to them. Electroencephalography (EEG) allows the study of the electrical activity of the brain. It allows determining, for example, whether the operator is able to focus on the realization of his tasks. The main goal of the article was to develop an algorithm for determining the state of brain activity by analysing the EEG signal. For this purpose, methods of EEG signal acquisition were described, basic types of brain waves were discussed, and exemplary states of brain activity were recorded. Particular attention was paid to technical aspects related to signal analysis. The LabVIEW environment was used to implement the created algorithm. The results of the research showing the operation of the developed EEG signal analyser were also presented.

Origin of surface-bonded oxygen on dendritic Ag particles towards 3D-nanocrystalline carbon formation during CO2 electrochemical reduction reaction

Formation of nanocrystalline carbon allotropes under the electrocatalytic reduction reaction of CO2 (CO2RR) on the dendritic Ag electrocatalysts was investigated at the applied potential −1.6 V vs. Ag/AgCl under the electrolyte system containing [BMIM]+[BF4]-, propylene carbonate, and water. The surface Ag − O bonds play an important role in developing the N+ stabilized highly energetic negatively charged Ag nanoclusters on which the nanocrystalline solid carbon was formed. Herein, the surface-bonded oxygen on dendritic Ag particles was originated from (i) the ultrathin natural silver oxide layers (unmodified Ag), (ii) anodization treatment (AD), and (iii) cyclic voltammetry treatments at a scan rate 1 (CV1) or 200 mV/s (CV200) for 5 cycles. Their capability to catalyze CO2RR towards solid carbon products depends on the stabilization of the active state of negatively charged nascent Ag nanoclusters under [BMIM]+[BF4]-. Even though each catalytic system yielded a major crystalline solid carbon product, a slight shift towards gaseous CO formation was noted in the case of AD compared to the unmodified Ag, CV200, and CV1, respectively. The increased intricacy in the three-dimensional structure of dendritic Ag particles following CV1 post-treatment, coupled with a stronger Ag − O bond could hinder agglomeration of anion Ag clusters. The crystalline solid carbon films containing sp2 − sp3 hybridization were grown on the facets of Ag nanocrystals as the building blocks and were matched with graphite and Diamond-C structures. The discoveries have significance in propelling the progress of electrocatalysts containing oxides, aiming to attain enhanced yields of higher value nanocrystalline carbon products through CO2RR.

Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway plays a critical protective role against viral infections. Metazoan STING undergoes multilayers of regulation to ensure specific signal transduction. However, the mechanisms underlying the regulation of bacterial STING remain unclear. In this study, we determined the crystal structure of anti-parallel dimeric form of bacterial STING, which keeps itself in an inactive state by preventing cyclic dinucleotides access. Conformational transition between inactive and active states of bacterial STINGs provides an on-off switch for downstream signaling. Some bacterial STINGs living in extreme environment contain an insertion sequence, which we show codes for an additional long lid that covers the ligand-binding pocket. This lid helps regulate anti-phage activities. Furthermore, bacterial STING can bind cyclic di-AMP in a triangle-shaped conformation via a more compact ligand-binding pocket, forming spiral-shaped protofibrils and higher-order fibril filaments. Based on the differences between cyclic-dinucleotide recognition, oligomerization, and downstream activation of different bacterial STINGs, we proposed a model to explain structure-function evolution of bacterial STINGs.

China’s Road towards Decarbonization: Unrealistic Promise or a Credible Commitment?

This article argues that in low- and middle-income countries, market forces alone are structurally inadequate to spark the rapid development of renewable energy resources and initiate the replacement of obsolete technologies with cleaner technologies. Using the theoretical perspective of new structural economics as a point of departure, the examination of system-level constraints to the transformation of renewable energy reveals that active state participation in the energy sector can, on the one hand, play a key role in limiting fossil fuel consumption and, on the other, accelerate the development of renewable energy technologies. Analysis of the structural characteristics that underlie the gradual deceleration of fossil fuel extraction and the acceleration of renewable energy deployment suggests that China has laid the necessary prerequisites to reconcile policy objectives of promoting energy transformation and ensuring long-term economic growth.

