Coccidioides spp are thermally dimorphic fungi found in geographically defined areas of the Western Hemisphere. The primary portal of entry is respiratory, with a symptomatic pneumonic disease as the most common presentation. Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis. This study aims to explore the spectrum of coccidioidal cavities and the evaluation and management in a cohort of patients seen at Kern Medical over the last 12 years.

Consciousness is usually interpreted as a state of being aware of one’s environment as well as self, while awareness is understood as knowledge of something. Despite their semantic differences, in philosophy, these terms are often used interchangeably, as is the case of the hard problem of consciousness proposed by Chalmers, which in fact is the hard problem of awareness. Trilogy paradigm of consciousness (or simply “trilogy”) offers a new paradigm where consciousness is the result of a unique interaction between awareness and the decision-making process. By conferring the input of awareness to the decision-making process, a new mental function of awareness-based choice selection (ABCS) or true free will emerges. Likewise, application of the power of decision-making to the process of awareness gives rise to discretionary selection of information for awareness (DSIA) or intentional attention. The intertwined actions of ABCS and DSIA comprise “I” which is the faculty of our consciousness and is what sets natural intelligence (NI) apart from artificial intelligence (AI). Based on trilogy, mind is an unconscious compilation of all mental function excluding ABCS and DSIA that are the essence of consciousness. As humans, we are a union of “I,” our minds, and our bodies.

The purpose of this study is to check out the involvement of entropy in Mpemba effect. Provided that preheating of the water the cooling duration is reduced, we theoretically show that water gains more entropy when warmed and re-cooled to the original temperature.

The EPR paradox is known as an interpretive problem, as well as a technical discovery in quantum mechanics. It defined the basic features of two-quantum entanglement, as needed to study the relationships between two non-commuting variables. In contrast, four variables are observed in a typical Bell experiment. This is no longer the same problem. The full complexity of this process can only be captured by the analysis of four-quantum entanglement. Indeed, a new paradox emerges in this context, with straightforward consequences. Either quantum behavior is capable of signaling non-locality, or it is local. Both alternatives appear to contradict existing knowledge. Still, one of them has to be true, and the final answer can be obtained conclusively with a four-quantum Bell experiment.

We present the real number system as a natural generalization of the natural numbers. First, we prove the co-finite topology, $Cof(\mathbb N)$, is isomorphic to the natural numbers. Then, we generalize these results to describe the continuum $[0,1]$. Then we prove the power set $2^{\mathbb Z}$ contains a subset isomorphic to the non-negative real numbers, with all its defining structure of operations and order. Finally, we provide two different constructions of the entire real number line. We see that the power set $2^{\mathbb N}$ can be given the defining structure of $\mathbb R$. The constructions here provided give simple rules for calculating addition, multiplication, subtraction, division, powers and rational powers of real numbers, and logarithms. The supremum and infimum are explicitly constructed by means of a well defined algorithm that ends in denumerable steps. In section 5 we give evidence our construction of $\mathbb N$ and $\mathbb R$ are canonical; these constructions are as natural as possible. In the same section, we propose a new axiomatic basis for analysis. In the last section we provide a series of graphic representations and physical models that can be used to represent the real number system. We conclude that the system of real numbers is completely defined by the order structure of $\mathbb N$.}

The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

This paper deals with the merger of the two lightweight stream ciphers—A5/1 and Trivium. The idea is to make the key stream generation more secure and to remove the attacks of the individual algorithms. The bits generated by the Trivium cipher (output) will act as the input of the A5/1 cipher. The registers used in the A5/1 cipher will be filled by the output bits of the Trivium cipher. The three registers will then be connected to generate an output which will be our required key stream.

We prove: (1) the set of all Diophantine equations which have at most finitely many solutions in non-negative integers is not recursively enumerable, (2) the set of all Diophantine equations which have at most finitely many solutions in positive integers is not recursively enumerable, (3) the set of all Diophantine equations which have at most finitely many integer solutions is not recursively enumerable, (4) analogous theorems hold for Diophantine equations D(x₁, …, x_p) = 0, where p ∈ N\{0} and for every i ∈ {1, …, p} the polynomial D(x₁, …, x_p) involves a monomial M with a non-zero coefficient such that x_i divides M, (5) the set of all Diophantine equations which have at most k variables (where k ≥ 9) and at most finitely many solutions in non-negative integers is not recursively enumerable.

