Bovine coronavirus (BCoV) is one of the most common pathogens affecting cattle of all ages. BCoV possesses multiple tissue tropism in cattle, particularly in the respiratory and enteric tracts of the affected animals. Viral entry is a crucial step in the replication cycle of all viruses, including BCoV. The process of viral entry requires the orchestration between several proteins from the virus and the host side. The coronavirus spike glycoproteins contributed substantially to other viral infections and the molecular pathogenesis of coronaviruses, including BCoV. Meanwhile, among all corona-viruses, the hemagglutinin esterase enzyme is found in only BCoV and the human corona-virus-OC43 (HCoV-OC43). The viral receptors are among the key players in the viral entry and could explain the viral tropism, at least in part. The presence of some host cell proteases also en-hances the virus replication from the entry until the release of the virus from the host cells. Previous studies have shown that the 9- O-acetylated sialic acids could potentially act as receptors for the BCoV. However, little is known about the BCoV receptors and if other co/receptors might be needed to ensure viral entry to the host cells. In addition to that, the roles of other host cell proteases, such as Furin and TMPRSS2, in BCoV infection have not yet been well studied. The main objectives of the current study are to identify some novel receptors for BCoV and some host cell proteases that might enhance virus replication. We used some in silico docking tools to predict some new BCoV receptors out of some known other coronavirus receptors (ACE-2, NRP1, DPP4, APN, and CEACAM1). Our results postulated the potential actions of the host Furin and TMPRRS2 enzymes in the activation of BCoV-S glycoprotein, which potentially enhances BCoV replication. Our modeling confirms the high binding affinities of both the 9- O-acetylated sialic and the NRP1 with the BCoV-S and BCoV-HE compared to the ACE-2, DPP4, and CEACAM-1, suggesting their roles as receptors for BCoV. Our prediction models show the potential bindings of the Furin and TMPRSS2 to the BCoV-S polybasic cleavage site (RRSRR|A). To our knowledge, this is the first study to investigate the bovine coronavirus interaction with some other potential host receptors, particularly ACE-2, NRP1, DPP4, APN and CEACAM1, TMPRSS2, and the bovine Furin protease.

Piezoelectric c-axis oriented zinc oxide (ZnO) thin films, from 1.8 up to 6.6 µm thick, have been grown by radio frequency magnetron sputtering technique onto fused silica substrates. A delay line consisting in two interdigital transducers (IDTs) with wavelength λ = 80 µm was photolith-ographically implemented onto the surface of the ZnO layers. Due to the IDTs split finger con-figuration and metallization ratio (0.5), the propagation of both the fundamental, third and nineth harmonic Rayleigh waves is excited; also, three leaky surface acoustic waves (SAWs) were detected travelling at velocity close to that of the longitudinal bulk wave in SiO2. The acoustic waves propagation in ZnO/fused silica was simulated by using 2D finite-element method (FEM) tech-nique to identify the nature of the experimentally detected waves. It turned out that, in addition to the fundamental and harmonic Rayleigh waves, also high-frequency leaky surface waves are ex-cited by the harmonic wavelengths; such modes are identified as leaky-Sezawa (LS) waves under cut-off. The velocity of all the modes was found in good agreement with the theoretically calcu-lated values. The existence of a low-loss region for the Sezawa wave below the cut off was theo-retically predicted and experimentally assessed.

Bioactive peptides are sequences of amino acids, cut from the parent protein with en-zymes or high pressure processing that can impart a tertiary health benefit to the con-sumer that goes beyond basic human nutrition. This study explores mesopelagic fish in-cluding Maurolicus muelleri and Benthosema glaciale as sources of peptides with an-ti-inflammatory, heart health beneficial, antioxidant and other bioactivities. Bioactive peptides were generated post-catch using different enzymatic hydrolysis processes ap-plied to mesopelagic species caught from experimental cruises targeting these fish. Maurolicus muelleri and Benthosema glaciale were the dominant species processed. Bi-oactive hydrolysates included a Maurolicus muelleri Alcalase hydrolysate and a Maurolicus muelleri autolysis. Hundreds of peptide sequences were identified using mass spectrome-try from active hydrolysates. In silico analysis was used to rank identified peptide se-quences in terms of overall bioactivity using Peptide Ranker, anti-inflammatory activity using PrepAIP, ability to impart Umami flavours with Umami-MRNN and dipeptidyl peptidase IV inhibitory potential using AntiDMPpred . Thirty peptides were selected fol-lowing in silico analysis. Several of the selected peptides had sequence homology with peptides derived from other fish proteins including Atlantic salmon (peptide QCPLHR-PWAL) and thin-lipped mullet (peptide FDAFLPM). Seven peptides predicted to have an-ti-inflammatory, anti-type 2 diabetes or Umami potential using in silico strategies were chemically synthesized and their anti-inflammatory activities confirmed using in vitro bioassays with COX-1 and COX-2 enzymes. The peptide QCPLHRPWAL inhibited COX-1 and COX-2 by 82.90% (+/-0.54) and 53.84% respectively and had a selectivity index greater than 10. This peptide warrant further research as a novel anti-inflammatory/pain relief peptide. Other bioactivities associated with DPP-IV inhibition and Umami flavours de-velopment are discussed. Identified peptides offer potential for use in functional foods or topical agents to prevent pain and inflammation associated with diseases like psoriasis, arthritis and inflammatory bowel disease, however further research in vivo is required.

The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis or ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding to them, in vivo studies are required to understand the physiological significance and contribution of environmental factors to regulation of PipX complexes. Here we have used the NanoBiT complementation system to analyse regulation of complex formation in Synechococcus elongatus between PipX and each of its two best characterized partners, PII and NtcA. Our results confirm previous in vitro analysis on regulation of PipX-PII and PipX-NtcA complexes by 2-oxoglutarate and on regulation of PipX-PII by the ATP/ADP ratio, showing the disruption of PipX-NtcA complexes by increased levels of ADP-bound PII in Synechococcus elongatus. The demonstration of a positive role of PII on PipX-NtcA complexes under the initial response to nitrogen starvation or the impact of a PipX point mutation on the activity of PipX-PII and PipX-NtcA reporters are further indications of the sensitivity of the system. This study reveals additional regulatory complexities in the PipX interaction network, opening the way to future research in cyanobacteria.

The availability of current land cover and land use (LCLU) information for monitoring the status of land resources has considerable value in ensuring sustainable land use planning. Similarly, the need to provide updated information on the extent of LCLU change in West Africa has become apparent, given the increasing demand for land resources driven by the rapid population growth in the sub-region. SERVIR West Africa, a regional consortium jointly supported by USAID and NASA to foster the use of geospatial and earth observation data and science for decision-making on critical environmental and food security challenges, in collaboration with the Food and Agriculture Organization of the United Nations (FAO), is building technical capacity in the sub-region to develop and implement harmonized regional land cover classification system for LULC change monitoring in West Africa, based on the Land Cover Meta Language (LCML-ISO 19144-2). This article focuses on the process, potential opportunities, outputs of this collaboration, exemplary use cases, and recommendations for the next steps.

Byers Peninsula is considered one of the largest ice-free areas in Maritime Antarctica. Since 2006, the Spanish Polar Program has taken part in a large number of environmental studies involving effects of climate changes in lives cycles, limnology and microbiology. Soils from maritime Antarctica are generally weakly developed and have chemical, physical and morphological characteristics strongly influenced by the parent material. However, biological activity during the short Antarctic summer promotes intense transference of nutrients and organic matter in areas occupied by different species of birds and marine mammals. To mapping and monitoring those areas with high biological occupation, could be very useful to have models of edaphic properties prepared from satellite images. In this approach, Deep Learning and Linear Regression models of soil properties and spectral indexes as explicative variables were performed. We training models of soil properties closely related to biological activity such as Dissolved Organic Carbon (DOC) and the iron fraction associated with organic matter (Fe). We tested the best approach to model the spatial distribution of DOC, Fe and pH by training models of Linear Regression and Deep Learning over Sentinel2 and WorldView2 images. The most robust models were used to track possible areas with ornithogenic soils as well as areas of the Byers Peninsula that could support the highest biological development.

In order for the body to function properly, it needs not only food, but also nutrients and non-nutritive bioactive compounds that have an immunomodulating effect. This applies not only to healthy people, but especially to people with accompanying chronic diseases, including type 2 diabetes. Unfortunately, the current food industry and the use of highly processed food promote nutritional deficiencies. Many studies confirm their occurrence in patients with type 2 diabetes. The article presents the influence of selected nutrients on the functioning of the immune system, which ensures homeostasis of the body, with particular emphasis on type 2 diabetes. The role of macroelements, microelements, vitamins and selected substances, such as omega-3 acids, coenzyme Q10 and alpha-lipoic acid. The minimum scope of tests that should be performed in patients to directly or indirectly determine the degree of malnutrition in this group of patients is presented.

The sustainability of Indigenous Socioecological Systems (ISES) faces significant threats from global anthropogenic environmental changes, endangering Indigenous People (IP), who safeguard a substantial portion of the world's natural capital. Indigenous Traditional Food Systems (ITFS) are crucial within ISES, providing not only diverse and nutritious food but also holding cultural, spiritual, and economic significance. Despite embodying sustainable lifestyles, Indigenous voices remain underrepresented in climate and sustainability discussions. Addressing this gap, the research adopts the Political Ecological Theoretical Framework (PETF) to analyze the regulatory impact on the adaptability, resilience, and sustainability of ITFS. Two Indigenous communities, the Karen in Thailand and various groups in the Republic of Sakha (Yakutia) in Russia, serve as case studies. The study aims to establish a theoretical framework integrating Indigenous concerns into policies and regulations, emphasizing self-determination, cultural preservation, and land rights. Findings emphasize the necessity for comprehensive legal frameworks prioritizing Indigenous involvement in climate resilience and sustainability efforts, moving beyond symbolic gestures towards meaningful collaboration and decision-making power. Recognizing Indigenous vulnerability and engaging them as active partners is essential for navigating climate challenges within ISES and ITFS.

The regulation of intracellular pH in yeast (Saccharomyces cerevisiae) cells is critical for cell function and viability. In yeast, protons (H+) can be excreted from cell by the plasma membrane ATPase Pma1 and pumped into vacuoles by the vacuolar H+-ATPase. Because Pma1 is critical to the survival of yeast cells, it is unknown whether other compensatory components are involved in the pH homeostasis in the absence of Pma1. To elucidate how intracellular pH is regulated independently of Pma1, we employed a screening approach by exposing the yeast haploid deletion mutant library (ver 4.0) to the selective plant plasma membrane H+-ATPase inhibitor PS-1, which we previously reported. After repeated screenings and verification, we identified two proteins, ALY1 and ALY2, that play a role in the regulation of intracellular pH when Pma1 is deficient. Our research uncovers a new perspective on the regulation of intracellular pH related to Pma1 and also preliminarily reveals a role for ALY1 and ALY2 in the regulation of intracellular pH.

The craft guilds have been at the core of important historiographical debates on the economic, social and political history of medieval cities for twenty years. The aim of this article is to examine the seamen’s guilds in the town ports of Northern Peninsula in the late Middle Ages. This study analyzes fundamental aspects of the social assistance, labour organization and social identity of the town ports, located on the maritime border of the Kingdom of Castile. In contrast to the more classical view of the craft guilds as protectionist institutions, which only served the interests of a privileged group of masters, this analysis highlights the contribution of the seamen craft guilds to the organization of labor at sea, the training of sea workers, the ability to negotiate with merchants and avoid labor exploitation, the provision of social assistance to the most vulnerable population, and the ability to lead the social protest for the guilders’ representation in the urban government. In summary, it is concluded that the seafarers’ guilds were constituted as networks of mutual help between individuals in the labor, welfare and political spheres of the population of the town ports of Northern Iberia in the late Middle Ages.

