Background: Removable prostheses have seen a fundamental change recently because of advances in polymer materials, allowing improved durability and performance. Despite these advancements, notable differences still occur amongst various polymer materials and processing technologies, requiring a thorough grasp of their mechanical, physical, and therapeutic implications. Methods: Fours different processing techniques, all utilizing Polymethyl methacrylate (PMMA) as the main material, were used to construct complete dentures. The specimens underwent a mechanical test. Results: All the specimens broke under the influence of a certain force, rather than yielding through flow, as is characteristic for plastic materials. For each specimen, the maximum force (N) was recorded (figure 4), as well as the breaking energy, Conclusions: The best results were obtained in the case of the thermoplastic injection system and, surprisingly and contrary to those in the specialized literature, the worst results were recorded in the case of 3D printed samples.

Amidst increasing awareness of diet-health relationships, plant-derived bioactive peptides are recognized for their dual nutritional and health benefits. This study investigates bioactive peptides released after Alcalase hydrolysis of protein from chachafruto (Erythrina edulis), a nutrient-rich South American leguminous plant, focusing on their behavior during simulated gastrointestinal digestion. Evaluating their ability to scavenge radicals, mitigate oxidative stress, and influence immune response biomarkers, the study underscores the importance of understanding peptide interactions in digestion. Methods included previous enzymatic hydrolysis with Alcalase to obtain peptides, and results show significant radical scavenging and oxidative stress protection by chachafruto peptides. These findings highlight the potential of chachafruto bioactive peptides in functional foods and nutraceuticals, supporting human health through dietary interventions.

This paper describes the proposal and development of a proof of concept (PoC) for a data logger system designed for operation and fault detection in bench testing of combustion engines. The main objective was to develop a data logger system that collects data on vibration, sound, temperature, and CO2 levels to identify ignition and combustion faults, thereby contributing to reducing greenhouse gas emissions (GHG). The paper presents (i) the proposal and development and (ii) the open-source code: proof of concept for a data logger system focused on detecting faults and monitoring the operational condition of benchtop combustion engines. The results indicate the feasibility of the PoC for data acquisition and dataset creation for Research and Development purposes.

Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that receptors for adrenal steroids (aldosterone, cortisol), and sex steroids (estrogen, progesterone, testosterone) also are young, with an estrogen receptor and a 3-ketosteroid receptor first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. Through gene duplication and divergence of the 3-ketosteroid receptor, receptors that respond to androgens, glucocorticoids, mineralocorticoids and progestins evolved in vertebrates. Thus, an ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid receptors, evolved in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor, distinct glucocorticoid and mineralocorticoid receptors and estrogen receptor-α and -β in cartilaginous fishes (gnathostomes: sharks). Further evolution of mineralocorticoid signaling occurred with the evolution of aldosterone synthase in lungfish, a forerunner of terrestrial vertebrates. Adrenal and sex steroid receptors are not found in echinoderms: and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The evolution of steroid receptors at key nodes in the evolution of vertebrates, in which steroid receptors act as master switches to regulate differentiation, development, reproduction, immune responses, electrolyte homeostasis and stress responses, argues for an important role for steroid receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR) shuttles upon ligand binding and homodimerization from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors(TR), retinoic acid receptors (RAR), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXR) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and deprivation alone or with chemotherapy is the standard therapy for PCa. RAR activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TR support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, the trafficking of rod opsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for visual function. Two key mechanisms of this process are emphasized in this manuscript: Ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene opsin to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

Both bacteria product flagellin and macrophages are implicated in HIV infection/disease progression. However, the impact of their interaction on HIV infection and the associated mechanisms remain to be determined. We thus examined the effect of the flagellins on HIV infection of primary human macrophages. We observed that the pretreatment of macrophages with the flagellins from the different bacteria significantly inhibited HIV infection. The mechanistic investigation showed that the flagellin treatment of macrophages downregulated the major HIV entry receptors (CD4 and CCR5) and upregulated the CC chemokines (MIP-1α, MIP-1β, and RANTES), the ligands of CCR5. These effects of the flagellin could be compromised by a toll like receptor 5 (TLR5) antagonist. Given the important role of flagellin as a vaccine adjuvant in TLR5 activation-mediated immune regulation and in HIV infection of macrophages, future investigations are necessary to determine the in vivo impact of flagellin-TLR5 interaction on macrophage-mediated innate immunity against HIV infection and the effectiveness of flagellin adjuvant-based vaccines studies.

Long COVID, also referred to as post-COVID-19 condition, describes the lingering after-effects of COVID-19 infection. This complex syndrome encompasses a range of symptoms affecting physical well-being, cognitive function, and mental health. The widespread impact of long COVID extends beyond individual sufferers, placing significant strain on healthcare systems and causing far-reaching socioeconomic consequences. The scale of this multifaceted health crisis is unparalleled in recent history, affecting millions globally and challenging our understanding of post-viral conditions. This study aimed to explore the possibility of targeting G protein-coupled receptors (GPCRs) signaling pathway-related genes as therapeutics for long COVID using computational analysis. Targeting GPCRs and their signaling pathways holds significant promise for long COVID therapeutics, as these receptors are involved in crucial physiological processes including immune regulation, inflammation control, and neurotransmission. All of these are implicated in the diverse and persistent symptoms of long COVID, potentially offering a versatile approach to addressing multiple aspects of the condition simultaneously. This study identified 21 genes associated with GPCRs for further exploration as potential targets. Notably, GPCR genes such as HRAS, KRAS, GNAQ, and GNA11 were determined to be possible therapeutic targets for the pathophysiological mechanisms of long COVID. FDA-approved drugs targeting these genes were identified, including Binimetinib, Cabozantinib, Selumetinib, Panitumumab, Cetuximab, Adagrasib, Tipifarnib, and Sotorasib. Additionally, Naltrexone and Tipifarnib have emerged as potential new treatment options for long COVID. SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport, contributing to the pathophysiology of pulmonary edema in patients with COVID-19. Further research is required to translate the findings into the development of therapeutics and to investigate the relationship between viral infection and GPCR signalling.

Seedling establishment is often a critical bottleneck to revegetation of mine tailings and similar substrates with a low capacity to retain water and plant nutrients. Biochar and deactivated yeast are potential sustainable, low-cost materials with high nutrient- and water-holding capacity that could be used in this context as seed coatings to aid in seedling establishment on challenging sub-strates. We conducted a greenhouse study to assess the effectiveness of biochar and deactivated yeast, applied alone in a factorial combination, as seed coatings, on the germination, establish-ment, and early growth of white clover (Trifolium repens) and purple prairie clover (Dalea pur-purea). Coated seeds were applied to a mine tailing, a coarse granitic sand, and potting soil mix substates; seedling establishment and growth were monitored over 75 days. Results indicate strong interactive effects of seed coatings with species and substrate. Biochar coatings enhanced seedling establishment of Trifolium, with biochar or biochar plus yeast coatings giving the best results. In some cases, these effects persisted throughout the experiment: biochar coatings resulted in a ~5-fold increase in Trifolium biomass at harvest for plants in the potting soil mix but had neutral effects on sand or tailings. Biochar seed coatings also enhanced Dalea germination in some cases, but benefits did not persist. Our results indicate that biochar-based seed coatings can have lasting effects on plant growth well beyond germination, but also emphasize highly spe-cies-specific responses that highlight the need for further study of broader patterns and mecha-nisms.

Several recent surges in COVID-19 cases due to newly emerging variant strains of SARS-CoV-2 with greater transmissibility have highlighted the virus’s capability to directly modulate spike-ACE2 interactions and promote immune evasion by sterically masking the immunogenic epitopes. Recently, there have also been reports of the bidirectional transfer of coronavirus between different animal species and humans. The ability of coronavirus to infect and adapt to a wide range of hosts can be attributed to new variants that modify the molecular recognition profile of the spike protein (S protein). The receptor-binding domain of the spike protein specifically interacts with key host receptor molecules present on the host cell membranes to gain entry into the host and begin the infection cycle. In this review, we discuss the molecular, structural, and functional diversity associated with the coronavirus receptors across their different phylogenetic lineages and its relevance to various symptomatology in the rapid human-to-human infection in COVID-19 patients, tropism, and zoonosis. Despite this seeming diversity of host receptors, there may be some common underlying mechanisms that influence the host range, virus transmissibility, and pathogenicity. Understanding these mechanisms may be crucial in not only controlling the ongoing pandemic but also help in stopping the resurgence of such virus threats in the future.

The use of alternative fuels and electric vehicles is an opportunity to reducing exhaust emissions. We observe that the regulations on exhaust emissions from mobile sources are becoming gradually stricter on the all the world. As is widely known, using alternative fuels instead of conventional fuels helps lower vehicle emissions. The most popular alternative fuels are hydrogen, propane, biobutanol, methanol, dimethyl ether, etc. It is very important that more than a dozen alternative fuels are under development. The article contains a comparison of the operating costs of electric cars and cars with an internal combustion engine. This work shows also the characteristic of new alternative fuels and their impacts on exhaust emissions.

This study provides a comprehensive analysis of the conformational dynamics of pseudo-endocannabinoid receptors (p-CBRs) CB₁ and CB₂ in response to ligand binding. The ligands studied include N-arachidonoyl dopamine (NADA), Cannabidiol (CBD), known agonists (FUB-MDMB and E3R), and inverse agonists (Taranabant and AM630). Using homology models based on crystal structures (PDB ID: 5U09 for CB₁ and 5ZTY for CB₂), molecular docking, and molecular dynamics (MD) simulations, the research validates the structural integrity and dynamic behaviours of these pseudo-receptors. Induced-fit docking revealed NADA as having the highest binding affinity for both receptors, with docking scores of −13.92 kcal/mol for CB₁ and −13.32 kcal/mol for CB₂, facilitated by key hydrogen bond interactions. MD simulations over 250 ns at ~298 K showed successful equilibration, indicating the most stable interaction for NADA, thereby further validating the models. CB₁ and CB₂ exhibited distinct conformational responses to ligands, with Cα RMSD and Cα RMSF analyses suggesting a more rigid binding pocket for CB₁ and a flexible binding pocket for CB₂. These findings highlight the significance of receptor behaviour and dynamics in the development of cannabinoid-based therapeutics, supporting the potential of CBD and NADA as modulators for CB₁ and CB₂, respectively.

The global food production system faces several challenges, including significant environmental impacts due to traditional agricultural practices. The rising demands of consumers for food products that are safe, healthy, and have animal welfare standards have led to an increased interest in alternative proteins and the development of the cellular agriculture field. Within this innovative field, precision fermentation emerges as a promising technological solution to produce proteins with reduced ecological footprints. This review provides a summary of the environmental impacts related to the current global food production, and explore how precision fermentation can contribute to address these issues. Additionally, we will report on the main animal-derived proteins produced by precision fermentation, with a particular focus on those used in the food and nutraceutical industries. The general principles of precision fermentation will be explained, including strain and bioprocess optimization. Examples of efficient recombinant protein production by bacteria and yeasts, such as milk proteins, egg-white proteins, structural and flavoring proteins, will also be addressed, along with case examples of companies producing these recombinant proteins in a commercial scale. Through these examples, we will explore how precision fermentation supports sustainable food production and holds the potential for significant innovations in the sector.