Statistical and network analyses reveal mechanisms for the enhancement of macrophage immunity by manganese in Mycobacterium tuberculosis infection

Tuberculosis is a significant infectious disease that poses a serious risk to human health. Our previous research has indicated that manganese ions reduce the bacterial load of Mycobacterium tuberculosis in macrophages, but the exact immune defense mechanism remains unknown. Several critical proteins and pathways involved in the host's immune response during this process are still unidentified. Our research aims to identify these proteins and pathways and provide a rationale for the use of manganese ions in the adjuvant treatment of tuberculosis. We downloaded GSE211666 data from the GEO database and selected the RM (Post-infection manganese ion treatment group) and Ra (single-infection group) groups for comparison and analysis to identify differential genes. These differential genes were then enriched and analyzed using STRING, Cytoscape, and NDEx tools to identify the two most relevant pathways of the “Host Response Signature Network.” After conducting an in-depth analysis of these two pathways, we found that manganese ions mainly mediate (1) the interferon -gamma (IFN-γ) and its receptor IFNGR and the downstream JAK-STAT pathway and (2) the NFκB pathway to enhance macrophage response to interferon, autophagy, polarization, and cytokine release. Using qPCR experiments, we verified the increased expression of CXCL10, MHCII, IFNγ, CSF2, and IL12, all of which are cytokines that play a key role in resistance to Mycobacterium tuberculosis infection, suggesting that macrophages enter a state of pro-inflammatory and activation after the addition of manganese ions, which enhances their immunosuppressive effect against Mycobacterium tuberculosis. We conclude that our study provides evidence of manganese ion's ability to treat tuberculosis adjuvantly.

The March 2023 UAS-based high-resolution Digital Surface Model and orthomosaic of the NE flank of Stromboli volcano (Sicily, Italy)

Stromboli is a volcanic island in a persistent state of activity, located in the Tyrrhenian Sea off the northern coast of Sicily. During the night of 25 and 26 May 2022, a massive human-caused wildfire destroyed most of the vegetation cover on the NE flank of the island, just above the main village. On 12 August 2022, a particularly heavy rainfall event remobilized the loose volcaniclastic deposits that covered the burned volcanic flank, no longer protected by the vegetation. This event triggered several debris flows that were channeled by the roads and flooded several streets and buildings, causing severe damage to the village. In late-March 2023, just before the large spring vegetation growth, we conducted an Unmanned Aerial System (UAS) photogrammetric campaign over a sector of the NE flank of Stromboli Island, to acquire data on an area massively affected by the wildfire first and by the debris flows later. Here we present and share with the scientific community and civil authorities the results of this UAS campaign, which consists of a 1.4 km2 wide 10 cm-resolution Digital Surface Model (DSM) and 1.6 cm-resolution orthomosaic. These data clearly show the dramatic consequences of the 2022 tragic events at Stromboli. We also produced an elevation difference map by comparing the 2023 DSM here generated and the 2012 LiDAR DEM to provide a first overview of the thickness of the deposits that were removed from the Stromboli NE flank.

Real-World Health Care Outcomes and Costs Among Patients With Juvenile Idiopathic Arthritis in Spain

Background: Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in children. If inflammation is not adequately treated, joint damage, long-term disability, and active disease during adulthood can occur. Identifying and implementing early and adequate therapy are critical for improving clinical outcomes. The burden of JIA on affected children, their families, and the healthcare system in Spain has not been adequately assessed. The greatest contribution to direct costs is medication, but other expenses contribute to the consumption of resources, negatively impacting healthcare cost and the economic conditions of affected families. Objective: To assess the direct healthcare, indirect resource utilization, and associated cost of moderate-to-severe JIA in children in routine clinical practice in Spain. Methods: Children were enrolled in this 24-month observational, multicentric, cross-sectional, retrospective study (N = 107) if they had been treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), had participated in a previous study (ITACA), and continued to be followed up at pediatric rheumatology units at 3 tertiary Spanish hospitals. Direct costs included medication, specialist and primary care visits, hospitalizations, emergency visits or consultations, surgeries, physiotherapy, and tests. Indirect costs included hospital travel expenses and loss of caregiver working hours. Unitary costs were obtained from official sources (€, 2020). Results: Overall, children had inactive disease/low disease activity according to JADAS-71 score and very low functional disability as measured by Childhood Health Assessment Questionnaire score. Up to 94.4% of children received treatment, mainly with bDMARDs as monotherapy (84.5%). Among anti-TNFα treatments, adalimumab (47.4%) and etanercept (40.2%) were used in similar proportions. Annual mean (SD) total JIA cost was €7516.40 (€5627.30). Average cost of pharmacological treatment was €3021.80 (€3956.20), mainly due to biologic therapy €2789.00 (€3399.80). Direct annual cost (excluding treatments) was €3654.60 (€3899.00). Indirect JIA cost per family was €747.20 (€1452.80). Conclusion: JIA causes significant costs to the Spanish healthcare system and affected families. Public costs are partly due to the high cost of biologic treatments, which nevertheless remain an effective long-term treatment, maintaining inactive disease/low disease activity state; a very low functional disability score; and a good quality of life.