Background We aimed to compare the retinal, optic disc vascular density (ODVD) values, and acircularity index (AI) of patients with idiopathic macular telangiectasia type 2 (IMT) and healthy individuals using the optical coherence tomography angiography(OCTA) device. Methods The study included 39 patients with IMT and 37 healthy controls. The OCTA findings of the patients and controls were examined. Results The total, parafoveal and perifoveal vascular density of the superficial capillary plexus, choriocapillaris blood flow, inside-disc ODVD, retinal nerve fiber layer (RNFL), and retinal thicknesses were found to be statistically significantly lower and the foveal avascular zone value was statistically significantly higher in the IMT group compared to the control group (p=0.001, p=0.01, p=0.02, p=0.01, p=0.009, p=0.002, p=0.02, respectively).There was a statistically significant negative correlation between best-corrected visual acuity (BCVA) and AI (p=0.02), a statistically significant positive correlation between peripapillary vascular density and BCVA(p=0.04). Conclusion We consider that the lower retinal, choriocapillaris, and ODVD values, retinal and RNFL thicknesses in the patients with IMT compared to the controls were due to vascular damage, remodeling, fibrosis, proliferation, and Müller cell damage. Ellipsoid zone defect, AI, and peripapillary vascular density are important indicators in the evaluation of visual acuity in these patients.

This study evaluates the accessibility of primary care physicians (PCPs) in Eastern Quebec using an enhanced two-step floating catchment area (E2SFCA) methodology. The E2SFCA methodology considers both the population supply of PCPs and the travel time between PCPs and dissemination areas, and was found to be effective in identifying possibly underserved areas. The availability of primary care services is contingent upon the presence of adequate road infrastructure, and populations residing in areas with limited access to main road networks may experience compromised access to primary care. The study concludes that the E2SFCA methodology can facilitate the identification of areas experiencing a shortage of PCPs, and this information can be used to inform the development of regional medical workforce programs and support the establishment of rural residency initiatives.

Background & Aims: Gut microbial imbalances are linked to colorectal cancer (CRC), but archae-‎a's role remains underexplored. Here, we performed bioinformatic and statistical analysis looking ‎for archaeal taxonomic and functional signatures related to CRC. Methods: We analyzed pub-‎lished fecal metagenomic data from 390 subjects, comparing the archaeomes of CRC and healthy ‎individuals. We conducted a biostatistical analysis to investigate the relationship between Candi-‎datus Mancarchaeum acidiphilum (DPANN superphylum) and other archaeal species associated ‎with CRC. Using the Prokka tool, we annotated the data focusing on archaeal genes, subsequently ‎linking them to CRC and mapping them against UniprotKB and GO databases for specific ar-‎chaeal gene functions. Results: Our analysis identified enrichment of methanogenic archaea in ‎healthy subjects, with an exception for Methanobrevibacter smithii, which correlated with CRC. ‎Notably, CRC showed a strong association with archaeal species, particularly Natrinema sp. J7-2, ‎Ferroglobus placidus, and Candidatus Mancarchaeum acidiphilum. Furthermore, the DPANN ar-‎chaeon exhibited a significant correlation with other CRC-associated archaea (p < 0.001). Func-‎tionally, we found a marked association between MvhB-type polyferredoxin and colorectal can-‎cer. We also highlighted the association of archaeal proteins involved in the biosynthesis of leucine ‎and the galactose metabolism process with the healthy phenotype. Conclusion: The archaeomes ‎of CRC patients show identifiable alterations, including a decline in methanogens and an increase ‎in Halobacteria species. MvhB-type polyferredoxin, linked with CRC and species like Candidatus ‎Mancarchaeum acidiphilum, Natrinema sp. J7-2 and Ferroglobus placidus emerge as potential archaeal ‎biomarkers. Archaeal proteins may also offer gut protection, underscoring archaea’s role in CRC ‎dynamics.

As the core components of water jet propulsion system, water jet pump, directly affect the ship's propulsion performance. 3D reverse design method can effectively suppress the impeller secondary flow to get better performing hydraulic models. Aiming at fast and efficient optimization of the impellers, we parameterize the impellers and runner, and coupled with optimization algorithms and numerical calculations. It is an efficient and feasible way to coupling optimization based on multi-parameter, multi-objective and optimization algorithms, and parameterizing the impellers and guide vane geometry based on the 3D model designed by 3D reverse design method. In this paper, the waterjet propulsion pump is taken as the research object. According to the design method of the waterjet propulsion pump hydraulic model, the traditional axial flow blade design method, the modern ternary design theory of the blades, and the parametric three-dimensional reverse design method are selected to constructing an optimal design optimization strategy for the impeller of water-jet propulsion pump based on multi-parameter and multi-object genetic algorithm. Under the design conditions, the optimized pump efficiency reaches 89.28%, which is 1.24% higher than the original hydraulic model. The optimized pump head is 13.51 m, which is 0.39m more than the original hydraulic model. Under the design condition, the test measured head is 13.26m, the numerical calculation result is 1.88% higher than the test result, the test measured efficiency is 87.1%, the numerical calculation result is 2.5% higher than the test result. From the test results, the optimized impeller has higher hydraulic performance. Experiments have shown that it is feasible to optimize the design strategy.

We performed the accuracy assessment of three different Normalized Difference Water Indices (NDWIs) in water bodies during April 2019, a period in which floods occurred in a large proportion of the Southwest of the Buenos Aires Province (Argentina). The accuracy of the estimations using spaceborne medium-resolution multi-spectral imaging, and the reliability of three NDWIs to highlight shallow water features in satellite images, was evaluated using a high resolution airbone imagery as ground-truth. It is shown that these indices computed using Landsat 8 and Sentinel-2 imagery are only loosely correlated to the actual flooded area in shallow waters. Indeed, NDWI values vary significantly depending on the satellite mission used and the type of index computed.

Background and aim: To explore the discriminant accuracy of Cytokeratin 18 (CK18, including M65 and M30 forms) for an elevated fatty liver index (FLI) as a validated proxy of Non-Alcoholic Fatty Liver Disease (NAFLD), and cardiovascular disease (CVD) risk in the general population. Methods: Both serum CK18 forms were measured using a commercial immunoassay in randomly selected samples from 312 participants of the PREVEND general population cohort. FLI ≥60 was used to indicate NAFLD. Framingham Risk Score (FRS) and the SCORE2 were used to estimate the 10-year risk of CVD. Receiver Operating Characteristic (ROC) curve, linear/logistic regression models and Spearman's correlations were used. Results: Intricate associations were found between CK18, FLI and CVD risk scores. While M30 was the only independent predictor of FLI≥60, M65 discriminated best NAFLD individuals at very-high 10-years CVD risk according to SCORE2 (AUC:0.71; p=0.001). Values above the predefined manufacturer cut-off (400 U/l), were associated with an independent 5-fold increased risk (adjusted odds ratio: 5.44, p=0.01), with negative predictive value of 93%. Conclusions: Confirming that NAFLD is associated with an increased CVD risk, our results point to CK18 M65 as a candidate biomarker to identify NAFLD individuals at low CVD risk in European general population.

Hypercholesterolemia is a major risk for the development of cardiovascular diseases (CVDs), the main cause of mortality worldwide, and it is characterized by high levels of circulating cholesterol. The drugs currently available for hypercholesterolemia control have several side effects, so it is necessary to develop new effective and safer therapies. Seaweeds serve as sources of several bio-active compounds with claimed beneficial effects. Eisenia bicyclis (Aramé) and Porphyra tenera (Nori) are edible seaweeds which were previously recognized as rich in bioactive compounds. In the present study, we aim to evaluate the anti-hypercholesterolemia effect of these two seaweeds ex-tracts and their health potential. Both extracts, but more efficiently Aramé extract demonstrated to have liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitory activity and to reduce approximately 30 % cholesterol permeation through human Caco-2 cells simulating the intestinal lining, targets for hypercholesterolemia treatments. An untargeted metabolomic assay on human intestinal Caco-2 and liver Hep-G2 cells lines exposed to Aramé and Nori extracts revealed changes in the cell’s metabolism as indicators of the extract’s health beneficial effects. The metabolic pathways affected by exposure to both extracts were associated to lipid metabolism, such as phospholipids, and fatty acid metabolism, pathways of amino acid, cofactors and vitamins and cellular respiration metabolism. More profound for Aramé treated cells, but also seen for Nori ex-posed cells, the metabolites modifications were associated with the protection against CVDs and other diseases and, to the improvement of cells oxidative stress tolerance. The results obtained for the anti-hypercholesterolemia properties, in addition to the revelation of the positive impact on cells metabolism, are an important contribution for further evaluation of these seaweeds extracts as functional foods or for CVDs prevention.

This paper presents a proposal for a non-isolated bidirectional converter (NIBC) controlled by a deep neural network (DNN) to enable vehicle-to-vehicle (V2V) and vehicle-to-grid (V2G) charging, which contributes to the development of more efficient and sustainable transportation and energy systems. The DNN controller manages power flow in both directions, making it possible to charge electric vehicles (EVs) and discharge power from EVs to the grid with improved efficiency and performance compared to traditional control methods. The non-isolated topology used in this proposal offers several benefits, including reduced cost, smaller size, and higher efficiency. To train the DNN controller, a large dataset of simulations was used, and the results were validated with a hardware setup. The real-time performance of the DNN controller was compared to a proportional-integral (PI) based controller through simulated results. The findings of the study show that the DNN controller outperforms traditional PI controllers.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

United Nations Framework Convention on Climate Change (UNFCCC) has recently established the Reducing Emissions from Deforestation and forest Degradation (REDD+) program that requires countries to report their carbon emissions and sink estimates through national greenhouse gas inventories (NGHGI). Thus, developing automatic systems capable of estimating the carbon absorbed by forests without in-situ observation becomes essential. To support this important need, in this work we introduce ReUse, a simple but effective deep-learning approach to estimate the carbon absorbed by forest areas based on remote sensing. The novelty of the proposed method is in the use of the public above-ground biomass (AGB) data from the European Space Agency's Climate Change Initiative Biomass project as ground truth to estimate the carbon sequestration capacity of any portion of land on Earth using Sentinel-2 images and a pixel-wise Regressive UNet. The approach has been compared to two literature proposals, using a private dataset and human-engineered features. The results show a greater generalization ability of the proposed approach, with a decrease in Mean Absolute Error and Root Mean Squared Error, respectively, of 16.9 and 14.3 in the area of Vietnam and 4.7 and 5.1 in the area of Myanmar over the runner-up. Finally, as a case study, we reported an analysis made for the Astroni area, a nature reserve located near the metropolitan area of Naples in southern Italy, struck by a large fire, producing predictions consistent with values found by experts in the field. These results further support the use of such an approach for the early detection of AGB variations, both in urban and rural areas.

Arf-like protein 2 (ARL2) is a ubiquitously expressed small GTPase with multiple functions. In cell culture, ARL2 participates with tubulin cofactor D (TBCD) in the neogenesis of tubulin αβ-heterodimers, the building blocks of microtubules. To evaluate this function in retina, we conditionally deleted ARL2 in mouse retina at two distinct stages, either during embryonic development (retArl2-/-) or after ciliogenesis specifically in rods (rodArl2-/-). retArl2-/- retina sections displayed distorted nuclear layers and a disrupted microtubule cytoskeleton (MTC) as early as postnatal day 6 (P6). Rod and cone outer segments (OS) did not form. By contrast, rod ARL2 knockouts were stable at postnatal day 35 and revealed normal ERG responses. Cytoplasmic dynein is reduced in retArl2-/- inner segments (IS), suggesting that dynein may be unstable in the absence of a normal MTC. We investigated microtubular stability in the absence of either ARL2 (retARL2-/-) or DYNC1H1 (retDync1h1-/-), the dynein heavy chain, and found that both the retArl2-/- and retDync1h1-/- retinas exhibited reduced microtubules and nuclear layer distortion. The results suggest that ARL2 and dynein depend on each other to generate a functional MTC during early photoreceptor development.

I present an experimental paradigm to explore the interpersonal dynamics generating a collective mind. I hypothesized that collective organization is based on dual interpersonal modes: (1) symmetrical and (2) anti‑symmetrical. I specified the geometric topology of these modes by detecting the spatiotemporal patterns that embed cooperative agents in a three‑dimensional matrix. I found that the symmetrical mode is executed automatically and without guidance. Conversely, the anti‑symmetrical mode required explicit direction and recruited attention for execution. I demonstrate that self‑other mirror‑symmetry stabilized group dynamics, enabled fast and efficient symmetrical imitation that optimized information transmission, whereas anti‑symmetrical imitation was comparatively slow, inefficient, and unstable. I determined that the anti‑symmetrical mode spontaneously transitioned to the symmetrical mode under perturbations. Crucially, this renormalization mechanism never transitioned from symmetrical to anti‑symmetrical. These self-organizing dynamics speak to interpersonal symmetry‑breaking. In the present work, spontaneous group choice mandated that agents synchronize cooperative cycles in symmetrical space under internal or external perturbations. I provide examples to illustrate that this self-regulating pullback attractor manifests in invertebrates and vertebrates alike. I conclude by suggesting that inter‑agent symmetry provides the social stability manifold through which attention-driven interactions enable intrapersonal and interpersonal change.