This study investigates the necessity of particle asymmetry for self-propulsion in nanomotors. While conventional wisdom posits that asymmetric designs are crucial for generating phoretic forces or localized bubble propulsion, recent research suggests that symmetrical particles may also exhibit motility. To address this debate, we developed a robust workflow for synthesizing gold grafted silica nanoparticles with precise control over size and shape, enabling the direct comparison of their motile behavior by dynamic light scattering and particle tracking velocimetry. Our results indicate that the inherent asymmetry generated during isotropic gold nanoparticle deposition onto silica surfaces may enable particle motility.

Peroxisome proliferator-activated receptors (PPARs) are important targets for cannabidiol (CBD), which mediate many of its biological actions. The hypothesis of the present research assumed that PPARs affect the gut response to different challenge factors in chickens (C. perfringens vs lipopolysaccharides (LPS) from E. coli), and CBD can mediate the pathways of this response. The study proved that CBD and challenge factors significantly affect the expression level of PPARα (P=0.001) and selected genes determining gut barrier function. A positive correlation was demonstrated between PPARs and genes involved in the formation of tight junctions, immune and oxidative stress responses in chickens. Dietary supplementation with CBD actively mediated the expression rate of PPARs, but the mechanism of interaction between CBD and PPARs was different depending on the stress factor used. The addition of CBD to the birds’ diets did not contribute to reducing intestinal permeability under induced stress conditions and did not cause a stress-inducing effect resulting in the increase of cortisol and endotoxin concentration in the blood. CBD also supported the mechanisms of protecting intestinal cells from cytotoxic effects in a C. perfringens challenge. This study indicates the importance of research towards understanding the mechanisms of PPARs as a target for enhancing intestinal barrier function, provides new results on the biological action of CBD in chickens and shows a constant PPARs association with the jejunum mucosa of birds.

In this review we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

Some of neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that contains memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative disease characterized by deficit of cognition and alteration of behavior. Despite the huge efforts against Alzheimer's disease, there has been yet no successful treatment for this disease. Interestingly, several possible risk genes to cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes and/or caveolae formation, suggesting that caveolae may be a therapeutic target to consider cognitive dysfunctions. Interestingly, modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptors signaling may offer a novel approach to prevent and alleviate the cognitive dysfunction. A paradigm that both GLP-1 and NMDA receptors at caveolae sites is promising and crucial for the treatment of cognitive dysfunctions has been presented here, which might also be able to modify the progression of Alzheimer's disease. This research direction may open the potential to move a clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.

GABAA receptors are channel proteins crucial to mediating neuronal balance in the CNS. The structure of GABAA receptors allows for multiple binding sites and is key to drug development. Yet, the formation mechanism of the receptor’s distinctive pentameric structure is still unknown. This study aims to investigate the role of three predominant subunits of the human GABAA receptor in the formation of protein pentamers. Through purifying and refolding the protein fragments of the GABAA receptor α1, β2, and γ2 subunits, homopentamers were visualised with negative staining and Cryo-EM. To aid the analysis, AlphaFold2 was used to compare the structures. Results show that α1 and β2 subunit fragments successfully formed homo-oligomers, particularly homopentameric structures, while the predominant heteropentameric GABAA receptor was also replicated through the combination of the three subunits. However, it is still unclear whether γ2 subunits can form homopentamers or their main purpose is to bring together the α1 and β2 subunits to form GABAA receptors. Nevertheless, this study will lead to a deeper understanding of the atomic structure of GABAA receptors, especially in the formation mechanism of complex protein structures, and hopefully pave the way to the development of novel therapeutics for neuropsychiatric diseases.

Background: The identification of new cellular receptors has been increasing rapidly. A receptor is called “orphan” if an endogenous ligand has not been identified yet. Methods: Here we review receptors that contribute to prostate cancer and are considered orphan or partially orphan. This means that the full spectrum of their endogenous ligands remains unknown. Results: The orphan receptors are divided into two major families. The first group includes G protein-coupled receptors. Most are orphan olfactory receptors. OR51E1 inhibits cell proliferation and induces senescence in prostate cancer. OR51E2 inhibits prostate cancer growth, but promotes invasiveness and metastasis. GPR158, GPR110 and GPCR-X play significant roles in prostate cancer development and progression. However, GPR160 induces cell cycle arrest and apoptosis. The other major subset of orphan receptors are nuclear receptors. RORα inhibits tumor growth, but RORγ stimulates androgen receptor signaling. PXR contributes to metabolic deactivation of androgens and inhibits cell proliferation. TLX has pro-tumorigenic effects in prostate cancer, while its knockdown triggers cellular senescence and growth arrest. Estrogen-related receptor ERRγ can inhibit tumor growth but ERRα is pro-tumorigenic. Dax1 and Shp are also inhibitory in prostate cancer. Conclusion: There is a “zoo” of relatively underappreciated orphan receptors that play key roles in prostate cancer.

Background: Complementary and alternative medicines (CAM) are widely used, with pharmacies accounting for a significant share of the distribution market. Despite their popularity, many CAMs lack scientific evidence for effectiveness, and some can cause adverse health effects. Limited research exists on CAM-related adverse events and the effectiveness of CAM labels in conveying crucial information. Methods: This cross-sectional study aimed to investigate CAM utilization, consumer perspectives, and the influence of labels on CAM usage in Melbourne, Australia. Data were collected through an online questionnaire and analysed using descriptive statistics, Pearson's correlation, MANOVA, and regression analyses. Results: The study enrolled 125 current CAM users, primarily recruited from pharmacy and supermarket customers (age: predominantly 31-50; gender: 20.8% male, 79.2% female). Participants' perceptions of effectiveness and safety were positively correlated. Label warnings prompted information-seeking, but consultation with healthcare professionals (HCPs), particularly pharmacists, was infrequent (24%). Adverse reactions were reported by 18.5% of participants, with 8.3% experiencing severe reactions. The analysis revealed relationships between CAM usage and demographics. Ordinal logistic regression showed a significant association between calcium consumption and higher age groups (coefficient = 1.658, p = 0.006), while binary logistic regression identified higher iron consumption among females (coefficient = 2.177, p = 0.007). Conclusions: Label warnings significantly prompted consumers to seek more information about CAMs. However, a limited engagement of HCPs, especially pharmacists, suggests an opportunity for improved consumer education and pharmacist involvement in CAMs-related discussions. The findings highlight demographic influences on CAM usage being essential for developing targeted health interventions and policies. Addressing these aspects may lead to safer CAM practices and informed consumer decision-making.

Purinergic receptors (P2X) are ATP-gated ion channels with an elusive role in the CNS. While the P2X2 and P2X4 subtypes are widely expressed in most neurons (i.e. at the edge of the postsynaptic densities of excitatory synapses), the direct contribution of P2X to synaptic transmission is uncertain. Several P2X have been shown to participate in receptor cross-talk: an interaction where one receptor (e.g. P2X2) influences the activity of another (e.g. GABA or AMPA receptors.) In this study, we tested for interactions between P2X2 or P2X4 and N-methyl-D-aspartate receptors (NMDARs). Using two-electrode voltage-clamp electrophysiology experiments in X. laevis oocytes, we demonstrate that both P2X2 and P2X4 interact with NMDARs in an inhibitory manner. When investigating the molecular domains responsible for this phenomenon, we found that the P2X2 c-terminus (CT) could interfere with P2X2 and P2X4 interactions with NMDARs. We also report that 11 distal CT residues on the P2X4 facilitate the P2X4-NMDAR interaction, and that a peptide consisting of these P2X4 CT residues (11C) can disrupt the interaction between NMDARs and P2X2 or P2X4. Collectively, these results provide new evidence for the modulatory nature of P2X2 and P2X4, suggesting they might play a more nuanced role in the CNS.

Vitamin A, or retinol, is one of the most effective anti-ageing molecules, but it presents issues with photo-sensitivity and irritation. Retinol-like alternatives are emerging, but have so far been less effective. Here, we present a Silibum marianum extract (SME) as a retinol-like ingredient providing both safety and efficacy. SME was compared to the reference compound, retinol, and to the main alternative, bakuchiol. In ex vivo tests, skin explants from a 58-year-old donor were treated with pure retinol (0.1%), bakuchiol (0.2%) or SME (0.8%). After 5 days, collagen and hyaluronic acid levels were analysed. A placebo-controlled study involving 57 volunteers (ages 45-73 years) was also conducted, with products applied twice-daily for 56 days. Results were measured by AEVA-HE and VISA. Levels of collagen III were significantly increased by SME, by 23% and 16% compared to bakuchiol and retinol, respectively. Compared to bakuchiol, SME treatment increased hyaluronic acid production by 36%. In clinical tests, SME had a significantly stronger anti-wrinkle effect than bakuchiol – reducing the number of wrinkles on the forehead by 21%, and their circumference by 17% – producing effects similar to retinol, and better than bakuchiol. In the self-assessment, 43% of volunteers reported discomfort while using retinol, as compared to 0% for the SME formulation. By enhancing levels of collagen III – the youth collagen – and hyaluronic acid in the skin, SME paves the way for the maturation of collagen I fibrils and skin plumping. With its stronger efficacy compared to bakuchiol and enhanced safety profile compared to retinol, SME may be the next-generation of natural alternatives to retinoids.

This article provides a detailed analysis of non-invasive techniques for prediction and diagnosis of faults in internal combustion engines, focusing on the application of the Proknow-C and Methodi Ordinatio systematic review methods. Initially, the relevance of these techniques in promoting energy sustainability and mitigating greenhouse gas emissions is discussed, aligning with the Sustainable Development Goals (SDGs) of Agenda 2030 and the Paris Agreement. The systematic review conducted in the subsequent sections offers a comprehensive mapping of the state-of-the-art, highlighting the effectiveness of combining these methods in categorizing and systematizing relevant scientific literature. The results reveal significant advancements in the use of artificial intelligence (AI) and digital signal processors (DSP) to enhance fault diagnosis, as well as underscore the crucial role of non-invasive techniques in minimizing interference in monitored systems. Finally, concluding remarks point towards future research directions, emphasizing the need to develop digital twins for internal combustion engines and identify gaps for further improvements in fault diagnosis and prediction techniques.

Hydrogen has a leading role in accomplishing a net zero green-house gas emission future. Today’s challenge is producing green hydrogen to cover the fuel demand of transportation and industry, to gain independence from fossil fuels. This review’s goal is to demonstrate critically the existing methods of biomass treatment and assess their ability to scale up. Biomass is an excellent hydrogen carrier and biomass-derived processes are the main target for hydrogen production as it is an innovative pathway to green hydrogen production. Comparing the existing processes, thermochemical treatment is found to be far more evolved than biological or electrochemical treatment especially with regard to scaling prospects.