New corrosion inhibitor derived from coumarin-3-amine namely 3-((2-chlorobenzylidene)amino)coumarin was synthesized and characterized by CHN elemental analysis in addition to Fourier transform infrared and nuclear magnetic resonance techniques. The anti-corrosion ability of 3-((2-chlorobenzylidene)amino)coumarin to inhibit the impacts of corrosion has been demonstrated and damage reduction of the mild steel also. 3-((2-chlorobenzylidene)amino)coumarin, has been employed as a good corrosion inhibitor for mild steel in HCL solution. The efficiency of the inhibition was figured according to weight loss method and it was 74.6%.

Non-immunoglobulin based scaffold proteins (SPs) represent one of the key therapeutic target-specific and high-affinity binders in modern medicine. Among their cellular targets are signaling receptors, in particular, receptor tyrosine kinases, whose dysfunction leads to the development of cancer and other serious diseases. Successful applications of SPs have been reported for HER receptor type 2 (HER2), the member of the human epidermal growth factor receptor family that regulates the cell growth and differentiation. To extend blood residence of SPs and prevent their high accumulation in kidney, these proteins are often fused with serum albumin. Promising results for the HER2-binding activity were obtained for SP G3 from DARPins (Designed Ankyrin Repeat Proteins) family fused with albumin-binding domain (ABD) [1]. Interestingly, detected HER2-G3 binding strongly depended on the position of G3 module in the sequence of the constructs. Further improvement of these constructs for biomedical applications requires deciphering the molecular mechanism responsible for this effect. Here, we investigate the structural and dynamic aspects of ABD-G3 and G3-ABD chimeras using NMR spectroscopy and molecular modeling. Based on biophysical data, we came to the conclusion that extensive interdomain contacts form in both constructs, although the binding interfaces and complex stability are somewhat different. Also, it was shown that the domain linker plays an important role – it limits the accessibility of detected protein-protein binding sites depending on the order of the domains in chimeric molecules. The results create a solid structural basis for the rational design of new effective SP-constructs targeting signaling receptor in the cell.

Early detection of PDAC remains challenging due to the lack of early symptoms and absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics sig-natures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used western blot-ting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal dis-tributions were performed using one-way ANOVA followed by Tukey’s post hoc test and pair-wise tests were performed using t tests. P≤0.05 was considered statistically significant. Protein cluster of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium binding protein A13 (S100A13), and tumor necrosis factor-β (TNF-β) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described in the literature target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166 and S100A13 as potential meaningful biomarker candi-dates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with identifier PXD053169.

The study concentrated on Myzostomida, which are microscopic polychaetes that live in symbiosis with feather stars, within the coastal waters of Hainan Island. Specimens were collected by researchers using SCUBA diving techniques, leading to the identification of a new species, as well as the documentation of four species that had not been previously recorded in Chinese waters. This discovery stands apart from the seven known Myzostomida species found near Hong Kong and the Dapeng Peninsula in Shenzhen. It underscores significant gaps in our comprehension of marine life in the South China Sea, suggesting the existence of unexplored biodiversity within the region.

This paper presents geometric analyses of welded frames after free relaxing and vibratory stress relief (VSR). Respected frames were tested components of a prototype packaging machine. Two types of relaxation were carried out to remove stresses introduced as a result of welding process. One of the frame was subjected to free relaxing, while the other one to accelerated vibration relaxing. Detection of the frame geometry changes was performed using a photogrammetric system. In addition, an evaluation of the geometry change was conducted for fifteen variants of steel frame support. A comparative analysis of the geometric deviations of the frames after free and vibratory stress relief confirmed the assumption that the frame after vibration stress relief better reproduces the nominal dimensions. Nevertheless, it should be emphasized that after vibratory stress relief the frame is not subject to further deformation, which is a desirable effect. In the case of free relaxing, the frame undergoes dimensional changes in a random manner. In summary, carrying out accelerated vibratory stress relief allows control of spontaneous dimensional changes in the designed frame of a packaging machine resulting from spontaneous relaxation of stresses arising from the welding process. The shortening of the relaxation process of the welded frame is also an unquestionable advantage.

Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

This study investigates the land surface temperature (LST) distribution from thermal infrared data for analyzing the characteristics of surface coverage using the Vegetation-Impervious-Soil (VIS) approach. A set of ten images, obtained from Landsat-5 Thematic Mapper, between 2001 and 2010, were used to study the urban environmental conditions of 47 neighborhoods of Porto Alegre city, Brazil. Porto Alegre has had the smallest population growth rate of all 27 state capitals in the last two decades in Brazil, with an increase of 11.55% in inhabitants from 1,263 million in 1991 to 1,409 million in 2010. We applied the environmental Kuznets curve (EKC) theory in order to test the influence of the economically-related scenario on the spatial nature of social-environmental arrangement of the city at neighborhood scale. Our results suggest that the economically-related scenario exerts a non-negligible influence on the physically driven characteristics of the urban environmental conditions as predicted by EKC theory. The linear inverse correlation R2 between household income (HI) and LST is 0.36 and has shown to be comparable to all other studied variables. Future research may investigate the relation between other economically-related indicators to specific land surface characteristics.

Particulate matter (PM) contains heavy metals that affect various cellular functions and gene expression associated with an array of acute and chronic diseases, in humans. However, their specific effects on the stem cells remain unclear. Here, we report the effects of PM collected from Jeddah city on bone marrow mesenchymal stem cells (BM-MSCs) on proliferation, cell death, related gene expression and systems biological analysis aiming to understand the underlying mechanisms. Two different sizes (PM_2.5-₁₀) were tested in vitro at various concentrations (15 to 300 µg/ml) and durations (24 to 72 h). PMs induced cellular stress including membrane damage, shrinkage and death. Lower concentrations of PM_2.5 increased BM-MSCs proliferation, while higher concentrations decreased it. PM₁₀ decreased BM-MSCs proliferation in a concentration-dependant manner. The X-Ray Fluorescence spectrometric analysis showed that PM contains high levels of heavy metals. Ingenuity Pathway Analysis (IPA) and hierarchical clustering analyses showed that heavy metals were associated with signalling pathways involving cell stress/death, cancer and chronic diseases. qRT-PCR results showed differential regulation of the apoptosis genes (BCL2, BAX); upregulation of inflammation associated genes (TNF-a and IL-6) and downregulation of cell cycle regulation gene (P53). We conclude that PM could affect different cellular functions and predispose to debilitating diseases.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within BLA governs these modulatory effects. However, most of the current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a neutral hippocampal-dependent task. We combined a weak version of the object location task (OLT) with mild predator odor exposure (POE) for our experiments. To investigate the role of the BLA in memory modulation, a subset of the animals (Wistar rats) were treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected either 90 minutes after drug infusion or 24 hours after the OLT test. The samples were used to determine the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc) - two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE is a behavioral paradigm suitable for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

This paper constituted an extension of two previous studies concerning the mathematical development of the grain boundary grooving in polycrystalline thins films in the cases of the evaporation/condensation and diffusion taken separately. The thermal grooving processes are deeply controlled by the various mass transfer mechanisms of evaporation–condensation, surface diffusion, lattice diffusion, and grain boundary diffusion. This study proposed a new original analytical solution to the mathematical problem governing the grain groove profile in the case of simultaneous effects of evaporation-condensation and diffusion in polycrystalline thin films submitted to thermal and mechanical stress, and fatigue effects; by resolving the corresponding fourth-order partial differential equation ∂y∂t=C∂2y∂x2-B∂4y∂x4 obtained from the approximation y'2≪1. The comparison of the new solution to that of diffusion alone proved an important effect of the coupling of evaporation and diffusion on the geometric characteristics of the groove profile. A second analytical solution based on the series development was also proposed. It was proved that change of the boundary conditions of the grain grooving profile largely affected the different geometric characteristics of the groove profile.