The aim of this study was to investigate the role of DNA methylation in the regulation of in vitro and in vivo cartilage formation. Based on the data of an RNA chip-assay performed on chondrifying BMP2-overexpressing C3H10T1/2 cells, the relative expression of Tet1 (tet methylcytosine dioxygenase 1), Dnmt3a (DNA methyltransferase 3) and Ogt (O-linked N-acetylglucosamine transferase) genes was examined with RT-qPCR in mouse cell-line based and primary micromass cultures. RNA probes for in situ hybridization were used on frozen sections of 15-day-old mouse embryos. DNA methylation was inhibited with 5-azacytidine during culturing. We found very strong but gradually decreasing expression of Tet1 throughout the entire course of in vitro cartilage differentiation along with strong signals in the cartilaginous embryonic skeleton. Dnmt3a and Ogt expressions did not show significant changes with RT-qPCR and gave weak in situ hybridization signals. Inhibition of DNA methylation applied during early stages of differentiation reduced cartilage-specific gene expression and cartilage formation. In contrast, it had stimulatory effect when added to differentiated chondrocytes. Our results indicate that the DNA demethylation-inducing Tet1 is a significant epigenetic factor of chondrogenesis, and inhibition of DNA methylation exerts distinct effects in different phases of in vitro cartilage formation.

Gut microbiota and its metabolites like short chain fatty acids (SCFAs) are linked with pathology of Alzheimer’s disease (AD)- a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from SCFAs produced by microbiota in the gut. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists, using in-silico library of more than 144,000 natural compounds, and 15 compounds were selected based on binding with FFAR2 agonist sites. Further, cell culture toxicity and FFAR2 stimulatory experiments demonstrated that Fenchol (a natural compound commonly present in basil) was potent FFAR2 agonist in neuronal cells. Interestingly, we also demonstrated that Fenchol protects Aβ-stimulated neurodegeneration in FFAR2 dependent manner. In addition, Fenchol reduced AD like phenotypes such as Aβ-accumulation and, learning and memory behaviors in Caenorhabditis (C.) elegans. Fenchol increased Aβ-clearance by increasing proteasome/lysosome activity and reduced senescence in neuronal cells. These results demonstrated that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while activating it by Fenchol as a natural agonist reverse it by promoting Aβ-clearance and reducing cellular senescence; thus stimulation of FFAR2 signaling can be a therapeutic approach to prevent/ treat AD.

This study aimed to assess the response of 3D printed PLA scaffolds biomimetically coated with apatite on human primary osteoblast spheroids and evaluate the biological response to its association with Bone Morphogenetic Protein 2 (rhBMP-2) in rat calvaria. PLA scaffolds were produced via 3D printing, soaked in simulated body fluid (SBF) solution, and characterized by physical-chemical, morphological, and mechanical properties. The in vitro biological response was assessed with human primary osteoblast (HOb) spheroids. The in vivo analysis was conducted through the implantation of 3D printed PLA scaffolds either alone, covered by apatite (PLA-CaP) or PLA-CaP loaded with rhBMP-2 (PLA-CaP+rhBMP-2) on critical-sized defects (8 mm) of rat calvaria. Increased cell adhesion and in vitro release of growth factors (PDGF, bFGF, VEGF) was observed for PLA-CaP scaffolds when pre-treated with FBS. PLA-CaP+BMP2 presented higher values of newly formed bone (NFB) than other groups at all experimental periods (p&lt;0.05), attaining 44.85% of NFB after 6 months. These findings indicate that functionalization of PLA scaffolds with biomimetic apatite can improve its biological properties in the presence of complex biological media. Its association with BMP2 may enhance bone repair, suggesting this strategy as a promising candidate for bone tissue engineering.

The cyclooxygenase-2 (COX-2) is a potent enzyme that converts arachidonic acid to prostaglandins (PG), including PGE2, a key mediator of inflammation and angiogenesis. Importantly, COX-2 is activated in response to inflammatory stimuli, where it is also believed to promote the development and progression of head and neck cancers (HNC). COX-2 can mediate its protumorigenic effect through various mechanisms such as inducing cell proliferation, inhibition of apoptosis, and suppressing the host’s immune response. Furthermore, COX-2 can induce the production of vascular endothelial growth factors, hence promoting angiogenesis. Indeed, the ability of COX-2 inhibitors to selectively restrict the proliferation of tumor cells and mediating apoptosis provides promising therapeutic targets for cancer patients. Thus, in this comprehensive review, we summarized the reported differential expression patterns of COX-2 in different stages of head and neck carcinogenesis—from potentially premalignant lesions to invasive carcinomas. Furthermore, we examined the available meta-analysis evidence for COX-2 role in the carcinogenesis of HNC. Finally, further understanding of the biological processes of COX-2 and its role in orchestrating cell proliferation, apoptosis and angiogenesis may give therapeutically beneficial insight to develop the management plan of HNC patients and improve their clinical outcomes.

In this paper a full state feedback control of a double inverted pendulum on a cart (DIPC) are designed and compared. Modeling is based on Euler-Lagrange equations derived by specifying a Lagrangian, difference between kinetic and potential energy of the DIPC system. A full state feedback control with H infinity and H 2 is addressed. Two approaches are tested: open loop impulse response and a double inverted pendulum on a cart with full state feedback H infinity and H 2 controllers. Simulations reveal superior performance of the double inverted pendulum on a cart with full state feedback H infinity controller.

The technology-driven world of the 21^st century is currently confronted with a major threat to humankind in the form of the coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of April 22, 2020, COVID-19 has claimed 169, 006 human lives and had spread to over 200 countries with more than 2,471,136 confirmed cases. The perpetually increasing figures associated with COVID-19 are disrupting the social and economic systems globally. The losses are unmatched and significantly higher compared to those from previously encountered pathogenic infections. Previously, two CoVs (SARS-CoV and Middle East respiratory syndrome-CoV) affected the human population in 2002 and 2012 in China and Saudi Arabia, respectively. Based on genomic similarities, animal-origin CoVs, primarily those infecting bats, civet cats, and pangolins, were presumed to be the source of emerging human CoVs, including the SARS-CoV-2. The cohesive approach amongst virologists, bioinformaticians, big data analysts, epidemiologists, and public health researchers across the globe has delivered high-end viral diagnostics. Similarly, vaccines and therapeutics against COVID-19 are currently in the pipeline for clinical trials. The rapidly evolving and popular technology of artificial intelligence played a major role in confirming and countering the COVID-19 pandemic using digital technologies and mathematical algorithms. In this review, we discuss the noteworthy advancements in the mitigation of the COVID-19 pandemic, focusing on the etiological viral agent, comparative genomic analysis, population susceptibility, disease epidemiology, animal reservoirs, laboratory animal models, disease transmission, diagnosis using artificial intelligence interventions, therapeutics and vaccines, and disease mitigation measures to combat disease dissemination.

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is however not expressed in systemic tissues, where there is high-affinity RBP4 binding and ROL uptake. We tested the hypothesis, that the second retinol-binding protein 4 receptor 2 (Rbpr2) which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, that were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatments rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

Enterovirus 71 (EV71) infection hand-foot-mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children, thereby representing a serious public health hazard. It is important to determine the mechanisms underlying the regulation of EV71 infection. In this study, we initially reveal that the interleukin enhancer binding factor 2 (ILF2) down-regulates EV71 50% tissue culture infective dose (TCID50), attenuates EV71 plaque formation unit (PFU), thereby repressing EV71 infection. Moreover, we reveal a distinct mechanism by which EV71 antagonizes ILF2-mediated antiviral effects. Chip data analyses show that ILF2 mRNA is reduced upon EV71 infection. Cellular studies indicate that EV71 infection represses ILF2 mRNA expression and protein production in human leukemic monocytes (THP-1) differentiated macrophages and in human rhabdomyosarcoma (RD) cells. Additionally, EV71 non-structural protein 2B interacts with ILF2 in human embryonic kidney (HEK293T) cells. Interestingly, in the presence of EV71 2B, ILF2 is translocated from the nucleus to the cytoplasm and co-localizes with 2B in the cytoplasm. Therefore, we reveal a distinct mechanism by which EV71 antagonizes ILF2-mediated antiviral effects by inhibiting ILF2 expression and promoting ILF2 translocation from the nucleus to cytoplasm through its 2B protein.

In this article, the effect of substitution of Zr and Ga in Dy2Fe17 prepared by arc melting technique are studied. The substitution of Zr and Ga in Dy2Fe17 was found to have an important effect on their structure and magnetic properties. The Rietveld analysis conformed that the crystalline system wereTh2Ni17 structure. Lattice parameters a (Å) and c (Å), unit cell volume (Å3), bonding distance (Å) were calculated by using Rietveld analysis. The unit cell volume of Dy2Fe17-xZrx and Dy2Fe16Ga1-xZrx increase linearly with the Zr and Ga substitution. The substitution of Zr and Ga are limited up to x=1 in order to avoid the decrease in saturation magnetization. The Curie temperature (Tc) of Dy2Fe17-xZrx and Dy2Fe16Ga1-xZrx are found to be Zr content dependent. The Curie temperature is found to be increasing first and then decrease for higher Zr content. The maximum curie temperature was observed 510K at x = 0.75 for Dy2Fe17-xZrx and 505.1 K at x = 0.5 for Dy2Fe17-xZrx which are102 K and 97 K higher than Dy2Fe17. The room temperature Mössbauer analysis shows the decrease in average hyperfine field and increase in isomer shift with Zr doping.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

G protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5'-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions as well as in the pathology of many diseases including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review deals with the Prostaglandin E receptor EP4, a member of the EP family of GPCR, as a promising newer therapeutic target for treating breast cancer. We show that aberrant over-expression of cyclooxygenase (COX)-2, an inflammation-associated enzyme, occurring in 40-50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune (NK and T) cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis (due to upregulation of VEGF-A), lymphangiogenesis (due to upregulation of VEGF-C/D) and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All these events were primarily mediated by activation of the PGE receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs - miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients, for monitoring SLC-ablative therapies such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents such as PD-1 or PD-L1 inhibitors.

A “watch and wait” strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an in-dependent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p) a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p) the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell’C index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the Integrated Discrimination Improvement (IDI) and the Net Reclassification Index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a bio-logical context to the clinical evidence, a miRNA-mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 Artificial Intelligence (AI) selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

In the symptomatic treatment of gastrointestinal disorders, high dosages of zinc oxide (ZnO) were conventionally employed. However, concerns regarding the potential for microbial resistance and ecological detriment have arisen due to the excessive application of this compound. These concerns highlight the urgency to minimize the use of ZnO and to explore sustainable nutritional solutions. Hydrolysable tannins (HTs), known for their role in traditional medicine for acute gastrointestinal issues, emerge as a promising alternative. This study examined the combined effect of food-grade HTs and lower ZnO concentration on relevant biological functions of Caco-2 cells, a widely used model of the intestinal epithelial barrier. We found that, when used together, ZnO and HTs (ZnO/HTs) enhanced tissue repair and improved epithelial barrier function, normalizing the expression and functional organization of tight junction proteins. Finally, the ZnO/HTs combination strengthened enterocyte defence against oxidative stress induced by inflammation stimuli. In conclusion, combining ZnO and HTs may offer a suitable and practical approach for decreasing ZnO levels in veterinary medical applications.