Additives for anaerobic digestion (AD) can play a significant role in optimising the process by increasing biogas production, stabilising the system and improving digestate quality. The role of additives largely boils down to: (i) enhancing direct interspecies electron transfer (DIET) between microbial communities, resulting in improved syntrophic interactions and methane production rates (e.g. biochar, magnetite and carbon nanotubes), (ii) adsorption of toxic substances that may inhibit microbial activity (e.g. activated carbon, zeolites), (iii) improving microbial activity and increasing process stability (e.g. cobalt, nickel, iron, selenium), (iv) maintaining optimal pH levels for microbial activity (e.g. magnesium oxide), (v) reducing inhibition (the aforementioned adsorbents and conductive substances), (vi) accelerating the decomposition of complex organic materials into simpler compounds that are more easily digested by microorganisms, thereby increasing the rate of hydrolysis (enzymes, including cellulases, proteases and lipases). Through the aforementioned action, additives can significantly affect AD performance. The function of these materials varies, from enhancing microbial activity to maintaining optimal conditions and protecting the system from inhibitors. The choice of additives should be carefully tailored to the specific needs and conditions of the digester to maximise benefits and ensure sustainability. In light of these considerations, this paper characterizes the most commonly used additives and their combinations based on a comprehensive review of recent scientific publications, including a report on the results of conducted studies. The publication features chapters that describe: carbon-based conductive materials, metal oxide nanomaterials, trace metal and biological additives, including enzymes and microorganisms. It concludes with a chapter summarising reports on various additives and discussing their indications for functional systems with determined properties. A notable advantage of this work is the updated literature data, clear summaries, and a substantive description of the performance of the additives discussed.

The energy supply for isolated systems remains a current challenge in Brazil and worldwide, particularly when known solutions are compared regarding cost, the ability to supply energy on demand, and sustainability. In this context, green hydrogen, which has been considered one of the main paths for the decarbonization of the energy chain, is also seen as a potential solution for energy supply in isolated systems. Based on a literature review of articles addressing the topics of green hydrogen and isolated systems, an analysis is conducted on the application of green hydrogen as an energy supply solution for isolated systems. The review identified and collected data on important parameters for comparing solutions, such as CAPEX, OPEX, energy cost, and the price per kilogram of hydrogen. Using these data, analyses were performed to provide an overview of the application of green hydrogen in isolated systems. One of the objectives of this work is to present a comprehensive analysis of the green hydrogen chain and its application in the context of electricity generation, particularly for isolated systems in Brazil.

Platelet P2Y₁₂ is an important ADP receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio-analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma we demonstrate that UTP inhibits P2Y₁₂ but not P2Y₁ receptors and antagonises 10 μM ADP-induced platelet aggregation in a concentration-dependent manner with an IC₅₀ value of ~250 μM. An 8-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC₅₀ of 30 μM. The 4-thio analogue (4S-UTP) with an IC₅₀ of 7.5 μM was 33-fold more effective. A 3-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y₁₂ receptors was verified by P2Y₁₂ receptor binding and cAMP assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y₁₂ receptor antagonists that may be useful for therapeutic intervention.

Abstract: The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRa and GRb), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e. GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have lower expression of GRb, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. Increased expression of GRb can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. Endogenous expression of GRb in the TM may relate to differences in the development of GC-OHT among the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease modifying therapies to better treat these two sight threatening forms of glaucoma.

The selectivity in selective autophagy pathways is achieved via the selective autophagy receptors (SARs) – proteins that bind a ligand on the substrate to be degraded and the Atg8-family protein on the growing autophagic membrane, phagophore, effectively bridging them. In mammals, the most common ligand of SARs is ubiquitin, a small protein modifier that tags substrates for their preferential degradation by autophagy. Consequently, the most common SARs are the ubiquitin-binding SARs, such as SQSTM1/p62 (sequestosome 1). Surprisingly, there is only one SAR of this type in yeast – Cue5, which acts as a receptor for aggrephagy and proteaphagy – pathways that remove the ubiquitinated protein aggregates and proteasomes, respectively. However, recent studies described the ubiquitin-dependent autophagic pathways that do not require Cue5, e.g. stationary phase lipophagy for intracellular lipid droplets and nitrogen starvation-induced mitophagy for mitochondria. What is the role of ubiquitin in these pathways? Here, we propose that the ubiquitinated lipid droplets and mitochondria are recognized by the alternative ubiquitin-binding SARs. Our analysis identifies the proteins that could potentially fulfill this role in yeast. We think that matching of the ubiquitin-dependent (but Cue5-independent) autophagic pathways with the ubiquitin-and-Atg8-binding proteins enlisted here might uncover the novel ubiquitin-binding SARs in yeast.

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS > 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (< 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS > 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by re-stricted and repetitive behaviors as well as difficulties with social interaction. Nu-merous studies have revealed aberrant lipid mediators and autoimmunity as a recog-nized etiological cause of ASD that is amenable to therapeutic intervention. Methods: In this study, the relationship between the relative cyclooxygenase-2, / pros-taglandin E2 ratio (COX-2/PGE2) as lipid mediator marker and anti-nucleosome au-toantibodies as autoimmunity marker of ASD was investigated using multiple regres-sion and combined receiver operating characteristic (ROC) curve analyses. The study also sought to identify the linear combination of these variables that optimizes the partial area under the ROC curves. There were forty ASD children and forty age- and sex-matched controls included in the current study. Results: Using combined ROC curve analysis, a notable increase in the area under the curve was seen. Additionally, it was reported that the combined markers had improved specificity and sensitivity. Conclusions: This study shows that using a ROC curve analysis to measure the predictive value of specific biomarkers linked to lipid metabolism and autoimmunity in children with ASD should improve our understanding of the etiological mechanism of ASD and how it is related to metabolism. Early diagnosis and intervention may be facilitated by this knowledge.

Keywords: Vascular Malformation, Diode Laser, Angioma, Blue light, Conservative

In the past years, consumers have increased their interest to buy healthier food products, rejecting those products with more additives and giving preference to the fresh ones. Moreover, the current environmental situation has made society more aware of the importance of reducing the production of plastic and food waste. In this way and considering the Food Industry need of reducing the food spoilage along the food chain, edible coating has been considered as an eco-friendly food packaging that can replace traditional plastic packaging providing an improvement in the product’s shelf-life. Edible coating are thin layers applied straightaway on the food materials’ surface, that are made of biopolymers that usually incorporate other elements, such as nanoparticles or essential oils, to improve their physicochemical properties. These materials must provide a barrier that can prevent the pass of water vapor and other gasses, the microbial growth, the moisture loss, and the oxidation, so the shelf-life could be extended. The aim of this review was to compile the current data available to give a global vision of the formulation process and the different ways to improve the characteristics of the coats applied in both fruits and vegetables. In this way, the suitability of compounds in by-products produced during the Food Industry chain were also considered for the edible coating production.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

Using desi-cow waste products like Jeevamrit, natural farming is widespread among farmers for improving soil biology and productivity. Jeevamrit enhances soil chemical and microbiological properties without needing large quantities of farmyard manure (FYM), as a sustainable farming practice with a reduced carbon footprint. Despite its traditional use, Jeevamrit faces criticism due to a lack of scientific evidence. This study investigated the comparative effect of Jeevamrit and chemical fertilizers on the growth and yield of marigold cv. Siracole. In this study mother block of marigold was raised for both summer and winter seasons. The cuttings were harvested from the mother block and then kept for rooting. The rooted cuttings were planted at monthly intervals and evaluated for flowering parameters and compared to those treated with RDF (30:20:20 N, P, and K g/m2). Soil supplied with Jeevamrit enhanced bacteria (26.33%), fungi (18.92%), and actinomycetes (31.21%) populations compared over the recommended dose of fertilizers (RDF) (i.e. N:P: K @ 30:20:20 g m-2). Jeevamrit-treated plants have marketable flower yield per square meter (3.98 %) and shelf life (9.93 %) compared to RDF. The study concludes that Jeevamrit @ 2 liter m-2 is a sustainable and effective alternative to traditional fertilizers for enhancing marigold production in the mid-hills of the Himalayan region, where natural farming is already accepted.

The use of chemical pesticides in agriculture contributes to soil, water and air pollution, biodiversity loss and can harm non-target species. The European Commission has already established a Harmonized Risk Indicator to quantify the progress in reducing the risks linked to pesticides. Therefore, there is an increasing need to promote biopesticides or so-called low-risk pesticides (LRP). Extract from Melaleuca alternifolia – tea tree oil (TTO) is known for its antiseptic, antimicrobial, antiviral, antifungal, and anti-inflammatory properties. Tea tree oil has been extensively studied in pest management as well as in the pharmaceutical and cosmetic industry and there are already products based on its active substances on the market. This review focuses on the overall evaluation of tea tree oil in terms of effectiveness and safety as a biopesticide for the first time. The collected data can be an added value for further evaluation of tea tree oil in terms of the authorization extension as a fungicide in 2026.

Neurological / neurovascular disorders constitute the leading cause of disability and second leading cause of deaths in the world. Some of the major neurological / neurovascular disorders or diseases include stroke, Alzheimer’s disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, etc. Their pathophysiology is considered as highly complex and has been blamed as the main obstacle in the development of any drugs for these diseases. In this review, we have described the endothelin system, their involvement in neurovascular disorders, importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN - sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders / diseases. We have highlighted the results of our pre-clinical and clinical studies related to these diseases. The phase I, safety and tolerability study of sovateltide has shown it as a highly safe and well tolerable compound at tested dosages, while pre-clinical and clinical phase II studies have demonstrated its efficacy in treating acute ischemic stroke, where it is currently being developed as a “First in Class” drug. Its testing in Alzheimer’s disease (AD), acute spinal cord injury and neonatal hypoxic-ischemic encephalopathy (HIE) is currently being carried out and are at different stages of drug development. Successful completion of these studies will prove the involvement of ETBRs signaling in neurological / neurovascular diseases and help in development of novel neurological drugs in future.

Background Olfactory perception is an important physiological function for the human well-being and health. Loss of olfaction, or anosmia, caused by viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received a considerable attention especially in the persistent cases that take long time to recover. Objectives This review discusses the integration of different components of the olfactory epithelium to serve as a structural and functional unit, and explores how they are affected during viral infections, leading to the development of olfactory dysfunction. Methods The review mainly focused on the role of receptors mediating the disruption of olfactory signal transduction pathways such as ACE2, TMPRSS2 protease, neuropilin 1 (NRP1), basigin (CD147), olfactory, TRPV1, purinergic, and interferon gamma receptors. Furthermore, the compromised function of the epithelial sodium channel (ENaC) induced by SARS-CoV-2 infection and its contribution in olfactory dysfunction is also discussed. Results Collectively, this review provides fundamental information about the many types of receptors that may modulate olfaction and participate in olfactory dysfunction. It will help to understand the underlying pathophysiology of virus-induced anosmia which may help in finding and designing effective therapies targeting molecules involved in viral invasion and in olfaction. Conclusion This wide and complex spectrum of receptors that mediates the pathophysiology of olfactory dysfunction reflects the many ways by which anosmia can be therapeutically managed.

A viable radiation dominated era in the early universe is best described by the standard (FLRW) model of cosmology. In this short review, we demonstrate reconstruction of the forms of F(R) in the modified theory of gravity, and the metric compatible F(T) together with the symmetric F(Q) in alternative teleparallel theories of gravity from different perspectives, primarily rendering emphasis on a viable FLRW radiation era. Inflation has also been studied for a particular choice of the scalar potential. The inflationary parameters are found to agree appreciably with the recently released observational data.