Structural Insights into the Activation of Human Aryl Hydrocarbon Receptor by the Environmental Contaminant Benzo[a]pyrene and Structurally Related Compounds

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS protein family and responding to hundreds of natural and chemical substances. It is primarily involved in the defense against chemical insults and bacterial infections or in the adaptive immune response, but also in the development of pathological conditions ranging from inflammatory to neoplastic disorders. Despite its prominent roles in many (patho)physiological processes, the lack of high-resolution structural data has precluded for thirty years an in-depth understanding of the structural mechanisms underlying ligand-binding specificity, promiscuity and activation of AHR. We recently reported a cryogenic electron microscopy (cryo-EM) structure of human AHR bound to the natural ligand indirubin, the chaperone Hsp90 and the co-chaperone XAP2 that provided the first experimental visualization of its ligand-binding PAS-B domain. Here, we report a 2.75 Å resolution structure of the AHR complex bound to the environmental pollutant benzo[a]pyrene (B[a]P). The structure substantiates the existence of a bipartite PAS-B ligand-binding pocket with a geometrically constrained primary binding site controlling ligand binding specificity and affinity, and a secondary binding site contributing to the binding promiscuity of AHR. We also report a docking study of B[a]P congeners that validates the B[a]P-bound PAS-B structure as a suitable model for accurate computational ligand binding assessment. Finally, comparison of our agonist-bound complex with the recently reported structures of mouse and fruit fly AHR PAS-B in different activation states suggests a ligand-induced loop conformational change potentially involved in the regulation of AHR function.

Real-World Health Care Outcomes and Costs Among Patients With Juvenile Idiopathic Arthritis in Spain.

Background: Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in children. If inflammation is not adequately treated, joint damage, long-term disability, and active disease during adulthood can occur. Identifying and implementing early and adequate therapy are critical for improving clinical outcomes. The burden of JIA on affected children, their families, and the healthcare system in Spain has not been adequately assessed. The greatest contribution to direct costs is medication, but other expenses contribute to the consumption of resources, negatively impacting healthcare cost and the economic conditions of affected families. Objective: To assess the direct healthcare, indirect resource utilization, and associated cost of moderate-to-severe JIA in children in routine clinical practice in Spain. Methods: Children were enrolled in this 24-month observational, multicentric, cross-sectional, retrospective study (N = 107) if they had been treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), had participated in a previous study (ITACA), and continued to be followed up at pediatric rheumatology units at 3 tertiary Spanish hospitals. Direct costs included medication, specialist and primary care visits, hospitalizations, emergency visits or consultations, surgeries, physiotherapy, and tests. Indirect costs included hospital travel expenses and loss of caregiver working hours. Unitary costs were obtained from official sources (€, 2020). Results: Overall, children had inactive disease/low disease activity according to JADAS-71 score and very low functional disability as measured by Childhood Health Assessment Questionnaire score. Up to 94.4% of children received treatment, mainly with bDMARDs as monotherapy (84.5%). Among anti-TNFα treatments, adalimumab (47.4%) and etanercept (40.2%) were used in similar proportions. Annual mean (SD) total JIA cost was €7516.40 (€5627.30). Average cost of pharmacological treatment was €3021.80 (€3956.20), mainly due to biologic therapy €2789.00 (€3399.80). Direct annual cost (excluding treatments) was €3654.60 (€3899.00). Indirect JIA cost per family was €747.20 (€1452.80). Conclusion: JIA causes significant costs to the Spanish healthcare system and affected families. Public costs are partly due to the high cost of biologic treatments, which nevertheless remain an effective long-term treatment, maintaining inactive disease/low disease activity state; a very low functional disability score; and a good quality of life.