Neurofibromatosis type 2 (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2-deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2-deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

A growing body of research has identified fetal risk factors associated with adult diseases that form the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. This theory proposes a critical developmental period during which the fetus is highly susceptible to specific environmental influences that significantly impact health from short to long term. Maternal stress and T2DM during pregnancy are among these influences, likely leading to fetal overexposure to glucocorticoids and suggesting a shared pathway between maternal dysregulated HPA axis and fetal environmental insults. Studies demonstrate that prenatal glucocorticoid exposure alters fetal HPA axis function, affecting brain function, tissue glucocorticoid availability, and fetal growth in utero. These programmed changes, such as altered HPA axis function and reduced fetal growth, contribute to metabolic disorders persisting into adulthood. T2DM is preceded by a prediabetic state, often asymptomatic, which shares similar pathophysiological complications with T2DM, including HPA axis dysregulation observed in animals. Therefore, investigating prediabetes during pregnancy alongside maternal HPA axis function and its effects on fetal outcomes is crucial, as these areas remain understudied. This review aims to synthesize existing literature on pre-existing T2DM during pregnancy, its links to fetal programming via HPA axis changes, and possible links to pregestational prediabetes.

Modern organic synthesis is majorly focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-Mass spectroscopy. Major highlights of the reported work include: atom economical process, extremely milder reaction conditions, operational simplicity, high isolated yields, and excellent catalyst turnover number. The molecular docking studies suggest that the compound 4n has the hydrogen bonding, hydrophobic and π-pair interactions with the active site of active sites of CXT M 15 receptor.

The bipartite entanglement is comprehensively investigated in the mononuclear molecular complex (Et3NH)[Ni(hfac)2L], where HL denotes 2-(2-hydroxy-3-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-3-oxide-1-oxyl and hfacH stands for hexafluoroacetylacetone. From the magnetic point of view, the molecular compound (Et3NH)[Ni(hfac)2L] consists of an exchange-coupled spin-1 Ni2+ magnetic ion and a spin-12 nitronyl-nitroxide radical substituted nitrophenol. The nickel-radical molecular complex affords an experimental realization of a mixed spin-(12, 1) Heisenberg dimer with a strong antiferromagnetic exchange coupling J/kB= 505 K and two distinct g-factors gRad=2.005 and gNi=2.275. By adopting this set of magnetic parameters we demonstrate that the Zeeman splitting of a quantum ferrimagnetic ground-state doublet due to a weak magnetic field may substantially reinforce the strength of bipartite entanglement at low temperatures. The molecular compound (Et3NH)[Ni(hfac)2L] maintains sufficiently strong thermal entanglement even at room temperature, vanishing only above 546 K. Specifically, the thermal entanglement in the nickel-radical molecular complex retains approximately 40% of the maximum value corresponding to perfectly entangled Bell states at room temperature, which implies that this magnetic compound provides suitable platform of a molecular qubit with potential implications for room-temperature quantum computation and quantum information processing.

First, an introductory essay is carried out to build a historical, economic-productive and legal theoretical framework of the origin and formation of Secondary Technical Schools in Europe, North America and the Argentine Republic. Then a normative introduction to Technical Education is carried out at the Technical School No. 2 “Independencia” of Concordia, Entre Ríos, Argentine Republic. Its regulations and Laws that govern technical education. We continue analyzing the development of five (5) case studies generated in the E.E.T. No. 2 “Independence” of the city of Concordia, Province of Entre Ríos, Argentine Republic. Case study No. 1: Face masks for Covid-19, designed with CAD-STL software and printed in polylactic acid (PLA) with 3D printers, for protection from SARS-CoV-2 (Coronavirus) or Covid-19. Case study No. 2: TURBO: air extractor/blower for environments contaminated by COVID-19. Case study No. 3: ROBOT-T2: Educational Robot Made by Students and Teachers of the Technical School No. 2 (E.E.T. No. 2) “Independencia”, Concordia, Entre Ríos, Argentine Republic. Case study No. 4: Self-construction EcoBlock, for social housing. Case study No. 5: Relationships of all sciences with abductive thinking, creativity, design, art and the main relationships between Social Sciences (philosophy, logic, hermeneutic research methodology, etc.) with Exact and Natural Sciences (mathematics, physics, chemistry, biology, genetics), other sciences and disciplines such as engineering, medicine, etc. We obtain the conclusions of the development. Bibliography.

Promoting organic foods production and consumption contributes to accomplishing United Nations sustainable development goals. Social commerce provides a promising opportunity to develop the organic food industry. However, there is limited knowledge regarding customer behaviors in relation to purchasing organic foods via social commerce platforms. Therefore, this study expanded upon the unified theory of acceptance and use of technology (UTAUT-2) to develop a comprehensive model that explains how customers' social commerce trust and behavioral intentions to purchase organic foods using Instagram social commerce affect their purchasing behaviors. The research model was analyzed by employing partial least squares structural equation modeling (PLS-SEM) for the data collected from a quantitative survey of 410 customers who used Instagram to purchase organic foods in Iran. The results revealed that facilitated purchasing conditions, hedonic motivations, social influence, rating and reviews, and influencers’ endorsements increase customers' purchase intentions. Moreover, Instagram’s recommendations and referrals, influencers’ endorsements, as well as social influence boost customers' trust in the social commerce platform. Eventually, it was determined that influencers’ endorsements, social commerce trust, and purchase intention determine a customer’s organic foods purchasing behaviors. This research provides valuable insights for organic food marketers to optimize their social commerce strategies.

In ore regions impacted by mining and metal smelting emissions, distinguishing between geogenic anoma-lies and anthropogenic contamination poses a significant challenge. In a study from two areas with different mining histories in the Ore Mountains, Czech Republic, we demonstrate that targeted sampling of topsoils and subsoils respecting local geology and correct soil data treatment respecting soil textural variability effects are indispensable to correctly construct and interpret geochemical maps and identify anthropogenic contam-ination by As, Cu, Pb, and Zn. The list of analysed elements must include both potentially toxic and lithogenic elements, otherwise natural controls of soil composition cannot be deciphered. By using empirical cumulative distribution functions, we found that local backgrounds for As/Fe and Pb/Ti are significantly naturally ele-vated (5.7 to 9.8 times and 2.1 to 2.7 times higher, respectively) compared to the global averages. We con-structed geochemical maps with topsoil minus subsoil concentrations to show the main directions of spreading anthropogenic contamination. The anthropogenic diffuse contamination contribution was calcu-lated (1.12·10-4 and 1.42·10-4 for As/Fe and 16.5·10-4 and 16.2·10-4 for Pb/Ti, respectively), which corresponds to topsoil enrichment by ca. 15 and 14 mg kg-1 for As and ca. 35 and 42 mg kg-1 for Pb in the two study areas. Our study thus provided the first published quantitative estimates of geogenic and anthropogenic contribution to this well-known montane area. The obtained estimates were comparable to the results obtained previously from the local peat archives. The approach we used is efficient in deciphering natural and anthropogenic controls of PTEs in geochemically complicated areas.

The skeletal muscle plays a critical role in regulating systemic blood glucose homeostasis. Impaired skeletal muscle glucose homeostasis associated with type 2 diabetes mellitus (T2DM) has been observed to significantly affect the whole-body glucose homeostasis, thereby resulting in other diabetic complications. T2DM does not only affect skeletal muscle glucose homeostasis, but it also affects skeletal muscle structure and functional capacity. Given that T2DM is a global health burden, there is an urgent need to develop therapeutic medical therapies that will aid in the management of T2DM. Prediabetes is a prominent risk factor of T2DM that usually goes unnoticed in many individuals as it is an asymptomatic condition. Hence, research on prediabetes is essential because establishing diabetic biomarkers during the prediabetic state would aid in preventing the development of T2DM, as prediabetes is a reversible condition if it is detected in the early stages. Literature predominantly documents the changes in skeletal muscle during T2DM, but the changes in skeletal muscle during prediabetes remain unknown. In this review, we seek to review the existing literature on prediabetic and T2DM associated changes in skeletal muscle function.

The particulars of stimulus-response experiments done on dynamic biosystems clearly limit what one can learn and validate about their structural interconnectivity (topology), even when collected kinetic output data are perfect (noise-free). As always, available access ports and other data limitations rule. For linear systems, exponential modes, visible and hidden, play an important role in understanding data limitations, embodied in what we call dynamical signatures in the data. We show here how to circumscribe and analyze modal response data in compartmentalizing model structures – so that modal analysis can be used constructively in systems biology model building – for nonlinear (NL) as well as linear biosystems. We do this by developing and exploiting the modal basis for dynamical signatures in hypothetical (perfect) input-output data associated with a structural model – one that includes inputs and outputs explicitly – and for NL as well as linear biosystems. The methodology establishes model dimensionality (size, complexity) from particular data sets; helps select among multiple candidate models (model distinguishability); helps in designing new experiments to extract “hidden” structure; and helps to simplify (reduce) models to their essentials. For NL biosystems, results are not as comprehensive, similarly informative about their dominant dynamical properties, and unified with linear models on invariant 2-dimensional manifolds in phase space. Some automation of these highly technical aspects of biomodeling is also introduced.

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany and the retraction of phenformin (N-Phenethylbiguanide) because of the letal complication of acidosiss,metformin (1-1-dimethylbiguanide) was first released in France in 1959 and then in the USA in 1995 for oral treatment of diabetes type 2. Acute gastrointestinal side effects often lead to dose reduction and strongly limit adherence to therapy.Main long-term consequences are deficency of vitamin B12 and of iron and sometimes also acidosis development. Intravenously injected F18-labelled glucose in metformin-treated type 2 diabetics accumulates in the the small and even more in the large intestine.The densitometry picture observed in metformin-treated diabetics is similar to that observed in patients after bowel-cleansing or chronically taking different types of laxatives where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to „attraction“ of glucose from the hepatocyte to the intestine,possibly through its secretion into the bile.Metformin is not different from the other biguanides ,synthalin B and phenformin.The mechanism of action,and the side effects are comparable to those of laxatives.

Proteomics in respiratory allergic diseases has such a battery of techniques and programs that one would almost think that there is nothing impossible to find, invent or mold. All these resources that we document here, are involved in solving problems in allergic diseases, both diagnostic, prognostic, treatment and immunotherapy development. The main perspectives, according to this version, are in three strands and / or lockout immunological system: 1) In blocking the diapedesis of cells involved, 2) modifications and blocking of paratopes and epitopes being understood by modifications to antibodies, antagonism or blocking them and 3) blocking FcεR1 receptors to prevent specific IgEs from sticking to mast cells and basophils. These tools and targets in the allergic landscape are, in our view, the prospects in the field.

The effect of the antioxidant vitamin C in cancer has been studied for over 30 years with conflict-ing results ranging from total absence of effect, to possible protective effect, to potential therapeutic effect when administered in high doses. The aim of the study was to define the effect of vitamin C in breast cancer and the possible involvement of sphingomyelin metabolism. Therefore, the effect of low and high dose of vitamin C on cells reproducing luminal A type (MCF7) and triple negative type (MB231) of breast cancer was analyzed. The results showed that high dose of vitamin C produced effects only in MCF7 cells such as decreased cell viability, modulation of cell cycle re-lated genes, unexpected change in cell phenotype due to estrogen receptor downregulation, catabo-lism of sphingomyelin with a large increase in ceramide. In conclusion, we demonstrated that high doses of VitC on the one hand reduce the growth of lu-minal A type breast cancer cells and on the other hand induce their phenotypic change towards hormone therapy resistant cells. The effect of vitamin C on therapeutic treatment failure of luminal A breast cancer and the possible involvement of high ceramide levels were discussed.

This paper presents an innovative testing framework, testFAILS, designed for the rigorous evaluation of AI Linguistic Systems, with a particular emphasis on various iterations of ChatGPT. Leveraging orthogonal array coverage, this framework provides a robust mechanism for assessing AI systems, addressing the critical question, "How should we evaluate AI?" While the Turing test has traditionally been the benchmark for AI evaluation, we argue that current publicly available chatbots, despite their rapid advancements, have yet to meet this standard. However, the pace of progress suggests that achieving Turing test-level performance may be imminent. In the interim, the need for effective AI evaluation and testing methodologies remains paramount. Our research, which is ongoing, has already validated several versions of ChatGPT, and we are currently conducting comprehensive testing on the latest models, including ChatGPT-4, Bard and Bing Bot, and the LLaMA model. The testFAILS framework is designed to be adaptable, ready to evaluate new bot versions as they are released. Additionally, we have tested available chatbot APIs and developed our own application, AIDoctor, utilizing the ChatGPT-4 model and Microsoft Azure AI technologies

Advanced MRI methods and PET using radiolabeled amino acids provide valuable information in addition to conventional MR imaging for brain tumor diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumor progression from treatment-related changes, and the early assessment of response to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumors. PET is only required in equivocal situations, and spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumors compared with a single modality. This systematic review focuses on studies that were able to demonstrate the additive value of amino acid PET and ‘advanced’ MRI in the diagnosis of brain tumors. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterization of newly diagnosed tumors. However, data concerning the delineation of tumor extent and biopsy guidance are of limited value. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumor recurrence from treatment-related changes. Here, PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of brain tumors, for which hybrid PET/MRI offers optimal conditions.