CD44 glycoprotein is ubiqutously present and situated at the extracellular surface of cell. Its role as an adhesion recptor was modified depending upon the state of post addition of glycomoeties under varied microenvironment. Many alternative spliced variants of CD44 were expressed by human cells depending upon the attainment during mutifunctional signal disposition. The function of splice factors, and hnRNPA family (Heterogenous ribonucleoproteins A) were dicussed in context to CD44 alternative variants. Glioma cell cline U87 MG were used in this study to search more about the affect of hnRNPA1 and hnRNPA2/B1 knockdown in CD44 V6 and CD44V10 expression. We found in preliminary study that splice factor knock down reduces the alternative splice variants of CD44 such as V6 & V10. Therefore, potential of this study to elaborate further the mechanism in vivo model, to validate the alternative spliced variant in context to interaction with extracellular microenvironment.

Endo-reticular stress induces the unfolded protein response including a highly conserved set of genes crucial for cell survival against a variety of onslaughts. Among the activated stress response genes is Ire1, which undergoes auto-phosphorylation and acquires a regulated Ire1-dependent mRNA decay activity. Ire1P non-canonically splices the mRNA for Xbp1 in the cytoplasm. This spliced Xbp1 serves as mRNA encoding a transcription factor for unfolded protein response genes. Meanwhile the mRNA decay function of Ire1P degrades other cellular mRNAs and can cause changes to the translation machinery by altering regulators in a cell specific manner. Naïve splenic B cells differentiate into Antibody Secreting Cells and activate Ire1 phosphorylation early on after LPS stimulation, within 18 hrs. When Ire1 is activated in B cells, in addition to Xbp1 splicing, there are large-scale changes in mRNA; inhibition of the mRNA degradation function of Ire1 both reduces the number and changes the type of genes involved in altered splicing patterns, including factors for snRNA transcription. Some of the splicing changes seen at 18 hrs after LPS persist into the late stages of antibody secretion, up to 72 hrs, while others are supplanted by new splicing changes introduced by the induction of ELL2, a transcription elongation factor. ELL2 changes mRNA processing patterns and is necessary for Immunoglobulin secretion. RNA splicing patterns in antibody secreting cells are thus shaped by endo-reticular stress, ELL2 induction, and are associated with changes in the levels of snRNAs.

The information about the BCoV receptors, co/receptors that might be involved in the BCoV entry to the host cells is inconceivable. In addition to that, the roles of other host cell proteases, such as Furin and TMPRSS2, have not yet been well studied during BCoV replication. The current study’s main objectives are to identify some novel BCoV receptors and host cell proteases that might fine-tune the BCoV replication, tissue tropism, and molecular pathogenesis. We used a combination of some in silico prediction, molecular docking, and gene expression profile tools to predict some new BCoV receptors out of some known other coronavirus receptors and some host cell enzymes that are potentially involved in BCoV replication. To achieve these goals, we applied the in-silico prediction tools to check the potential interactions between eh BCoV/S glycoprotein and some known coronaviruses receptors (ACE2, APN1, NPR1, CECAM-1, AXL, and DPP4). We also established some potential models for the interaction between the BCoV/S and some common host cell proteases proved to play important roles in other coronavirus replication cycle (Furin, TMPRRS2, and Cathepsin-L). To confirm our prediction models, we assessed the gene expression profiles of these potential receptors and proteases in some bovine cell lines infected with BCoV using the next generation sequencing and the qRT-PCR assay. Our results show that the NPR1, AXL1 and the ACE2 have the strongest and firm binding affinities to the BCoV-S protein. Our prediction models and gene expression profiles show the potential bindings of the Furin and TMPRSS2 to the BCoV-S polybasic cleavage site (RRSRR|A). Notably, high expression of the host cell Furin was observed in response to both BCoV/Ent and BCoV/Resp infection, whereas TMPRSS2 expression was upregulated in the case of the BCoV/Ent infection, positioning Furin as a common receptor for different BCoV isolates. Further research is needed to study the roles of these top-ranked receptors and host cell proteases in molecular pathogenesis, and tissue tropism.

The spin-torsion theory is a gauge theory approach to gravity that expands upon Einstein's general relativity (GR) by incorporating the spin of microparticles. In this study, we further develop the spin-torsion theory to examine spherically symmetric and static gravitational systems that involve free-falling macroscopic particles. We posit that the quantum spin of macroscopic matter becomes noteworthy on cosmic scales. We further assume that the Dirac spinor and Dirac equation adequately capture all essential physical characteristics of the particles and their associated processes. A crucial aspect of our approach involves substituting the constant mass in the Dirac equation with a scale function, allowing us to establish a connection between quantum effects and the scale of gravitational systems. This mechanism ensures that the quantum effect of macroscopic matter is scale-dependent and diminishes locally, a phenomenon not observed in microparticles. For any given matter density distribution, our theory predicts an additional quantum term, the quantum potential energy (QPE), within the mass expression. QPE induces time dilation, distance contraction, and thus mimics a gravitational well. When applied to cosmology, our theory yields a static cosmological model. The QPE serves as a counterpart to the cosmological constant introduced by Einstein to balance gravity in his static cosmological model. The QPE also offers a plausible explanation for the origin of the Hubble redshift (traditionally attributed to the universe's expansion). The predicted luminosity distance-redshift relation aligns remarkably well with SNe Ia data from the cosmological sample of SNe Ia. In the context of galaxies, QPE functions as the equivalent of dark matter. The predicted circular velocities align well with the rotation curve data from the SPARC (Spitzer Photometry and Accurate Rotation Curves database) sample. Importantly, our conclusions in this paper are reached through a conventional approach, with the sole assumption of the quantum effects of macroscopic matter on large scales, without the need for additional modifications or assumptions.

Vancomycin is one of the ‘last-line’ classes of antibiotics used in the treatment of life-threatening infections caused by Gram-positive bacteria. Even though vancomycin was discovered in 1950s it was widely used after 1980s for the treatment of infections caused by methicillin-resistant Staphylococci as prevalence of such strains were increased. However, currently it is evident that vancomycin resistant Staphylococcusaureusandvancomycin-resistant Enterococci have been developed as a result of various reasons including use of avaparcin, which is an analog of vancomycin, as feed additive in livestock. In present day context, more attention should be paid on prevention of emergence of resistance for the antibiotics in order to keep antibiotics effective. In order to prevent emergence of resistance, proper guidance for the responsible use of antimicrobials is indispensable. Therefore, almost all stakeholders who use antibiotics should have in depth understanding on the antibiotic they use. As such, it is imperative to be aware of the important aspects of vancomycin. In the present review, efforts have been made to discussthe pharmacokinetics and pharmacodynamics, indications, emergence of resistance, control of resistance, adverse effects and alternative therapy for vancomycin.

Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Recent epidemiological studies conducted in developing countries identified Shigella species as the most predominant pathogenic bacteria responsible for diarrhea. Antimicrobial therapy is necessary for Shigella infections; however, the rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. To identify alternative antimicrobial compounds with activity against Shigella species, the pathogens responsible for bacterial diarrhea. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing benzothiazoles backbone, and their combination with certain antibiotics. In continuation to our effort in searching potent antimicrobial compounds, we have found this time around that two acetaminophen derivatives containing benzothiazoles backbone (4a and 4b) could inhibit the growth of Shigella flexneri with common MIC value of 12.5 µg/ml. These compounds were established through a time-kill kinetics’ study to be bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a & b) were found to be poorly active (MIC: 100 µg/ml) against this pathogen. Combination studies of 4a and 4b with the least susceptible antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity. The present study demonstrates that the azobenzothiazole dyes 4 (a & b) can be repurposed as potential anti-Shigella compounds, which can serve as scaffolds for the development of new agents against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes or chronic pulmonary obstruction. Here we review progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation and in vivo actions of in order to understand the translational impact of studying this important class of pharmacological agents. We overview newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

We are encouraged to look beyond ɅCDM as there are no satisfactory explanations for either dark energy or dark matter. A data centred phenomenological approach supports an explanation where dark energy is Holographic Dark Information Energy, HDIE. HDIE explains many effects attributed separately to Ʌ and CDM. HDIE mimics Ʌ with sufficient energy and an equation of state parameter, w= -1.03±0.05 at redshifts z<1.35 to account for accelerating expansion. HDIE is clumped around galaxies at densities that distort space-time, explaining many CDM attributed effects. The present ratio of HDIE/baryons ~2.15, required for the observed expansion history, is equivalent to a dark matter fraction ~68%, consistent with many galaxies. The HDIE/baryon model is based largely on proven physics, provides a common explanation for dark energy and dark matter, and solves the cosmological coincidence problem. At earlier times, z > ~1.35, HDIE was phantom, w = -1.82±0.08, enabling the model to be falsified. HDIE fits Planck dark energy wo-wa plots at least as well as Ʌ, and is consistent with other results that suggest dark energy was phantom at earlier times. A new w-parameterisation is proposed, as the usual CPL parameterisation is biased and unsuitable for distinguishing between HDIE/baryon and ɅCDM models.

Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.

We have synthesized and examined a series of calix[4]arene-based chemosensors containing thiosemicarbazone or thiourea as a binding site and a pyridine-chromophore unit in various conformations. These conformations include pinched cone (I), cone (III and IV), and 1,3-alternate (II and V). Our objective was to assess the binding abilities of these sensors towards anions and cations using different spectroscopic techniques. All receptors demonstrate the ability to recognize cations, with notable distinctions between them. Receptor I demonstrates a broad spectrum of ion recognition, encompassing Ag+, Cu2+, Co2+, Ni2+, and Zn2+. Receptors IV and V also exhibit complex formation with Co2+, Ni2+, and Cu2+ ions. Sensors II and III demonstrate exceptional selectivity for recognizing the copper (II) ion. When studying anions, only receptor I yielded satisfactory results. This is due to the thiosemicarbazone bridge and its spatial orientation in the pinched cone conformation, which allows for an interaction to occur. It is worth noting that sensors IV and V, which are fluorescent molecules due to the triazolo pyridine unit in their structure, exhibit particularly noteworthy behavior. The highest association constant is observed for cobalt (II) complexes, with values of 6.59 and 2.38 (x1012 mol/L)-2 for receptors IV and V, respectively. Our findings indicate that there are no significant differences in selectivity and sensitivity between ca-lix[4]arene receptors in 1,3-alternate and cone conformations.

G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activate agonist-receptor-G protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and  opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling - proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). Ligand-free signaling of intracellular 5-HT2A receptors could mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close gaps in our knowledge of ligand-free GPCR signaling.

Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. Besides, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41) and FFAR4 (GPR120). FFAR2 and FFAR3are activated by short chain fatty acids like acetate, propionate and butyrate whereas FFAR1 and FFAR4 are activated by medium and long chain fatty acids like palmitate, oleate, linoleate and others. FFARs have generated considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR based therapies to treat patients with obesity and Type 2 Diabetes.

Cytokines are a family of proteins which play a major role in the regulation of immune system, and enter the development of several diseases from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being spent in therapy and diagnosis, producing inhibitory drugs, as well as biosensors for a rapid, poor invasive, and effective detection. In this regards, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of receptors of cytokine IL-6, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an ideal experiment.