Vascular calcification (VC) is associated with increased cardiovascular risks in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors, like empagliflozin, can improve cardiovascular and renal outcomes. We assessed the expression of Runt-related transcription factor 2 (Runx2), interleukin (IL)-1β, IL-6, AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase 1 (HO-1) in inorganic phosphate–induced VC in mouse VSMCs to investigate the mechanisms underlying empagliflozin’s therapeutic effects. We evaluated biochemical parameters, mean artery pressure (MAP), pulse wave velocity (PWV), transcutaneous glomerular filtration rate (GFR), and histology in an in vivo mouse model with VC induced by an oral high-phosphorus diet following a 5/6 nephrectomy in ApoE−/− mice. Compared to the control group, empagliflozin-treated mice showed significant reductions in blood glucose, MAP, PWV, and calcification, as well as increased calcium and GFR levels. Empagliflozin inhibited osteogenic trans-differentiation by decreasing inflammatory cytokine expression and increasing AMPK, Nrf2, and HO-1 levels. Empagliflozin mitigates high phosphate–induced calcification in mouse VSMCs through the Nrf2/HO-1 anti-inflammatory pathway by activating AMPK. Animal experiments suggested that empagliflozin reduces VC in CKD ApoE−/− mice on a high-phosphate diet.

This study is the first report of the successful cultivation of Dinophysis norvegica isolated from Japanese coastal waters (7 of 48 isolated cells were established as the clonal cultures, 14.5%) and their toxin content and production. The strains were maintained at relatively high abundance (>2,000 cells mL-1) for more than one year when fed on Mesodinium rubrum with the addition of Teleaulax amphioxeia. At the end of the one-month incubation, the total amounts of pectenotoxin-2 (PTX2), dinophysistoxin-1 (DTX1) and okadaic acid (OA) were 132.0-375.0 ng mL-1 (n = 7), 0.7-3.6 ng mL-1 (n = 3) and trace level OA (n = 1), respectively. Similarly, the cell quota of PTX2 and DTX1 were 60.6-152.4 pg cell-1 (n = 7) and 0.5-1.2 pg cell-1 (n = 3), respectively. These data indicated that toxin production varies depending on the strains in this species. In the growth experiment, D. norvegica grew, but it was very slow first 12 days. However, after that they grew exponentially with the maximum growth rate of 0.56 divisions day-1 (during Day 24-27), reaching a maximum concentration of 3,000 cells mL-1 at the end of incubation (Day 36), suggesting that they have a long lag phase. In the toxin production, OA was not at a detectable level (≤ 0.010 ng mL-1) during the 36 days of incubation except for Day 6. The concentration of DTX1 and PTX2 showed similar patterns as described for vegetative growth, but the toxin production still increased on Day 36 (1.3 ng mL-1 and 154.7 ng mL-1 in DTX1 and PTX2, respectively). The findings of this study provide novel information on the toxin content and production in D. norvegica as well as details on the culturing and maintenance of the species.

In an era of rapid technological improvements, state-of-the-art methodologies and tools dedicated to protecting and promoting our cultural heritage should be developed and extensively employed in the contemporary built environment and lifestyle. At the same time, sustainability principles underline the importance of the continuous use of historic or vernacular buildings as part of the building stock of our society. Adopting a holistic, integrated, multi-disciplinary strategy can bridge technological innovation with conserving and restoring heritage buildings. The paper presents ongoing research and results of the application of Machine Learning methods for the remote monitoring of the built environment of the historic cluster in Cypriot cities. This study is part of an integrated, multi-scale, and multi-discipline study of heritage buildings towards the creation of an online HBIM platform for urban monitoring.

Advances in nanomedicine bring the attention of researchers to the molecular targets which can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide on the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby the recent advances in the field of applications of various nanoplatforms which are able to reach the GRPR expressing cells are reviewed.

Fire regimes in mountain landscapes of southern Europe have been shifting from their baselines due to the accumulation of fuel fostered by long-standing rural abandonment and fire exclusion policies. Understanding the role of fire on biodiversity is paramount to implement adequate management to mitigate the impacts of altered fire regimes and land abandonment on biodiversity. Here, we explored to what extent the spatiotemporal variation in burn severity has affected bird abundance of a mountain abandoned landscape located in the Atlantic-Mediterranean transition (NW Iberia). We took advantage of: (1) satellite images of Sentinel 2 and Landsat missions to compute burn severity indicators from 2010 to 2020, and (2) standardized bird surveys carried out over 206 point-counts along the breeding season of 2021. Bird abundance models were built from burn severity metrics together with well-known fire regime attributes (% of burnt area and time since fire). Our results showed that the spatiotemporal variation of burn severity significantly correlated with the abundance of the 39% of the modeled species, supporting the role of pyro-diversity in driving bird populations in our region. The burnt area also explained abundance patterns for 28% of species. Time since fire only correlated with the abundance of 3 species. Our findings confirm the importance of incorporating burn severity indicators into the toolkit of decision makers to anticipate the response of birds to fire management.

The main functions of the automated systems rely on the advanced sensors for detection and perception of the environment around the vehicle. Radars and cameras are commonly utilized to detect the potential obstacles and vehicles ahead on the road. Nevertheless, cameras can generate spurious detections in the extreme weather conditions such as fog, rain, dust, snow, dark, and heavy sunlight in the sky. Due to limitations in vertical field view of the radars, single radars are not reliable to detect the height of the targets precisely. In this paper, a triple radar arrangement (long-range, medium-range, and short-range radars) based on sensor fusion technique is proposed to detect objects with different size in level 2 Advanced Driver-Assistance (ADAS) system. The typical objects including truck, pedestrians, and animals are detected in different scenarios. The developed model considered ISO 26262 and ISO/PAS 21448 to reasonably address insufficient robustness and inability of the sensors. The models of sensor and level 2 ADAS systems are developed using MATLAB toolbox and Simulink. Sensor detection performance is determined by running simulations with triple radar setup. Obtained results demonstrate that the proposed approach generates accurate detections of targets in all tested scenarios.

Large population passages of the SARS-CoV-2 in the past two and a half years have allowed the circulating virus to accumulate an increasing number of mutations in its genome. The most recently emerging Omicron subvariants have the highest number of mutations in the Spike (S) protein gene and these mutations mainly occur in the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the S gene. The eCDC and the WHO recommend partial Sanger sequencing of the SARS-CoV-2 S gene RBD and NTD on the PCR-positive samples in diagnostic laboratories as a practical means of determining the variants of concern to monitor a possible increased transmissibility, increased virulence, or reduced effectiveness of vaccines against them. The author’s diagnostic laboratory has implemented the eCDC/WHO recommendation by sequencing a 398-base segment of the N gene for the definitive detection of SARS-CoV-2 in clinical samples, and sequencing a 445-base segment of the RBD and a 490-509-base segment of the NTD for variant determination. This paper presents 5 selective cases to illustrate the challenges of using Sanger sequencing to diagnose Omicron subvariant when the samples harbor a high level of co-existing minor subvariant sequences with multi-allelic single nucleotide polymorphisms (SNPs) or possible recombinant Omicron subvariants containing a BA.1 NTD and a BA.2 RBD, which can only be detected by using specially designed PCR primers. The current large-scale surveillance programs using next-generation sequencing (NGS) do not face similar problems because NGS focuses on deriving consensus sequence.

Lung cancer is a common malignant tumor of the lung and the leading cause of cancer mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80%–85% of lung cancer, 40% of NSCLCs will have spread beyond the lungs by the time it is diagnosed. Long non-coding RNA (LncRNA) prostate androgen-regulated transcript 1 (PART-1) was reported that promote the development of several cancers. In the current study, we conducted experiments to investigate the role of PART-1 in the proliferation, invasion, and migration of NSCLC. The expression level of the PART-1 gene increased significantly in the NSCLC cell lines, including A549, H1229, H1650, H1975, and PC9. Knocking down of PART-1 inhibited the proliferation, invasion, and migration of A549 cells, moreover, decreased the tumor proliferation in nude mice. We confirmed that PART-1 targeted miR-204-3p directly, and miR-204-3p targeted the insulin-like growth factor binding protein 2 (IGFBP-2) directly. Furthermore, we discovered that PART-1 involved the NSCLC progression by regulating the miR-204-3p-targeted IGFBP-2 pathway. LncRNA PART-1 might be a target for treating NSCLC, and a warning sign of diagnosis of early lung cancer.

Forest degradation is known to be widespread in the tropics, but is currently very poorly mapped, in part because there is little quantitative data on which satellite sensor characteristics and analysis methods are best at detecting it. To improve this, we used data from the Tropical Forest Degradation Experiment (FODEX) plots in the southern Peruvian Amazon, where different numbers of trees had been removed from four 1 ha forest plots, carefully inventoried by hand and Terrestrial Laser Scanning before and after the logging to give a range of biomass change (ΔAGB) values. We conducted a comparative study of six multispectral optical satellite sensors (WorldView-3, SkySat, SPOT-7, PlanetScope, Sentinel-2 and Landsat 8) at 0.3 – 30 m spatial resolution, to find the best combination of sensor and remote sensing indicator for change detection. Spectral reflectance, the Normalized Difference Vegetation Index (NDVI) and texture parameters were extracted after radiometric calibration and image preprocessing. The strength of the relationships between the change in these values and field-measured ΔAGB (computed in % ha−1) was analysed. The results demonstrate that: (a) texture measures correlates more with ΔAGB than simple spectral parameters; (b) the strongest correlations are achieved for those sensors with spatial resolutions in the intermediate range (1.5 - 10 m), with finer or coarser resolutions producing worse results, and (c) when texture is computed using a moving square window ranging between 9 - 14 m in length. Maps predicting ΔAGB showed very promising results using a NIR-derived texture parameter for 3 m resolution PlanetScope (R2 = 0.97 and RMSE = 1.80 % ha−1), followed by 1.5 m SPOT-7 (R2 = 0.74 and RMSE = 5.25 % ha−1) and 10 m Sentinel-2 (R2 = 0.71 and RMSE = 5.55 % ha−1). Texture models derived from 0.3 m WorldView-3 improved with increasing window size, with highest R2 of 0.62 and RMSE = 6.35 % ha−1 for a window of 14 m in length. The degradation in our field plots is invisible to the 30 m resolution Landsat data. Our findings imply that, at least for lowland Peru, low-medium intensity disturbance can be detected best in optical wavelengths using a texture measure derived from 3 m PlanetScope data. That such data are being collected daily, and currently released free as monthly mosaics over tropical forests as part of the Norway’s International Climate and Forest Initiative (NICFI), is excellent news for monitoring such degradation.

Gene expression variations of plant leaf are investigated by irradiating seed and leaf with oxygen or air plasmas. Enhancement of leaf growth is induced by oxygen plasma irradiation on seeds, which is supported by increased gene expression for protein synthesis, oxidative-reduction reactions and decreased gene expression concerning DNA methylation and histone modification. Suppression of leaf growth is observed by the oxygen plasma, which would be owing to increased gene expression concerning heat shock protein and redox reaction, and decreased expression of photosynthesis and glycoprotein. Also, gene expression variation due to air plasma irradiation is almost same as that of oxygen plasma. Active oxygen species are major factors in both oxygen and air plasmas for the variation of gene expressions in plant.

The presented study demonstrates the bi-sensor approach suitable for rapid and precise up-to-date mapping of forest canopy gaps for the larger spatial extent. The approach makes use of UAV RGB images on smaller areas for highly precise forest canopy mask creation. Sentinel-2 was used as a scaling platform for transferring information from UAV to a wider spatial extent. The various approaches of the improvement of the predictive performance were examined: (I) the highest R2 of the single satellite index was up to 0.57, (II) the highest R2 using multiple features obtained from the single date, S-2 image was 0.624 and, (III) the highest R2 on the multi-temporal set of S-2 images, was 0.697. Satellite indices such as ARVI, IPVI, NDI45, PSSRa, MCARI, CI, RI, and NDTI were the dominant predictors in most of the ML algorithms. The more complex ML algorithms such as SVM, Random Forest, GBM, XGBoost, and Catboost that provided the best performance on the training set exhibited weaker generalization capabilities. Therefore, a simpler and more robust Elastic Net algorithm was chosen for the final map creation.

Despite the publication in 2009 of a paper on ‘terms and definitions of immune thrombocytopenia’, (ITP) some unresolved issues remain and are reflected by the disagreement in the treatment suggested for primary ITP in adults. Considering that these disagreements could be ascribed to non-shared goals, a ‘consensus’ to classify the different lines of treatment for primary ITP in adults according to their indications and goals was proposed in October 2018 to the XIX annual meeting of the Italian Gruppo di Studio delle Piastrine (GSP), a non-profit platelet study group of scientists and physicians. Having approved the project, 60 potential co-authors and experts in the world were invited to take part to a consensus through e-Delphy method and nine of the 12 who initially accepted the invitation completed the work. Agreement was reached on a classification of four lines of treatment for primary ITP in adults based on their indications and goals. The consensus obtained regarded also the criteria, ‘timing’ included, to consider practicable elective splenectomy in these patients. In our opinion, the classification of the lines of treatment for primary ITP in adults here proposed could facilitate the realization of better shared evidence-based guidelines for the treatment of the disease.

Trichoderma atroviride is a strong necrotrophic mycoparasite antagonizing and feeding on a broad range of fungal phytopathogens. It further beneficially acts on plants by enhancing growth in root and shoot and inducing systemic resistance. Volatile organic compounds (VOCs) are playing a major role in all those processes. To date, T. atroviride IMI 206040 and T. atroviride P1 are among the most frequently studied T. atroviride strains and hence are used as model organisms to study mycoparasitism and photoconidiation. However, there are no studies available, which systematically and comparatively analyzed putative differences between these strains regarding their light-dependent behavior. We therefore explored the influence of light on conidiation and the mycoparasitic interaction as well as the light-dependent production of VOCs in both strains. Our data show that in contrast to T. atroviride IMI 206040 conidiation in strain P1 is independent of light. Furthermore, significant strain-and light-dependent differences in the production of several VOCs between the two strains became evident, indicating that T. atroviride P1 could be a better candidate for plant protection than IMI 206040.

Porcine circovirus type 2 (PCV2) is a small non-enveloped DNA virus that causes swine immunosuppression by inducing apoptosis in lymphocytes. The ORF3 protein plays a major role in PCV2-induced apoptosis in porcine kidney cells, but there is little information regarding this protein in PCV2-infected lymphocytes. In this study, hybridoma screening and epitope mapping were determined by using an indirect ELISA. The mAb 7D3 against ORF3 peptide (residues 35–65) of PCV2 were generated in this study. In vivo situation, the mAb 7D3 recognized ORF3 protein existed in PCV2-infected apoptotic porcine PBMCs. It is noteworthy that thimerosal interfered with the binding of mAb 7D3 to epitope and it was diminished by adding cysteine. Additionally, thimerosal interacting with cysteine-containing peptide was demonstrated by the PTI assay. Furthermore, thimerosal specifically interacted with the antigen-binding sites of mAb 7D3. This study suggested that thimerosal blockade the occlusion of the antigen-binding sites of mAb 7D3 to bind ORF3 peptide (residues 35–65) via thimerosal interacting with cysteine residues which should be located within the antigen-binding sites of mAb 7D3. Overall, the mAb 7D3 has been characterized and it will be a valuables tool in future studies of ORF3 function and the wider mechanism of cell apoptosis caused by PCV2 infection. Similarly, these techniques will be useful for applications in detecting thimerosal too.

A Multicomponent Reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS₂ in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained, ensures postmodifications in view of N-bridgedheaded heterobicyclic structures.

Detection of PLA2R and THSD7A among primary membranous glomerulonephritis (MGN) patients transformed the diagnosis, treatment monitoring and prognosis. Anti-PLA2R can be detected in 70-90% of primary MGN patients while anti-THSD7A in 2-3% of anti-PLA2R negative primary MGN patients depending on the technique used. Serum and urine samples are less invasive and non-invasive respectively and can detect the presence of anti-PLA2R and anti-THSD7A with higher sensitivity and specificity, significant in patients’ monitoring and prognosis better than exposing patients to frequent biopsy which is an invasive procedure. Different techniques of detection of PLA2R and THSD7A in patients’ urine and sera were reviewed with the aim of providing newer and alternative techniques. We proposed the use of biomarkers (PLA2R and THSD7A) in making the diagnosis, treatment decision and follow up of patients with primary MGN. We also reviewed other prognostic renal biomarkers like retinol binding protein (RBP) and beta-2 microglobulin in order to detect progression of renal damage for early intervention.

Structure-based design and synthesis of two biphenyl-N-acyl-β-D-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.

FoxP3 is a transcription factor essential for the differentiation and function of T regulatory cells (Tregs). There are two major subsets of Tregs: natural Tregs (nTregs) generated in thymus and inducible Tregs (iTregs) produced in peripheral immune system. It has been documented that iTreg development is dependent on soluble mediators including interleukin 2 (IL2), transforming growth factor β (TGFβ) and all-trans-retinoic acid (ATRA). In our experiments we performed a gene expression array, followed by Real-time PCR experiments, to study the expression of genes regulated by 1,25-dihydroxyvitamin D (1,25D) or ATRA in cells of myeloid origin. Our experiments revealed that ATRA alone, but also a cocktail of mediators consisting of IL2, TGFβ and ATRA, upregulate the expression of FOXP3 gene in lymphoid cells, but also in normal and leukemic myeloid cells. The FoxP3 expression is followed by a phenotypic changes in cells of myeloid origin. Our results indicate that signaling pathways which are used in the late stages of T cell differentiation, are also active in the cells of myeloid lineage

Studies comparing provider and patient views and experiences of self-management within primary healthcare are particularly scarce in disadvantaged settings. In this qualitative study, patient and provider perceptions of self-management were investigated in five socio-economically disadvantaged communities in Stockholm. Twelve individual interviews and three group interviews were conducted. Semi-structured interview guides included questions on perceptions of diabetes diagnosis, diabetes care services available at primary health care centers, patient and provider interactions, and self-management support. Data was analysed using thematic analysis. Two overarching themes were identified. These were characterized by inherent dilemmas representing confusions and conflicts that patients and providers experienced in their daily life or practice respectively: adopting and maintaining new routines through practical and appropriate lifestyle choices (patients); and balancing expectations and pre-conceptions of self-management (providers). Patients found it difficult to tailor information and lifestyle advice to fit their daily life. Healthcare providers recognized that patients were in need of support to change behavior, but saw themselves as inadequately equipped to deal with the different cultural and social aspects of self-management. This study highlights patient and provider dilemmas that influence the interaction and collaboration between patients and providers with respect to communication and uptake of self-management advice.

This study presents a vibration control using actively tunable vibration absorbers (ATVA) to suppress vibration of a thin plate. The ATVA’s is made of a sandwich hollow structure embedded with the electrorheological fluid (ERF). ERF is considered to be one of the most important smart fluids and it is suitable to be embedded in a smart structure due to its controllable viscosity property. ERF’s apparent viscosity can be controlled in response to the electric field and the change is reversible in 10 microseconds. Therefore, the physical properties of the ERF-embedded smart structure, such as the stiffness and damping coefficients, can be changed in response to the applied electric field. A mathematical model is difficult to be obtained to describe the exact characteristics of the ERF embedded ATVA because of the nonlinearity of ERF’s viscosity. Therefore, a fuzzy modeling and experimental validations of ERF-based ATVA from stationary random vibrations of thin plates are presented in this study. Because Type-2 fuzzy sets generalize Type-1 fuzzy sets so that more modelling uncertainties can be handled, a semi-active vibration controller is proposed based on Type-2 fuzzy sets. To investigate the different performances by using different types of fuzzy controllers, the experimental measurements employing type-1 fuzzy and interval type-2 fuzzy controllers are implemented by the Compact RIO embedded system. The fuzzy modeling framework and solution methods presented in this work can be used for design, performance analysis, and optimization of ATVA from stationary random vibration of thin plates.

(1) Background: Adverse childhood experiences (ACEs) and positive childhood experiences (PCEs) have potential to impact long-term health outcomes. Understanding these interrelationships can inform the development of interventions to promote societal health (2) Methods: D/PMH was defined as a diagnosis of depression and/or more than 14 days of poor mental health in the previous month. Those reporting poor physical health for more than 14 days in the previous month or categorising their physical health as ‘fair’ or ‘poor’ were deemed to have PG/PPH. Seven categorical questions based on subscales in the Child and Youth Resilience Measure-28 were used to define PCEs.(3) Results: Increased ACEs exposure use significantly associated with increased odds of D/PHM (p&lt;0.001), increased odds of PG/PHH (p=0.010) and decreased odds of AR-SES (p&lt;0.001). Increased exposure to PCEs was significantly associated with decreased odds of D/PHM (p&lt;0.001), increased odds of PG/PHH (p&lt;0.001) and decreased odds of AR-SES (p&lt; 0.001). For all outcomes, exposure to PCEs reduced the strength of the association between ACEs and outcomes. (4) Conclusions: A positive dose response between the number of ACEs and adult D/PMH, PG/PPH and lower AR-SES exists within the Australian population. PCEs weaken this association, demonstrating their mitigating potential. PCEs promoted adult outcomes, irrespective of ACEs.

This strategy had a very fast and good impact on the patient’s health; the CCM improved heart failure symptoms, hemodynamics flow and cardiac functionality. Moreover, after a relatively short time, the patient comes from persistent AF to Sinus Rhythm, although he starts with a severe bi-atrial dilatation. These parameters were stable during an extended follow-up of 18 months.

Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 x 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 x 2.633 Gy (41.6 Gy10) or 18 x 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score adjusted Cox regression) to a historical control group (N=266) receiving 10 x 3.0 Gy (32.5 Gy10). In the phase 2-cohort, 50 (of 62 planned) patients were evaluable for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 x 2.633 Gy or 18 x 2.333 Gy was well tolerated and appeared superior to 10 x 3.0 Gy.

A heterograft copolymer with an alginate backbone, hetero-grafted by polymer pendant chains displaying different Lower Critical Solution Temperatures (LCSTs), combined with a pH-responsive Poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) diblock copolymer forming micellar nanoparticles, was investigated in aqueous media at various pH. Due to its thermoresponsive side chains, the copolymer forms hydrogels with thermo–induced sol–gel transition, above a critical temperature, Tgel (thermo–thickening). However, by lowering pH of the medium in acidic regime, a remarkable increase of the elasticity of the formulation was observed. This effect was more pronounced in low temperatures (below Tgel) suggesting secondary physical crosslinking, which induces significant changes in the hydrogel thermoresponsiveness, transforming the sol–gel transition to soft gel–strong gel. Moreover, the onset of thermothickening shifted to lower temperatures followed by broadening of the transition zone, implying intermolecular interactions between the uncharged alginate backbone with the PNIPAM side chains, likely through H–bonding. The shear–thinning behavior of the soft gel in low temperatures provides injectability, which allows 3D–printing potential applications. Furthermore, the heterograft copolymer/nanoparticles composite hydrogel, encapsulating a model hydrophobic drug in the hydrophobic cores of the nanoparticles, was evaluated as pH-responsive drug delivery system. The presented tunable drug delivery system might be useful for biomedical potential applications.