This paper develops mathematical models examining possible roles of oxytocin and oxytocin receptors in the development of autism. This is done by demonstrating that mathematical operations on normalized data from the Stanford study (K.J. Parker, 2016), which establishes a correspondence between severity of autism in children and their oxytocin blood levels, generates a graph that is the same as the graph of mathematical operations on a normalized theoretical model for the severity of autism. This procedure establishes the validity of the theoretical model and the significance of oxytocin receptors in autism. A steady-state model follows, explaining the constant baseline concentrations of oxytocin observed in the cerebral spinal fluid and blood in terms of the neuromodulation by oxytocin of oxytocin receptors on the magnocellular neurons that produce oxytocin in nuclei in the hypothalamus. The implications of these models for possible roles of oxytocin and oxytocin receptors in autism is considered for several unrelated conditions that may be associated with autism. These are: oxytocin receptor desensitization and down-regulation as factors during labor in offspring autism development; reductions in the oxytocin receptor numbers in the fixed oxytocin receptor expression that occurs before birth; MAST Immune System disease; and the excess number of dendritic spines from lack of pruning observed in brains of autistic people. Research into the feasibility of generating magnocellular neurons and other neurons from adult stem cells is suggested as a way of doing invitro studies of oxytocin and oxytocin receptors to assess the validity of theories presented in this paper.

Due to its application as an anti-cancer drug, pazopanib (1) has attracted the interest of many researchers and several studies on pazopanib synthesis have been reported over the years. This paper provides a novel route for synthesizing N,2,3-trimethyl-2H-indazol-6-amine (5) which is a crucial building block in the synthesis of pazopanib from 3-methyl-6-nitro-1H-indazole (6). By alternating between the reduction and two methylation steps compound 5 was obtained in comparable yield (55.0%) to what has been reported (54%). Noteworthy, the last step of N2-methylation also yielded N,N,2,3-tetramethyl-2H-indazol-6-amine (5’) as a new compound ever reported. Furthermore, the data presented in this paper can serve as instrumental for future research aimed at further refining the synthesis process of pazopanib.

N-methyl-D-aspartate receptors (NMDARs) are the main class of ionotropic receptor for the ex-citatory neurotransmitter glutamate. It plays a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of sev-eral subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) and/or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, excitotoxicity. The present review will discuss the physiopathological impacts of NMDAR and particularly GluN2A and GluN2B subu-nits in cognitive processes and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease). The pharmacology of different NMDAR antagonists and their po-tentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising developments as a tomography radiotracer for NMDARs, an anxiolytic in post-traumatic stress disorder and a neuroprotective agent in Alzheimer's disease.

Chimeric antigen receptors (CARs) is one of the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastoma, the most common extracranial pediatric solid tumors with diverse comportment, could be a promising candidate for using CARs therapies. Several methods harness CARs modified cells in neuroblastoma to increase therapeutic efficiency, albeit the assessment has still been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reason behind the inadequate response against neuroblastoma of CARs modified cells are still not well understood. It is essential to update the present reveal of comprehension of CARs to improve the efficiency of CARs therapies. This review summarizes the crucial features of CARs and its design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic competence, and focuses on devising strategies currently investigated to improve the efficacy of CARs for neuroblastoma immunotherapy.

Despite several decades’ effort to detect and identify phytoplasmas (Tenericutes: Mollicutes) using PCR and Sanger sequencing focusing on diseased plants, knowledge of phytoplasma biodiversity and vector associations remains highly incomplete. To improve protocols for documenting phyto-plasma diversity and ecology, we used DNA extracted from phloem-feeding insects and com-pared traditional Sanger sequencing with a next-generation sequencing method, Anchored Hy-brid Enrichment (AHE) for detecting and characterizing phytoplasmas. Among 22 of 180 leaf-hopper samples that initially tested positive for phytoplasmas using qPCR, AHE yielded phyto-plasma 16Sr sequences for 20 (19 complete and 1 partial sequence) while Sanger sequencing yield-ed sequences for 16 (11 complete and 5 partial). AHE yielded phytoplasma sequences for an addi-tional 7 samples (3 complete and 4 partial) that did not meet the qPCR threshold for phytoplasma positivity or yielded non-phytoplasma sequences using Sanger sequencing. This suggests that AHE is more efficient for obtaining phytoplasma sequences. Twenty-three samples with sufficient data were classified into eight 16Sr subgroups (16SrI-B, I-F, I-AO, III-U, V-C, IX-J, XI-C, XXXVII-A), three new subgroups (designated as 16SrVI-L, XV-D, XI-G) and three possible new groups. Our results suggest that screening phloem-feeding insects using qPCR and AHE sequencing may be the most efficient method for discovering new phytoplasmas.

Despite many calls to reduce or eliminate the use of mechanical restraint, it is still widely used in many countries. Studies using patient interviews have a very clear message: Patients experience mechanical restraint as the most humiliating intervention. There seems to be a lack of alternatives with violent patients. We developed a method using 30 kg bags, originally designed for fitness purposes, to be attached to a patient's wrist or ankle under 1:1 supervision. The method was tested with 10 experienced nurses and de-escalation trainers. A video was made and presented to six outpatients who had previously experienced mechanical restraint. All participants were interviewed. Transcribed interviews were analysed using qualitative content analysis. All participants approved of the method as a milder and less humiliating alternative to mechanical restraint. Nurses' main concerns were the risk of falls and the use of the bags as a weapon. The latter could be controlled by using an additional bag. Patients were generally positive, especially if there was a history of abuse. The method should be further developed to replace at least part of mechanical restraints. As with all ‘milder means‘, care should be taken to really replace restraint and not to introduce additional coercion.

Location-and-scale transformation of a random variable underpins normal distribution, but it is however fundamentally incorrect for scale estimation such as relative dispersion. In this paper, a parametrized alternative to a normal distribution, called scaloc-normal distribution, is proposed that efficiently works and is fundamentally correct with absolute and relative dispersion estimators. The Monte Carlos simulation experiment was used to generate a total of 600,000 artificial datasets in 600 different simulation scenarios from loc-normal (normal) and scaloc-normal distributions. The absolute and relative dispersion were estimated and compared from the two distributions. The results show that scaloc-normal distribution is a good parametrized alternative to loc-normal distribution, fundamentally correct and efficient with both standard deviation and coefficient of variation. The key statistical advancement from loc-normal to scaloc-normal distribution is its fundamental correctness (i.e., scale-invariant property) with an efficient relative estimator of dispersion (i.e., coefficient of variation). Parametrically, the loc-normal and scaloc-normal distributions are very different, but both have linear transformations.

Infection-related cardiovascular diseases (CVDs) represent a significant health challenge, necessitating novel therapeutic strategies targeting key receptors involved in inflammation and infection. Antimicrobial peptides (AMPs) offer a promising approach, potentially disrupting pathogenic processes. This study aimed to investigate the efficacy of AMPs as therapeutic agents by examining their interactions with critical CVD-related receptors. A comprehensive computational approach was utilized to assess the interactions between AMPs and receptors associated with CVDs. Molecular docking studies were conducted to evaluate AMP binding to target receptors: ACE2, CRP, MMP9, NLRP3, and TLR4. The top-performing AMPs were further analyzed through 100 ns molecular dynamics (MD) simulations, and their binding affinities were quantified using MM/PBSA calculations. The analysis revealed that Tachystatin, Pleurocidin, and Subtilisin A exhibit strong binding affinities to key CVD-related receptors, including ACE2, CRP, and MMP9. These AMPs demonstrated the potential for disrupting receptor-peptide interactions critical to infection and inflammation. MD simulations confirmed the stability of AMP-receptor complexes, with MM/PBSA calculations showing significant binding energies. Future directions include conducting in vitro and in vivo studies to validate the therapeutic efficacy and safety of these AMPs in clinical settings.

Applying cold to a bone injury can aid healing, though its mechanisms are complex. This study investigates how cold therapy impacts bone repair to optimize healing. Cold was applied to a rodent bone model, with physiological responses analyzed. Vasoconstriction was mediated by an increase in TRP channels, TRPA1 (p=0.012) and TRPM8 (p&lt;0.001), within cortical defects enhancing sensory response and blood flow regulation. Cold exposure also elevated hypoxia (p &lt; 0.01) and VEGF expression (p &lt; 0.001), promoting angiogenesis vital for bone regeneration. Increased expression of osteogenic proteins PGC-1α (p = 0.039) and RBM3 (p&lt;0.008) suggests stimulated reparative processes. Enhanced osteoblast differentiation and ALP presence at days 5 (three-fold, p=0.014) and 10 (two-fold, p=0.010) were observed, along with increased osteocalcin (OCN) at day 10 (two-fold, p = 0.010) indicating presence of mature osteoblasts capable of mineralization. These findings highlight cold therapy's multifaceted effects on bone repair, offering insights for therapeutic strategies.

Caffeine is the most popular and widely-consumed behaviourally-active substance in the world. This review focuses on the influence of caffeine on the cardiovascular system, with a special focus on blood platelets. For many years, caffeine was thought to have a negative effect on the cardiovascular system mainly due to increasing blood pressure. However, more recent data suggests that habitual caffeine consumption may reduce the risk of cardiovascular disease and hypertension. This could be a significant finding as cardiovascular disease is the leading cause of death worldwide. Caffeine is known to inhibit A1 adenosine receptors, through which it is believed to modulate inter alia coronary blood flow, total peripheral resistance, diuresis and heart rate. Although few publications have reported the effects of caffeine on platelet function, it seems reasonable to conclude that caffeine has antiplatelet activity. Platelet activation is known to play a crucial role in the development of arterial thrombotic diseases such as coronary heart disease and stroke, and hence there is a need to develop novel platelet inhibitors. One promising strategy to develop effective antiplatelet therapy involves targeting multiple pathways of platelet activation. Therefore, this review also examines the concept of dual antiplatelet therapy and the potential benefits associated with the therapeutic use of combined P2Y12 antagonists and adenosine receptor agonists in cardioprotection.

An event of increasing interest during host-pathogen interactions is the differentiation of patrolling monocytes (MOs) and the polarization of naive MOs into macrophage subsets (MФs). Therapeutic strategies aimed at modulating this event are under investigation. This review focuses on the mechanisms of induction, development, and profile of MФs polarized toward classically proinflammatory (M1) or alternatively anti-inflammatory (M2) phenotypes in response to bac-teria, fungi, parasites, and viruses. It highlights nuclear (PPARγ), cytoplasmic, and cell surface receptors (pattern recognition receptors/PPRs), microenvironmental mediators, and immune signaling. MФs polarize into phenotypes: M1 MФs, activated by IFN-γ, pathogen-associated mo-lecular patterns (PAMPs, e.g. LPS)/DAMPs and membrane-bound PPRs ligands (TLRs/CLRs lig-ands); or M2 MФs (a, b, c and d), induced by IL-4, -10 and -13, antigen-antibody complexes, and helminth PAMPs. The kinetics of M1 and M2 polarization evolve in a pathogen-specific manner, with or without canonicity, and can vary widely. Ultimately, this can result in varying degrees of host protection or more severe disease outcome. While the host is driving an effective MФs po-larization, pathogens are attempting to shift it to increase pathogenicity. The latter results from a bias toward an ineffective M1 or M2 response due to microbial virulence factors, culminating in pathogen evasion of host defenses. Plasticity of M1/M2 phenotypes is also ensured by cellu-lar/genomic reprogramming. Because modulation of this event can occur at multiple points, providing a therapeutic/vaccine design target to boost microbicidal (M1) or tissue repair (M2) response during the inflammation-to-resolution transition; new insights and emerging perspec-tives may have clinical implications.