This work presents noble composites of AAILs@MCM-48 by functionalizing ordered mesopo-rous silicon MCM-48 with two amino acid-based ionic liquids (AAILs) ([Emim][Gly] and [Em-im][Ala]) to improve carbon capture and selectivity of CO2 over nitrogen. Thermogravimetric and XRD analyses of the composites show that the MCM-48 support's thermal and structural in-tegrity was preserved after the AAILs were encapsulated. An N2 adsorption-desorption study at 77 K also confirms AAIL encapsulation in the porous support. Under post-combustion flue gas conditions, both [Emim][Gly]@MCM-48 and [Emim][Ala]@MCM-48 demonstrated improved CO2 adsorption in comparison to unmodified MCM-48, with a CO2 partial pressure of around 0.15 bar. In terms of maximal CO₂ uptake, the 40wt%-[Emim][Gly] composite outperformed the others at 303K, with values of 0.74 and 0.82 mmol g-1, respectively, at 0.1 and 0.2 bar. These numbers show a 10x and 5x increase, respectively, as compared to the pure MCM-48 under iden-tical conditions. In addition, the selectivity of the composites was improved significantly, at 0.1 bar, the selectivity of composites containing 40wt% [Emim][Ala] increased to 17, compared to 2 for pristine MCM-48.

Candidiasis is one of the global public health problems. In fluconazole resistant Candida spp. (FRCS), mutations in ergosterol biosynthesis gene 11 (ERG 11) have been commonly found. This study aimed to determine the profile of FRCS isolates and to detect mutations in part of ERG 11 gene in fluconazole resistant Candida albicans (FRCA) isolates. Study was conducted on 150 isolates of FRCS obtained from patients admitted in a tertiary care hospital, South India from September 2019 to December 2021. Candida spp. was identified by MALDI-TOF MS and fluconazole resistance was detected by VITEK 2 system. Following which a part of the ERG 11 gene of the FRCA isolates were amplified, purified, sequenced and a phylogenetic tree was constructed. Out of the 150 FRCS, the most common FRCS was C. auris followed by C. glabrata, C. krusei, C. parapsilosis, C. albicans, C. tropicalis and C. guilliermondii. Sequencing of amplicons detected a single missense mutation and 44 silent mutations. We opined that fluconazole resistance in FRCA isolates may be due to mecha-nisms other than the studied one in our region. Phylogenetic analysis of amplified sequences of 12 FRCA isolates observed three clusters and all 12 sequences showed relatedness to Malaysian 2019 isolates.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to the epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancers types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer, however, there have been strong advancements made in the incorporation of anti HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since, its ground breaking discovery there has been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

This paper presents a) the novel hybrid learning method to train the type-1 non-singleton interval type-3 (IT3) fuzzy logic systems (IT3 NSFLS-1) and b) the novel method named enhanced Wagner-Hagras (EWH) IT3 NSFLS-1 fuzzy systems which includes the level alpha 0 output to calculate the output y alpha using the average of the outputs y alpha k instead of their weighted average. The development of the proposed methodology uses the orthogonal least square (OLS) method to train the consequent parameters and the back propagation (BP) method to train the antecedent parameters. This proposal dynamically changes the parameters of only the level alpha 0 minimizing some criterion function as new information becomes available to each level alpha k. The antecedent sets are type-2 fuzzy sets, the consequent sets are fuzzy centroids, the inputs are type-1 non-singleton fuzzy numbers with uncertain standard deviations, and the secondary membership functions are modeled as two Gaussians with uncertain standard deviation and the same mean. Based on the firing set of the level alpha 0, the proposed methodology calculates each firing set of each level alpha k to dynamically construct and update the EWH IT3 NSFLS-1 (OLS-BP) system. The algorithm was tested in a hot strip mill facility to predict the transfer bar surface temperature showing its superior capability to obtain the industrial pyrometer’s knowledge uncertainty for tuning and its better performance when compared with IT2 SFLS, IT2 NSFLS-1, GT2 SFLS, GT2 NSFLS-1, IT3 SFLS, and IT3 NSFLS-1 trained with the BP-BP algorithm.

Abstract: Astrocytes (ACs) are the most abundant human cell in the brain and importantly, are the master connecting and communicating cells that provide structural and functional support of brain cells at all levels of organization. Further, they are recognized to be the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste and comprise the glymphatic system, which is critically dependent on the proper waste removal by the pvACef polarized aquaporin 4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role for synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI) and associate with white matter hyperintensities, lacunes, aging, accepted to be biomarkers for cerebral small vessel disease, increased in obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

Biofilm formation and lipopolysaccharide (LPS) are implicated in the pathogenesis of gastrointestinal (GI) diseases caused by Gram-negative such as Escherichia coli and Salmonella enterica serovar Typhimurium. Grape seeds, wine industry by-products, have antioxidant, antimicrobial, and anti-inflammatory activities. In the present study, the protective effect of procyanidin-rich grape seed extract (prGSE), from unfermented pomace of Vitis vinifera cv Bellone, on bacterial LPS-induced oxidative stress and epithelial barrier integrity damages has been studied in a model of Caco-2 cells. The in vitro activity of prGSE against formation of biofilm of S. Typhimurium and E. coli, has been investigated. In vivo, prGSE activity using infected Galleria mellonella larvae has been evaluated. The results showed that the prGSE, if administered with LPS, can significantly reduce the LPS-induced permeability alteration. Moreover, the ability of the extract to prevent Reactive Oxygen Species (ROS) production induced by LPS treatment of Caco-2 cells has been demonstrated. prGSE inhibited the biofilm formation of E. coli and S. Typhimurium. In in vivo activity, increased survival of infected G. mellonella larvae after treatment with prGSE has been demonstrated. In conclusion, grape seed extracts could be used in the reduction of GI damage caused by bacterial endotoxin and biofilm of Gram-negative bacteria.

Animal-assisted pedagogy (AAP) is well known in classroom practice, but scientific evidence is still lacking. At the same time, the biggest challenge in education systems worldwide is the social in-tegration of students. In a pre-post design, 30 heterogeneous students (16f/14m) from four different school classes (grades 5-7) were interviewed (problem-centred interview) about their social inclu-sion and their social climate in class before and after being taught selected subjects with a school dog (of different breeds) for one school term. At the second measurement point, they were also asked about their perception of AAP. The data was analysed both qualitatively (Kuckartz) and in terms of the number of quotes on the main topics using MAXQDA analysis software. The presence of a dog in the classroom leads to an improved social climate and more social integration. In ad-dition, the perception of the other students and the teacher changes to a more positive and friendly image. Through AAP, a new social role is added to the classroom, where caring and bonding are prioritised. Social interaction and norms are influenced and sterotypical and individual roles can be changed. Therefore, AAP can be a key to promoting social inclusion in the school environment.

Forests, integral to human civilization, hold immense value and play a vital role in maintaining ecological harmony. Despite India's goal of extensive forest coverage, significant progress is still needed. Uncontrolled forest fires pose a severe threat, particularly in Uttarakhand's Pauri Garhwal district. To address this challenge, a comprehensive study examined surface and subsurface hydrological factors influencing the forest fire occurrences, such as elevation, aspect, slope, vegetation, proximity to human settlements, proximity to waterbodies, Active faults and lineament density. A total of 15 such factors were integrated with advanced techniques of remote sensing and GIS and coupled with historical fire data to create a precise forest fire risk map using the support vector machine algorithm. Forest fire risk map was classified into 5 distinct risk zones, Very High Risk (47.38 Km2), High Risk (275.98 km2, Moderate Risk (985.49 km2), Low Risk (1741.17 km2) and Very Low Risk (2374.11 km2) aiding in proactive fire management. By embracing this innovative tool, decision-makers can protect forests, preserve biodiversity, and ensure a sustainable future for generations to come.

The process of anaerobic digestion used for methane production can be enhanced by incorporating stimulating materials. The effects of these materials are dependent on various factors including the processed substrate, process conditions, and the type and amount of the stimulating material used. As part of the study, three different stimulating materials - iron powder, lime, and milled porous ceramic - were added to the 30-day anaerobic digestion of the brewer's spent grain to improve its performance. Different doses ranging from 0.2 to 2.3 gTS×L-1 were tested, and methane production kinetics were determined using the first-order model. The results showed that the methane yield ranged from 281.4±8.0 to 326.1±9.3 ml×gVS-1, while substrate biodegradation ranged from 56.0±1.6 to 68.1±0.7%. The addition of lime reduced methane yield at almost all doses by -6.7% to -3.3%, while the addition of iron powder increased methane yield from 0.8% to 9.8%. The addition of ceramic powder resulted in a methane yield change ranging from -2.6% to 4.6%. These findings suggest that the use of stimulating materials should be approached with caution, as even slight changes in the amount used can impact methane production.

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and cochlear hypothalamic–pituitary–adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins, and Ca2+-linked transporters and voltage-gated channels. These findings suggest that pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss

We are all similar, but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly and yeast panels with insightful applications for translational research.

Three significant changes have occurred in the winter climate in Europe recently: increased UK flooding; Iberian drought; and warmer temperatures north of the Alps. The literature links all three to a persistent, significant increase in sea level pressure over Southern Europe, the Mediterranean, Iberia and the Eastern Atlantic (SEMIEA) which changes the atmospheric circulation system: forcing cold fronts to the north away from Iberia; and creating a south westerly flow around the northern perimeter of the high-pressure region bringing warmer, moist air from the subtropical Atlantic to the UK and Europe which increases precipitation in the UK and raises the temperature in Europe. I use the Last Millennium Ensemble, MERRA-2 and Terra-NCEP data to demonstrate that the extreme, anthropogenic, West African aerosol Plume (WAP) which only exists from December to April perturbs the northern, regional Hadley Circulation creating the high pressure in the SEMIEA. I also show that the anthropogenic WAP has only existed in its extreme form in recent decades as the two major sources of the WAP aerosols: biomass burning; and gas flaring have both increased significantly since 1950 due to: a four-fold increase in population; and gas flaring rising from zero to 7.4 billion m3/annum and note that this time span coincides with the changes in the three elements of the winter climate of Europe. I also suggest that it may be possible to eliminate the WAP and return the winter climate of Europe to its natural state after the crucial first step of recognising the cause of the changes is taken.

The aim of the study was to gain deeper insights in the potential for polyclonal stimulation of PBMC from cows and pigs with banana lectin (BanLec) from Musa paradisiaca. BanLec induced a marked proliferative response in cow and pig PBMC. The response in pigs was even higher than to Concanavalin A. Molecular processes associated with respective responses were examined with differential proteome analyses. Discovery proteomic experiments was applied to BanLec stimulated PBMC and cellular and secretome responses were analyzed with label free LC-MS/MS. In PBMC, 3955 proteins were identified. After polyclonal stimulation with BanLec, 459 proteins showed significantly changed abundance in PBMC. In respective PBMC secretomes, 2867 proteins were identified with 231 differentially expressed candidates as reaction to BanLec stimulation. The transcription factor `E74 like ETS transcription factor 1 (ELF1)` was solely enriched in BanLec stimulated PBMC. BanLec induced secretion of several immune regulators, amongst them positive regulators of activated T cell proliferation and Jak-STAT signaling pathway. Top changed immune proteins were CD226, CD27, IFNG, IL18, IL2, CXCL10, LAT, ICOS, IL2RA, LAG3 and CD300C. BanLec stimulates PBMC of cows and pigs polyclonally and induces IL2 pathway and further proinflammatory cytokines. Proteomics data are available via ProteomeXchange with identifier PXD027505.

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

2-(Adamantan-1-yl)-2H-isoindole-1-carbonitrile (1) has been identified as a neurobiological fluorescent ligand that may be used to develop receptor and enzyme binding affinity assays. Compound 1 was synthesised using an optimised microwave irradiation reaction and crystallised from ethanol. Crystallization occurred in the orthorhombic space group P212121 with unit cell parameters: a = 6.4487(12) Å, b = 13.648(3) Å, c = 16.571(3) Å, V = 1458(5) Å3, Z = 4. Density functional theory (DFT) (B3LYP/6-311++G (d,p)) calculations of 1 were carried out. Results showed that the optimised geometry is similar to the crystal structure parameters with a root-mean-squared deviation of 0.143 Å. Frontier molecular orbital energies and net atomic charges are discussed with a focus on potential biological interactions. Docking experiments within the active site of the neuronal nitric oxide synthase (nNOS) protein crystal structure were carried out and analysed. Important binding interactions between the DFT optimised structure and amino acids within the nNOS active site were identified that explain the strong NOS binding affinity reported. Fluorescent properties of 1 were studied using aprotic solvents of different polarities. Compound 1 showed the highest fluorescence intensity in polar solvents with excitation and emission values of 336 nm and 380 nm, respectively.

A series of defective ZSM-5 zeolites (~300 nm, SiO₂/Al₂O₃ ratio of 55, 100, 400 and 950) were intentionally prepared and systematically studied by XRD, SEM, ²⁹Si MAS NMR, argon physisorption, NH₃-TPD and FT-IR technologies. The nature, the amount and the accessibility of the acid sites of defective ZSM-5 zeolites are greatly different from reported ZSM-5 zeolites with perfect crystal structure. The co-existed strong Brønsted acid sites (Si(OH)Al) and weak Brønsted acid sites (hydroxyl nests) over defective ZSM-5 zeolites might lead to unique catalytic function. Zn(C₂H₅)₂ was grafted onto defective ZSM-5 zeolites through chemical liquid deposition (CLD) method. Interestingly, FT-IR spectroscopy studies find that Zn(C₂H₅)₂ was preferentially grafted on the hydroxyl nests with weak acidity rather than the Si(OH)Al groups with strong acidity over different defective ZSM-5 zeolites. Particularly, home-built operando dual beam FTIR-MS was applied to study the catalytic performance of Zn species locating at different sites of defective ZSM-5 zeolites under n-hexane transformation. Results show that Zn species grafted over hydroxyl nests obtain better dehydrogenation performance than Zn species over framework aluminum. This study provides guidance for the rational design of highly efficient alkane dehydrogenative aromatization catalysts.

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the OXPHOS system for ATP production. It requires, in addition, the import of thousands of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPR^mt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial PHB (prohibitin) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Direct Behavior Rating (DBR) as a behavioral progress monitoring tool can be designed as longitudinal assessment with only short intervals between measurement points. The reliability of these instruments has been evaluated mostly in observational studies with small samples based on generalizability theory. However, for standardized use in the pedagogical field, a larger and broader sample is required in order to assess measurement invariance between different participant groups and over time. Therefore, we constructed a DBR with multiple items to measure the occurrence of specific externalizing and internalizing student classroom behaviors on a Likert scale (1 = never to 7 = always). In a pilot study, two trained raters observed 16 primary school students and rated the student behavior over all items with a satisfactory reliability. In the main study, 108 regular primary school students, 97 regular secondary school students and 14 students in a clinical setting were rated daily over one week (five measurement points). IRT analyses confirmed the instrument’s technical adequacy, and latent growth models demonstrated the instrument’s stability over time. Further development of the instrument and study designs to implement DBRs are discussed.

Mitochondrial dysfunction and oxidative stress are thought to be relevant to the pathogenesis of age-related macular degeneration (AMD). Glutathione (GSH) homeostasis fulfills a number of important roles in mitochondria, such as maintenance of mitochondrial DNA and respiratory competency of cells. Although the transport of mitochondrial GSH (mGSH) is not fully understood, increasing evidence from non-ocular tissues suggests that OGC (2-oxoglutarate carrier, SLC25A11) and DIC (dicarboxylate carrier, SLC25A10) are involved in mGSH transport. However, whether OGC and DIC mediate the transfer of GSH into the mitochondria of retinal pigment epithelial cells (RPE) remains unknown. Thus, we investigated the expression, localization, and function of OGC and DIC in human RPE (hRPE) in relation to oxidative stress and GSH. Both OGC and DIC are expressed in hRPE and are localized in mitochondria. We also found a dose and time-dependent decrease of OGC and DIC expression under oxidative stress and increased expression in polarized RPE. Our data show that the downregulation of OGC and DIC resulted in increased apoptosis and mGSH depletion which can be overcome by co-treatment with GSH-MEE. These findings suggest that overexpression of OGC and DIC may be an effective strategy to decrease susceptibility to mitochondrial toxicants by elevation of mGSH.

: The cyber-physical gap (CPG) is the difference between the 'real' state of the world and the way the system perceives it. This discrepancy often stems from the limitations of sensing and data collection technologies and capabilities, and is an inevitable issue in any cyber-physical system (CPS). Ignoring or misrepresenting such limitations during system modeling, specification, design, and analysis can potentially result in systemic misconceptions, disrupted functionality and performance, system failure, severe damage, and potential detrimental impacts on the system and its environment. We propose CPG-Aware Modeling & Engineering (CPGAME), a conceptual model-based approach for capturing, explaining, and mitigating the CPG, on top of and in sync with the conventional system model, and as an inherent systems engineering activity. This approach enhances the systems engineer’s ability to cope with CPGs, mitigate them by design, and prevent erroneous decisions, actions, and hazardous implications. CPGAME is a generic, conceptual approach, specified and demonstrated with Object Process Methodology (OPM). OPM is a holistic conceptual modeling paradigm for multidisciplinary, complex, dynamic systems, which is also ISO-19450. We analyze the 1979 Three Miles Island 2 nuclear accident as a prime example of the disastrous consequences of unmitigated CPGs in complex systems.

The present study was aimed to evaluate the levels of oxidative stress markers in breast diseases by measuring the 8-hydoxy-2-deoxyguanosine (8-OHdG), vitamin A, vitamin C, vitamin E and total antioxidant status (TAS) alterations in relation to cell proliferation activity and disease progression. Significant increases in the level of oxidative damage marker 8-OHdG and cell proliferation activity were observed in breast carcinoma patients in comparison to benign and normal controls, which were accompanied by significant decrease in non enzymatic antioxidants and TAS concentrations. 8-OHdG and cell proliferation level were negatively correlated with non enzymatic antioxidants viz., Vitamin A, Vitamin C, vitamin E level and total antioxidant activity. Altered levels of biomarkers of oxidative stress and cell proliferation activity amongst the malignant, benign and controls suggest a correlation of increased oxidative stress and cell proliferation activity in the progression of disease in breast carcinoma patients. Among the oxidative stress markers and cell proliferation index, decreased level of vitamin A, vitamin C, vitamin E, TAS and increased level of 8-OHdG, cell proliferation index emerged as best predicted biomarkers for subjects with malignancy and benign breast disease.

A testable hypothesis with quantitative predictions is put forward, proposing that strong acids produced on land at a rate correlated with global population are an increas-ing cause of increasing atmospheric CO2 pressure (pCO2). This hypothesis widens the imbalance assumed between the global uptake of CO2 by photosynthesis and emissions of CO2 from all sources, including the combustion of fossil fuels, causing greater atmos-pheric pCO2. Our modelling tests for reactions of dissolved inorganic carbon show that increasing atmospheric CO2 is caused thermodynamically by falling land surface pH values, but only with bicarbonate present. Strong acids generated by oxygen from re-duced inorganic compounds of nitrogen and sulphur emit CO2 almost stoichiometrically from dissolved bicarbonate in the pH range of most global soils, between 6 to above 8. We show that each decrease of aqueous pH value of 0.01 units from acidification of sur-face water near pH 8 potentially increases the pCO2 in the atmosphere by about 7 ppmv. The surface pH value of the ocean near 8.10 in 2000 has been shown to decrease at this rate, a result of equilibrating with the rising atmospheric pCO2. Therefore, our qualita-tive estimates of increasing atmospheric CO2 driven by irreversible acidification on land are critical and need broad scale validation. Unfortunately, these acidifying processes on land from excessive nitrogen fertiliser, export of alkaline produce from farmlands and other processes were not considered by previous biogeochemical reviews. However, several very recent research studies showing CO2 emissions from soil during nitrifica-tion are consistent with our hypothesis. Despite counter measures to curb excessive CO2 emissions, including carbon capture and geological storage, the increasing Keeling curve for pCO2 may continue to rise because zero carbon policies do not address these causes. We recommend that this hypothesis be further tested by in situ experiments in neutral soils and water, designed to compare CO2 emissions under the acidifying conditions de-scribed in this article. Corrective counter measures can then be designed and applied.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising chemotherapeutic agent because of its selective apoptotic action on cancer cells. However, resistance to TRAIL-induced apoptosis remains a challenge in many cancers. The gintonin-enriched Panax ginseng extract fraction (GEF) has diverse pharmacological benefits. We explored the combined efficacy of GEF and TRAIL in inducing apoptosis in human renal cell carcinoma (RCC) cells. The effect of GEF treatment on viability, clonogenic potential, wound healing, and TRAIL-induced apoptotic signaling of RCC cells was studied in vitro. Our investigation revealed that GEF pre-treatment sensitized RCC cells to TRAIL-induced apoptosis, as evidenced by DNA fragmentation and cell proliferation, colony formation, and migration inhibition. This sensitization was linked to the upregulation of death receptors 4 and 5 and alterations in apoptotic protein expression; notably, decreased expression of Mu-2-related death-inducing gene, a novel anti-apoptotic protein. Our findings underscore the necessity of caspase activation for GEF/TRAIL-induced apoptosis using the pan-caspase inhibitor Z-VAD-FMK. It demonstrates that GEF sensitizes human RCC cells to TRAIL-induced apoptosis by upregulating DR4/5 and modulating apoptotic protein expression. These findings suggest a promising strategy for overcoming TRAIL resistance in cancer therapy and highlight the potential of GEF as a valuable adjunct to TRAIL-based treatments.

The combustion of PVC cables in fires results in the release of hydrogen chloride gas. In the European Union, Regulation (EU) No 305/2011, in force since 2017, requires the classification of cables permanently installed in buildings for reaction to fire, smoke, flaming droplets, and acidity. The additional classification for acidity is evaluated through EN 60754-2, involving pH and conductivity measurements. This study focuses on the essential research and development of low-smoke acidity PVC compounds for cables, mainly aiming to meet the stringent additional classifications for acidity, a1 or a2, which cannot be achieved with traditional PVC cables. Understanding the chemistry of thermal decomposition and combustion, especially in the presence of hydrogen chloride scavengers, is crucial for meeting the best acidity classification. The article reviews the current tube furnace tests used in the European Union for cable halogen and acidity assessments. It discusses the limitations of the existing method (EN 60754-2) and highlights the potential of emerging tests such as IEC EN 60754-3, which employs ion chromatography for improved sensitivity and specificity. In the experimental part of the article, various standard and low-smoke acidity cable compounds are tested using tube furnace experiments with different heating regimes. The concentrations of cations and anions in solution are measured through ion chromatography and inductively coupled plasma–optical emission spectrometry. This detailed analysis aims to identify the species influencing pH and conductivity, which is crucial for designing effective acid scavengers that do not impact conductivity. The conclusive results emphasize that HCl from PVC thermal decomposition is the primary driver of pH and conductivity, and the contribution from the decomposition of additives and byproducts from combustion is found to be negligible in most of the tested PVC compounds for cables. The findings underscore the importance of understanding the thermal decomposition of PVC compounds to design acid scavengers capable of trapping hydrogen chloride without adversely impacting conductivity.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition, yet its alignment with a specific host immunological pathway remains unclear. The THαβ host immunological pathway, recognized for its defense against viruses and prions, has recently emerged as a response to DNA, RNA, and protein pathogens. SLE patients often produce anti-double strand DNA antibodies and anti-nuclear antibodies, suggesting a potential association with the THαβ host immune reaction. Throughout the course of SLE, elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 are commonly observed. These cytokines and antibody isotypes are indicative of the THαβ host immunological pathway. Similarly, Myasthenia gravis, Grave’s disease, Graft versus host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjogren’s syndrome are also linked to THαβ-related type 2 hypersensitivities. Considering the potential association of these diseases with dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferons α/β could be explored to manage these disorders effectively.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases including PD and type 2 diabetes mellitus (T2DM) suggesting a crucial interplay between the gut–brain axis. GLP-1R agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between February 2023 and February 2024. We used the terms “GLP-1”, “GLP-1 receptor”, “GLP-1R agonists”, “PD”, “T2DM”, “insulin”, “neurodegenerative disease”, “glucose”, “animal models”, “clinical trials” in different combinations. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies are also very promising enhancing the possibility of adding GLP1-R agonists in the current armamentarium of drugs available for PD treatment.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B-cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flowcytometry. Basal levels of B2M in patients with CLL were measured using an Enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p< 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p< 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. African patients with CLL express elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there is no correlation between these immune checkpoint expressions and B2M levels.