In recent years, the interaction between adiponectin (APN), a versatile fat-associated adipokines, and eye disorders has become a captivating focus of interest. Unveiling the intricate relationship between APN and its receptors (AdipoRs) with aging eye disorders has emerged as a fascinating frontier in medical research. This review article delves into this captivating connection, illuminating the hidden influence of adipocytokine, APN on retinal health. This comprehensive review critically examines the latest findings and breakthroughs that underscore the pivotal roles of APN/AdipoRs signaling in maintaining ocular homeostasis and protecting against eye ailments. Here, we meticulously explore the intriguing mechanisms by which APN protein influences retinal function, lens clarity, and overall visual acuity. Drawing from an extensive array of cutting-edge studies, the article highlights APN's multifaceted functions, ranging from anti-inflammatory properties and oxidative stress reduction to angiogenic regulation within retinal and macula tissues. The involvement of APN/AdipoRs in mediating these effects opens up novel avenues for potential therapeutic interventions targeting prevalent aging eye conditions. Moreover, this review unravels the interplay between APN signaling pathways and age-related macular degeneration (AMD). The single-cell RNA seq results validate the expression of both the receptor isoform (AdipoR1/R2) in retinal cells. The transcriptomic analysis showed lower expression of AdipoR1/2 in dry AMD pathogenesis compared to healthy subjects. The inhibitory peptide (APN1) demonstrated over 75% suppression of CNV, whereas the control peptide did not exert any inhibitory effect on CNV. The elucidation of these relationships fosters a deeper under-standing of adipose tissue's profound influence on ocular health, presenting new prospects for personalized treatments and preventative measures. In conclusion, "Obesity Hormone's Role in Aging Eyes: Linking Adiponectin/AdipoRs to AMD" provides a captivating journey into the enthralling world of APN intertwining the realms of adipose biology and aged ophthalmology.

Parascaris sp. is the only ascarid parasitic nematode in equids and one of the most threatening infectious organisms in horses. Only a limited number of compounds are available for treatment of horse helminthiasis and Parascaris sp. worms have developed resistance to the three major anthelmintic families. In order to overcome the appearance of resistance, there is an urgent need for new therapeutic strategies. The active ingredients of herbal essential oils are potentially effective antiparasitic drugs. Carvacrol is one of the principal chemicals of essential oil from Origanum, Thymus, Coridothymus, Thymbra, Satureja and Lippia herbs. However, the antiparasitic mode of action of carvacrol is poorly understood so far. Here, the objective of the work was to characterize the activity of carvacrol on Parascaris sp. nicotinic acetylcholine receptors (nAChRs) function both in vivo with the use of worm neuro-muscular flap preparations and in vitro with two-electrode voltage-clamp electrophysiology on nAChRs expressed in Xenopus oocytes. We have developed a neuromuscular contraction assay on Parascaris body flaps and obtained acetylcholine concentration-dependent contraction responses. Strikingly, we observed that 300 µM carvacrol fully and irreversibly abolished Parascaris sp. muscle contractions elicited by acetylcholine. Conversely, carvacrol antagonized acetylcholine-induced currents from both the nicotine-sensitive AChR and the morantel-sensitive AChR subtypes. Thus, we show for the first time that the body muscle flap preparation is a tractable approach to investigate the pharmacology of Parascaris sp. neuro-muscular system. Our results suggest an intriguing mode of action for carvacrol being a potent antagonist of muscle nAChRs of Parascaris sp. worms which may account for its antiparasitic potency.

Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in Xenopus laevis oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα1. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na+ is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα1 potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα1 PAM.

Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.

Early Endosomes represent first line sorting compartments or even organelles for internalized molecules. They enable the transport of molecules or ligands to other compartments of the cell, such as lysosomes for degradation or recycle them back to the membrane by various mechanisms. Moreover, early endosomes function as signaling and scaffolding platform to initiate or prolong distinct signaling pathways. Accordingly, early endosomes have to be recognized as either part of a degradation or recycling pathway. The physical proximity of many ligand-binding receptors with other membrane bound proteins or complexes such as NADPH oxidases may result in an interaction of second messengers like reactive oxygen species (ROS) and early endosomes that promote correct recognition of individual early endosomes. In fact, redoxosomes comprise an endosomal subsection of signaling endosomes. One example of such potential interaction is epidermal growth factor receptor (EGFR) signaling. Here we summarize recent findings on EGFR signaling as a well-studied example for receptor trafficking and trans-activation and illustrating the interplay between cellular and endosomal ROS.

Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to those NRs modulation, OA exhibited prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.

This study introduces numerical advancements in an alternative design for the SPS Beam Dump Facility (BDF) at CERN. The design envisions a high-power operation target made of flowing liquid lead. The BDF is a proposed versatile facility at CERN, intended for both beam-dump-like and fixed-target experiments. The target behavior is assessed, assuming a proton beam with a momentum of 400 GeV/c, a pulse frequency of 1/7.2 Hz, and an average beam power of 355 kW. An evaluation is conducted using various Computational Fluid Dynamics (CFD) codes to analyze the behavior of liquid lead and to predict the thermal stress on the target vessel induced by the pulsed heat source generated by the charged particle beam. The comparison increases the reliability of the results, investigating the dependencies on the CFD modeling approach. The beam is modeled as a volumetric heat source with data coming from beam-lead interaction simulations provided by CERN and obtained with the Monte-Carlo code FLUKA. The velocity field and stress profiles are utilized to enhance the design of the lead loop and verify its viability and safety when operated with a liquid metal target.

The availability of petroleum asphalt, derived from non-renewable sources, is steadily declining alongside diminishing petroleum reserves. To reduce reliance on petroleum, alternative renewable natural sources are being explored as both modifiers and replacements for petroleum asphalt, particularly in asphalt binders. This study explores the chemical, rheological, and mechanical properties of Gopal, a bio-asphalt derived from Gondorukem (gum rosin) and crude palm oil (CPO). Two Gopal variants, Gopal-GEM130 and Gopal-GEG90, were analyzed using FTIR and EDX methods, with Pen 60 petroleum asphalt as a control. The results reveal that Gopal-GEG90 and Gopal-GEM130 exhibit 86% chemical similarity to Pen 60 asphalt. Gopal-GEM130 is less toxic and less alkaline compared to Pen 60, while Gopal-GEG90 is less toxic but more alkaline. Both variants fall under the same classification as Pen 60 in terms of rheological properties, with Gopal-GEG90 demonstrating slightly better stripping resistance but lower aging resistance. Gopal-GEM130 showed better stripping resistance and rutting performance, though with lower fatigue resistance and faster aging compared to Pen 60 asphalt. Both bio-asphalt variants align with performance grade PG64S, signifying their potential as alternatives to conventional petroleum asphalt.

Abstract: The search for alternative protein sources to soy-bean meal (SBM) in animal feeding is a strategic objective to reduce production costs and contribute to a sustainable animal produc-tion. Spirulina, due to the high protein content, has emerged as a potential cost-effective, sus-tainable, viable and high nutritional value food resource for many animal species. Insect larvae (Tenebrio molitor and Hermetia illucens) are also considered potential alternatives to SBM, given their high edible percentage of almost 100%, as well as a protein value higher than that of vegetable proteins. Rapeseed meal and grain legumes, such as faba beans, peas, lupins and chickpea can also be used as locally producible protein ingredients. This study reviews the nutritional value of these potential alternatives to SBM in pig diets, effects on animal perfor-mance, digestion, immune system, physicochemical and sensorial characteristics of meat, in-cluding processed meat products of pork. Limits on their use in pig feeding are also reviewed to indicate gaps to be filled in future research on the supplementation level of these potential al-ternative protein sources into pig diets.

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain on eye movements. Typical ON is associated with Multiple Sclerosis and is generally mild and steroid-responsive, whereas atypical forms are characterized by unusual features, such as optic disc edema, poor treatment response and bilateral involvement, and are often associated with autoantibodies against aquaporin-4 (AQP4) and Myelin Oligodendrocyte Glycoprotein (MOG). However, in rare cases AQP4 and MOG antibodies will come back negative, plunging the clinician in a diagnostic conundrum. Seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis is greatly different. The scope of this review is to describe possible, rarer etiologies of ON when AQP4 and MOG antibodies are negative and discuss their diagnosis and treatment.

Alternative splicing (AS) is a gene regulatory mechanism modulating gene expression in multiple ways. AS is prevalent in all eukaryotes including plants. AS generates two or more mRNAs from the precursor mRNA (pre-mRNA) to regulate transcriptome complexity and proteome diversity. Advances in next-generation sequencing, omics technology and bioinformatics tools, and computational methods provide new opportunities to quantify and visualize AS-based quantitative trait variation associated with plant growth, development, reproduction, and stress tolerance. Domestication, polyploidization and environmental perturbation may evolve novel splicing variants associated with agronomically beneficial traits. To date, pre-mRNAs from many genes are spliced into multiple transcripts that cause phenotypic variation for complex traits, both in model plant Arabidopsis and field crops. Cataloguing and exploiting such variation may provide new paths to enhance climate resilience, resource-use efficiency, productivity, and nutritional quality of staple food crops. This review provides insights into AS variation alongside gene expression analysis to select for novel phenotypic diversity for use in breeding programs. AS contributes to heterosis, enhances plant symbiosis (mycorrhiza and rhizobium), and provides a mechanistic link between the core clock genes and diverse environmental clues.

Porous ceramics can be realized by different methods and are used for manifold applications, like cross-flow-membranes or wall-flow-filters, porous burners, solar receivers, structural design elements or catalytic supports. Within this paper three different alternative process routes are presented, which can be used to manufacture porous ceramic components with different properties or even graded porosity. The first process route bases on additive manufacturing (AM) of macro porous ceramic components, the second on AM of a polymeric template, which is used to manufacture porous ceramic components via replica technique. Finally, the third process route bases on an AM technology, which allows the manufacturing of multi-material or multi-property ceramic components, like components with dense and porous volumes in one complex shaped component.

This study assesses the pursued impacts of Tulsi value chain development intervention on the livelihoods of rural poor in Uttarakhand state of India. Tulsi as an alternative livelihood, particularly for the rural poor, is less explored. With increased crop depredation of major cereal crops grown in the district by wild animals and pests, and decreasing availability of water agriculture, attempts were made to improve earnings from Tulsi as an alternative livelihood. Findings suggest that the average households’ gross profit from Tulsi farming increases by more than double within a span of two years. Total crop income of beneficiary farmers’ increases by 0.8 percent for every 1 percent increase in Tulsi income. Intervention helped enhance productivity of Tulsi, thereby enhancing earnings from Tulsi farming. Most importantly, intervention has shown a tremendous adoption rate. Towards the end of the intervention, the value chain work was out-scaled to another 19 villages in Chamoli district, thereby reaching out to more than 400 households.

There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish, ancestral to ray-finned fish and terrestrial vertebrates, both progesterone and 17,20-beta-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20-beta-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20-beta-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone’s opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.

Heat index (HI) is a biometeorological indicator that combines temperature and relative humidity. This study aimed to investigate the relationship between heat index and daily counts of diarrhoea hospitalisation in Dhaka, Bangladesh. Data on daily diarrhoea hospitalisations and meteorological variables from 1981–2010 were collected. We categorised heat index of >94.3°F, >100.7°F and >105°F as high, very high and extremely high heat index, respectively. We applied time-series adjusted generalised linear model (GLM) with negative binomial distribution to investigate the effects of heat index and extreme heat index on hospitalisations for diarrhoea. Effects were assessed for all ages, <5 children and by gender. A unit higher HI, and high, very high and extremely high HI were associated with 0.8%, 8%, 7% and 9% increase in diarrhoea hospitalisation in all ages, respectively. The effects varied slightly by gender and were most pronounced in <5 children with a rise of 1°F in high, very high and extremely high HI associated with a 14.1% (95% CI: 11.3% – 17.0%), 18.3% (95% CI: 13.4% – 23.5%) and 18.1% (95% CI: 8.4% – 28.6%) increase of diarrhoea, respectively. This suggest that heat index may serve as an alternative indicator for measuring the combined effects temperature and humidity on diarrhoea.

Growing popularity of smart and integrated buildings requires a review of methods to optimize the preheat of ventilation air. An integrated system permits using heat ex-changers located in the mechanical room or in the future even using an exterior wall as a heat exchanger. One may ask the question how does the earth-air heat exchanger (EAHX) technology fitts into this function. EAHX has many advantages but also has many unanswered questions. Some of the drawbacks are: a possible entry of radon gas, high humidity in the shoulder seasons as well as the need for two different air intake sources with a choice that depends on the actual weather conditions. While in winter, the EAHX may be used continuously to ensure thermal comfort, in other seasons, its operation must be automatically controlled. To generate the missing information about the EAHX technology we reviewed literature and examined two nearly identical EAHX systems, placed either in ground next to the building or under the basement slab. Effectively, the information provided in this paper, shows advantages of merging both these approaches while the EAHX shoud be placed under the house or near the basement foundation.

It has long been known that phytohormone auxin plays a promoting role in tuber formation and stress tolerance in potatoes. Our study aimed to identify and characterize the complete sets of auxin-related genes that presumably constitute the entire auxin signaling system in potato (Solanum tuberosum L.). The corresponding genes were retrieved from sequenced genomes of the doubled monoploid S. tuberosum DM1-3-516-R44 (DM) of the Phureja group, the heterozygous diploid line RH89-039-16 (RH), and the autotetraploid cultivar Otava. Both canonical and noncanonical auxin signaling pathways were considered. Phylogenetic and domain analyzes of deduced proteins were supplemented by their expression profiling and 3D molecular modeling. The canonical and ABP1-mediated pathways of auxin signaling appeared to be well conserved. Total number of potato genes/proteins presumably involved in canonical auxin signaling is 46 and 108 in monoploid DM and tetraploid Otava, respectively. Among studied potatoes, spectra of expressed genes obviously associated with auxin signaling were partly cultivar-specific and quite different from analogous spectrum in Arabidopsis. Most of the noncanonical pathways found in Arabidopsis appeared to be low probable in potato. This was equally applied to all cultivars used irrespective of their ploidy. Thus, some important features of the (noncanonical) auxin signaling pathways may be variable and species-specific.

Alternative fuels containing biocomponents produced in various technologies are introduced in aviation to reduce its carbon footprint but there is little data describing their impact on the performance and emissions of engines. The purpose of the work is to compare the performance and gas emissions produced from two different jet engines: the GTM-140 microturbine and the full-size DGEN380 turbofan, powered by blends of Jet A-1 and one of two biocomponents: 1) ATJ and 2) HEFA produced from used cooking oil (UCO) in various concentrations. The acquired data will be used to develop an engine emissivity model to predict gas emissions. Blends of the mineral fuel with synthetic components were prepared in various concentrations, and their physicochemical parameters were examined in the laboratory. Measurements of emissions from both engines were carried out in selected operating points using the Semtech DS gaseous analyzer and the EEPS spectrometer. The impact of tested blends on engine operating parameters is limited, and their use does not carry the risk of a significant decrease in aircraft performance or increase in fuel consumption. Increasing the content of biocomponents causes a noticeable rise in the emission of CO and slight increase for some other gasses (HC and NOx), which should not, however, worsen the working conditions of the ground personnel. This implies that there are no contraindications against using tested blends for fuelling gas-turbine engines.

The main goal of the Soil Moisture and Ocean Salinity (SMOS) mission over land surfaces is the production of global maps of soil moisture (SM) and vegetation optical depth (τ) based on multi-angular brightness temperature (TB) measurements at L-band. The operational SMOS Level 2 and Level 3 soil moisture algorithms account for different surface effects, such as vegetation opacity and soil roughness at 4 km resolution, in order to produce global retrievals of SM and τ. In this study, we present an alternative SMOS product which was developed by INRA (Institut National de la Recherche Agronomique) and CESBIO (Centre d’Etudes Spatiales de la BIOsphère). This SMOS-INRA-CESBIO (SMOS-IC) product provides daily SM and τ at the global scale and differs from the operational SMOS Level 3 (SMOSL3) product in the treatment of retrievals over heterogeneous pixels. Specifically, SMOS-IC is much simpler and does not account for corrections associated to the antenna pattern and the complex SMOS viewing angle geometry. It considers pixels as homogeneous to avoid uncertainties and errors linked to inconsistent auxiliary data sets which are used to characterize the pixel heterogeneity in the SMOS L3 algorithm. SMOS-IC also differs from the current SMOSL3 product (Version 300, V300) in the values of the effective vegetation scattering albedo (ω) and soil roughness parameters. An inter-comparison is presented in this study based on the use of ECMWF (European Center for Medium range Weather Forecasting) SM outputs and NDVI (Normalized Difference Vegetation Index) from MODIS (Moderate-Resolution Imaging Spectroradiometer). A 6 year (2010-2015) inter-comparison of the SMOS products SMOS-IC and SMOSL3 SM (V300) with ECMWF SM yielded higher correlations and lower ubRMSD (unbiased root mean square difference) for SMOS-IC over most of the pixels. In terms of τ, SMOS-IC τ was found to be better correlated to MODIS NDVI in most regions of the globe, with the exception of the Amazonian basin and of the northern mid-latitudes.

Recent trends concerning hydrogen as a fuel of the future and problems related to its production, storage and utilization increase the demand for efficient technologies related to these problems. A large part of such technologies is related to application of advanced materials based on various complex oxides which are used as efficient catalysts for fuel transformation into hydrogen and syngas, materials for membranes with selective permeability for hydrogen and syngas production, components of solid oxide fuel cells/electrolyzers as well as many other applications in energy, electrochemistry and catalysis. Such materials are typically based on oxides and solid solutions with perovskite and fluorite structures or their derivatives. Attention is also paid to the materials based on spinel, apatite, mayenite, sheelite, fergusonite structures. The above-mentioned materials are continuously studied in order to modify and optimize their functional properties. On the other hand, other classes of materials (weberites, monazites, etc.) are recently discovered and considered as candidate materials for the aforementioned applications due to their specific functional properties or a great potential of their improvement. In this review, some of these materials are considered.

Background: The use of complementary therapies in the population is increasing, so it is necessary to understand the training that health professionals receive in this type of therapy in their training plans, as they are often the primary source of information for patients. Our objective was to investigate Spanish universities that offer subjects on complementary therapies in their Nursing degree programs. Methods: Observational descriptive cross-sectional study. For this purpose, we used the document published on the website of the Ministry of Universities as a working document. Additionally, a literature search was conducted up to September 2023 in the PubMed database, along with reverse searches. Results: Out of a total of 62 universities, only 16 (29%) offer a subject related to this type of therapy, with most of them being elective courses. Conclusions: The training content on complementary care in Nursing degree programs in Spanish universities is scarce, highlighting the potential benefit of expanding and promoting it, in line with the recommendations of the World Health Organization.

Reducing meat consumption is better for the environment. Unfortunately, commercial plant-based meat substitutes are often more expensive than meat and thus have not seen widespread adoption. This paper analyzes commercially-available spirulina, soy, pea, and brown rice protein isolates characteristics to provide data for non-meat protein cost reductions. Thermal and rheological properties, viscosity, density, and particle size distribution are analyzed for further study on alternative protein-based food processing. Differential scanning calorimetry analysis produced dry amorphous-shaped curves and paste curves with a more distinct endothermic peak. Extracted linear temperature ranges for processing in food production for spirulina was 70-90ºC; soy protein was 87-116ºC; pea protein was 67-77ºC; and brown rice protein was 87-97ºC. Viscosity analysis determined each protein material was shear-thinning and that viscosity increased with decreased water concentration, with rice being an exception to the latter trend. The obtained viscosity range for spirulina was 15,100-78,000cP; soy protein was 3,200-80,000cP; pea protein was 1,400-32,700cP; and brown rice protein was 600-3,500cP. The results indicate that extrusion is a viable method for further processing of the protein isolates as this technique has a large temperature operating range and variable screw speed. Data provided here can be used to make single or multi-component protein substitutes.

This article traces the origination, distribution, kinematics, function, and nature of alternative lateral horse gaits, i.e. intermediate speed lateral-sequence gaits involving the synchronization of ipsilateral limbs in the swing phase. Such alternative lateral horse gaits (namely, the running walk, rack, broken pace, hard pace, and broken trot) have been prized by equestrians for their comfort, and have been found in select horse breeds for hundreds of years and even exhibited in fossil equid trackways. After exploring the evolution and development of alternative lateral gaits via fossil equid trackways, human art and historical writings, and the genetics and history of modern horse breeds, functional and biomechanical reasons are offered for the genesis of these gaits. The article concludes by tracing similarities and differences between and within the expression of these alternative lateral gaits by various horse breeds. Fast and low-swinging hard pacing gaits are common in several horse breeds of East and North Asia, high-stepping rack and running walk gaits are often displayed in European and North and South American breeds, the broken pace is found in breeds of Central Asia, Southeast Asia, West Asia, Western North America, and Brazil in South American, and the broken trot occurs in breeds of North Asia, South Asia, and the Southern United States, and Brazil South America.

Currently, there is increasing industrial demand for rare earth elements (REE) as these elements are now integral to the manufacture of many carbon-neutral technologies. The depleting REE ores and increasing mining costs are prompting to look for alternative sources for these valuable metals, particularly from waste streams. Although REE concentrations in most of the alternate resources are lower than current REE ores, some sources such as marine sediments, coal ash, and industrial wastes like red mud are looking promising with significant concentrations of REE in them. This review focuses on the alternative resources for REE such as ocean bottom sediments, continental shelf sediments, river sediments, stream sediments, lake sediments, phosphorites deposits, industrial waste products like red mud, and phosphogypsum, coal, coal fly ash, and related materials, waste rock sources from old and closed mines, acid mine drainage, and recycling of e-waste. Possible future Moon exploration and mining for REE and other valuable minerals are also discussed. It is evident that REE extractions from both primary and secondary ores alone are not adequate to meet the current demand, and sustainable REE recovery from the alternative resources described here is also necessary to meet the growing REE demand. An attempt is made to identify the potential of these alternative resources and sustainability challenges, benefits, and possible environmental hazards to meet the growing challenges in meeting the future REE requirements.

A progressive and chronic neurological condition called MSA (Multiple System Atrophy) is characterized clinically by varying degrees of dysautonomia, cerebellar ataxia, and parkinsonism. The concept of mitochondrial dysregulation in MSA is one perspective in handling this neurodegenerative disease. Damage to functional mitochondria is driven by the presence of ɑ-Synuclein-induced mitochondrial localization. The goal of MSA treatment up until now has been to reduce symptoms. One of the innovations in the treatment of MSA could be the novel idea based on mitochondrial reprogramming pathways. Mitochondrial reprogramming can be done in various ways in which the use of hydrogen, magnesium and low-dose hydrogen peroxide.

La minería es una industria intensiva en energía que requiere una fuente estable de electricidad. Con el aumento de la demanda de minerales y la disminución de las leyes, se espera que la demanda de energía aumente en un 36% para el 2035. Este aumento de la demanda depende del uso de combustibles fósiles ya que la electricidad producida y comprada en las empresas mineras se basan principalmente en el caso de los combustibles fósiles, los costos de los sistemas de almacenamiento de energía solar y eólica han caído a una escala sin precedentes, lo que alienta a las empresas mineras a probar estas tecnologías.Entre los factores que influyen en el uso de energía renovable, se encuentra el beneficio a la comunidad en la etapa de operación y cierre o post-cierre de un proyecto minero, el siguiente factor es el perfil de consumo eléctrico o demanda es importante para el cálculo de su almacenamiento o no, de las energías renovables a utilizar. Como tercer factor está el cálculo del consumo en los procesos. Los rangos de penetración determinarán si es posible su almacenamiento de energía, y si es posible utilizar control híbrido (solar - eólico), para ello es importante el uso de herramientas digitales como el programa Holmer, es una herramienta importante que técnica y económica.El gobierno debe tener una perspectiva que ayude en los temas regulatorios necesarios para impulsar proyectos de energía renovable con diferentes incentivos e intereses según el contexto minero.

Prostate cancer (PCa) is a major cause of cancer-related mortality worldwide, with a rising incidence observed over the years. The androgen receptor (AR) signaling pathway plays a pivotal role in male development and maintaining masculine characteristics. Dysregulation of AR signaling in prostate cancer can lead to disease progression and resistance to standard therapies. Understanding the intricate regulation and function of AR in both healthy and diseased states is crucial for developing effective treatment strategies. This review comprehensively explores the role of androgen receptors in prostate cancer susceptibility, disease progression, and treatment response by analyzing recent literature. An extensive search of peer-reviewed publications in major databases, including PubMed, Scopus, and Web of Science, was conducted using specific keywords related to androgen receptor, prostate cancer, disease progression, and treatment resistance. Relevant conference abstracts and clinical trial reports were also included. The review presents an overview of the role of androgen receptors in prostate cancer initiation, progression, and treatment resistance. It highlights emerging biomarkers associated with AR signaling dysregulation and their potential utility for early detection and personalized treatment approaches. Additionally, recent advances in targeting the AR pathway for novel therapeutic strategies to improve patient outcomes and overcome treatment resistance in advanced prostate cancer are discussed. The findings contribute to a comprehensive understanding of the AR signaling pathway in prostate cancer and offer insights into its multifaceted role in disease development and treatment response. They may pave the way for innovative therapeutic interventions and precision medicine approaches based on specific AR signaling profiles, enhancing patient care and reducing the burden of this lethal disease.

CD8 T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signal, cytokine stimulation and nutrients availability. This integration is achieved by signaling hubs such as the mechanistic target of Rapamycin (mTOR). mTOR is a conserved protein kinase, controlling cellular growth and metabolism in eukaryotic cells and therefore is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model to comprehend metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here we review the signaling pathways leading to mTOR activation in CD8 T and NK cells, focusing on activation by cytokines. We also discussed how this knowledge can contribute to immunotherapy development for intracellular pathogen and cancer treatment.

(1) Background: Many malignancies are driven by mutations which affect the gene for fibroblast growth factor receptor (FGFR) 1. Previously we have documented that signal transduction from FOP2–FGFR1 fusion protein in KG1 cells downregulated the expression of vitamin D receptor (VDR) gene. In this paper we investigated if also other FGFRs were responsible for the regulation of the VDR expression. (2) Methods: We used human myeloid leukemia cells U937, and bone cancer cell line U2OS, and cell transfection methods in order to address the above questions. (3) Results: In myeloid leukemia cells overexpression of FGFR 1-4 caused shift to granulocytic differentiation, upregulated expression of VDR, and sensitized these cells to 1,25-dihydroxyvitamin D (1,25D)-induced monocytic differentiation, while in bone cells, signal transduction activated by FGF1 was not responsible for regulation of VDR expression and activity. (4) Conclusions: Since the overexpression of FGFRs occurs in many neoplasms, it may be reasonable to use 1,25D analogs in these cancers, in which overexpression of FGFRs leads to VDR upregulation.

Human beings naturally move from one location to another in search of basic necessities. Road transportation is a low-cost, versatile, and widely accessible mode of transportation worldwide. However, using fossil-based (FB) fuels in transportation vehicles is inefficient, generates hazardous gases, and worsens environmental degradation. The current work assesses the application of clean fuels such as biofuels, natural gas, electricity, propane, and other emerging fuels to replace FB fuels in transport vehicles. Unlike FB fuels, the use of biohydrogen, biomethane, biodiesel, and bioethanol in transport vehicles resulted in emission reduction by 70 %, 63 %, 41 %, and 54 %, respectively, while electric vehicles lower maintenance costs, ensuring better engine performance, and better engine efficiency. The adoption of natural gas and propane as alternative fuels for transport vehicles is cost-effective, and promotes environmental sustainability. There is a need for targeted financial, infrastructural, and technical investments to further promote the application of these clean fuels for road transport application. The outcome of the study provides updated information and sensitizes automobile engineers, environmentalists, transport fleet operators, governments, and other stakeholders on the benefits derivable in the adoption of clean fuels as alternatives to FB fuels as transport vehicles fuel.

Market uncertainty has a significant impact on market performance. Previous studies put much efforts in investigations on market uncertainty related to information asymmetry and risk. However, they have neglected the uncertainty inherent in market transactions, which is also an important aspect of market performance, besides quantity of transactions and market efficiency. In this paper, we put forward the concept of transaction entropy to measure the market uncertainty and see how it changes with price. The definition of transaction entropy is the ratio of total information entropy of all traders to quantity of transactions, reflecting the level of uncertainty in making transactions. And the transaction entropy is the lowest at equilibrium, it will be decreasing in a shortage market, and increasing in a surplus market. Additionally, we make a comparison of total entropy of the centralized market with that of the decentralized market, revealing that the price filtering mechanism could effectively reduce market uncertainty. Overall, the introduction of transaction entropy enriches our understanding of market uncertainty and facilitates a more comprehensive assessment of market performance.

The formation of new blood vessels is a critical process for tumor growth and may be achieved through different mechanisms. Angiogenesis represents the first described and most studied mode of vessel formation, but tumors may also use alternative ways to secure blood supply and eventually acquire resistance to anti-angiogenic treatments. These non-angiogenic mechanisms have been described more recently and include intussusceptive microvascular growth (IMG), vascular co-option, and vasculogenic mimicry. Like solid tumors, also in lymphomas angiogenic and non-angiogenic pathways play a fundamental role in tumor growth and progression. In view of the relevant prognostic and therapeutic implications, a comprehensive understanding of these mechanisms is of paramount importance for improving the efficacy of treatment in patients with lymphoma. In this review, we summarize the current knowledge on angiogenic and non-angiogenic mechanisms involved in the formation of new blood vessels in Hodgkin’s and non-Hodgkin’s lymphomas.

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of APP is likely the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element (IRE). Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Rather, these mutations likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.

The statistical properties of a good estimator include robustness, unbiasedness, efficiency, and consistency. However, the commonly used estimators of dispersion have lack or are weak in one or more of these properties. In this paper, I proposed statistical mirroring as a good alternative estimator of dispersion around defined location estimates or points. In the main part of the paper, attention is restricted to Gaussian distribution and only estimators of dispersion around the mean that functionalize with all the observations of a dataset were considered at this time. The different estimators were compared with the proposed estimators in terms of alternativeness, scale and sample size robustness, outlier biasedness, and efficiency. Monte Carlo simulation was used to generate artificial datasets for application. The proposed estimators (of statistical meanic mirroring) turn out to be suitable alternative estimators of dispersion that is less biased (more resistant) to contaminations, robust to scale and sample size, and more efficient to a random distribution of variable than the standard deviation, variance, and coefficient of variation. However, statistical meanic mirroring is not suitable with a mean (of a normal distribution) close to zero, and on a scale below ratio level.

The demands for high power and low emissions put focus on energy efficiency when developing new engines. An important part is the UAV engine cooling system, which cools the engine structure below damaging temperatures. For high temperatures in the cooling system there is a risk that boiling occurs and while the initial nucleate boiling enhances the cooling effect, the subsequent Film boiling decreases the heat transfer drastically. It is important to understand the benefits and limitations of various fluids when designing a two-phase cooling system. This paper proposes an alternative organic coolant. Its normal application range is 15°C to 400°C, and its pressure range is from atmospheric to 10.6 bar. DOWTHERM A fluid possesses unsurpassed thermal stability at temperatures of 400°C. This fluid, in both the liquid and vapor form, is noncorrosive toward common metals and alloys. Even at the high temperatures involved, the equipment usually exhibits excellent service life. Original equipment in many systems is still being used after 30 years of continuous service. The numerical results, described in this paper, show the potential of DOWTHERM A as a good alternative for cooling a UAV engine. It will extend the working temperature range of the Diesel engine and will maintain the structural integrity of the piston, cylinder and the piston rings.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants of emerging concern, recognized for their toxicity and potential carcinogenic properties. PFAS chemicals are reported to act as endocrine disruptors through their interactions with various nuclear receptors (NRs). Despite their significant impact, comprehensive screenings and detailed analyses of PFAS binding strengths at both the orthosteric and allosteric sites of NRs are currently lacking in the literature. Our study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with key nuclear receptors such as the vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). We used advanced docking simulations to screen 9,507 PFAS chemicals at the orthosteric and allosteric sites of the PPARγ, PXR, VDR, and ERα. We verified the accuracy of our docking protocol through multiple docking procedures and validations. The python code used for PFAS chemical screening is deposited in the supplementary file. Among the PFAS assessed at the orthosteric site of the VDR, 21 demonstrated similar binding affinities compared to the calcitriol, while 130 PFAS, exhibited stronger binding affinities than calcitriol. At the VDR allosteric site, where lithocholic acid (LCA) natively binds, 412 PFAS matched the binding energies of LCA, and 2,229 showed even greater binding energies. Similar testing on the PXR, PPARγ, and ERα revealed that the orthosteric site of PPARγ had 1,863 PFAS binding with a higher affinity than native ligand ET1 and 693 PFAS binding at the allosteric site with greater affinity than T35 native ligand. At the PXR orthosteric site, 650 PFAS bound with a greater affinity than native ligand 4WH, while at the allosteric site, 9,148 PFAS demonstrated a greater binding affinity than the known allosetric ligand glycerol. At the orthosteric site of ERα, 40 PFAS displayed binding with a greater affinity than the native ligand estradiol and at the allosteric site, only 8 PFAS exhibited greater binding affinity than coactivator ligand SRC-1. Further, our mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and with endogenous or native ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. This study elucidates the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted environmental regulations and therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study called for the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of intervention strategies that target nuclear receptors. Our ongoing studies extend these findings by further investigating the interactions of PFAS and co-exposed chemicals with nuclear receptors. These investigations are supported by experimental verification, which will enhance our understanding of PFAS broad effects and aid in the design of effective mitigation strategies.