This paper presents the symmetries of differential equations associated with one-variable and Bivariate Hermite polynomials by proposing a representation of Lie algebra for these differential operators. Applying the Baker-Campbell-Hausdorff formula to these algebras, results in new relations and generating functions in one-variable and Bivariate Hermite polynomials. A general form of representation for other orthogonal polynomials such as Laguerre polynomials is introduced.

Patients with COVID-19 demonstrate higher rates of cardiovascular complications, including thromboses and thromboembolism. One may suppose that the action of SARS-CoV-2 transforms stable atherosclerotic plaques into unstable status. Cardiovascular complications in COVID-19 may be caused by progressive viral alteration the blood vessels, including vasa vasorum. A lethal case of ischemic brain disease caused by cerebral atherosclerosis and exacerbated with a stroke during COVID-19 infection is briefly described. The results of autopsy showed perivascular lymphocytic infiltration and signs of vasa vasorum vasculitis with thrombi of adventitial microvasculature. The data discussed in the article are interpreted in context of the concept giving the important role in atherogenesis to vasa vasorum.

The final assembly of appliances and automotive industries is a rigorous process, that has limited capabilities of full traceability associated with: (1) the parts installed, (2) their fabrication processes, and (3) the assembly work. This is also the case for each of its sub-assemblies The many parts and sub-assemblies that compose the final assembly, make full traceability a challenging fit, that is almost unsurmountable. Such full traceability along the entire supply-chain is not existent today and must be based on documentation of most assembled parts, assembly tasks, and inspection tasks that compose the full assembled product. In addition, security measures are needed to prevent hostile hacking and unauthorized approach to the assembly documentation throughout the entire supply chain. The related documentation and repeated verifications require considerable effort and have many chances for human errors. So, automating these processes has a great value. This article expounds a framework that harnesses block-chain and smart-contract technology to offer traceable and protected documentation of the assembly process. We expand the concept of a Bill-Of-Assembly (BOA) to incorporate data from the bill of materials (BOM), the associated assembly activities, the associated activities’ specification parameters and materials, and the associated assembly resources (machines and/or operators). The paper defines the operation of the BOA with blockchain and smart-contract technology, for attaining full traceability, safety, and security, for the entire assembled product. Future research could extend the proposed approach to facilitate the usage of the BOA data structure in constructing a digital twin of the entire simulated system.

Animal venoms are complex mixtures of bioactive peptides and enzymes that have garnered significant interest for their therapeutic potential, particularly in drug delivery systems. Among these peptides, cell-penetrating peptides (CPPs) have emerged as promising candidates due to their ability to traverse cellular membranes and deliver a variety of molecular cargos, including drugs, imaging agents, and nanoparticles. Recent advancements in omics technologies have enhanced our understanding of the structural and functional properties of CPPs, leading to their classification based on conformation, origin, and physicochemical characteristics. This review discusses the diverse types of CPPs, including three-finger toxins, disintegrins, and bradykinin-potentiating peptides, highlighting their roles in targeted drug delivery and therapeutic applications. The potential of venom-derived peptides in developing novel strategies for drug delivery and disease treatment is explored, emphasizing their impact on biotechnological and biomedical research.

Wicked problems, such as climate change, systemic poverty, and healthcare inequalities, rep- resent the most pressing and intractable challenges facing society today. We propose a novel approach that leverages complex systems theory as a comprehensive framework for understanding and tackling these challenges. By applying concepts such as state space analysis, attractors, and nonlinear dynamics, we offer a sophisticated toolkit for mapping the intricate web of interactions defining wicked problems and exploring potential interventions. Our approach moves beyond tradi- tional reductionist methods, embracing the inherent complexity and dynamism of these issues. We demonstrate how this framework can lead to more nuanced, adaptive, and effective strategies for addressing persistent societal problems. Despite the prevalence of wicked problems and the avail- ability of complex systems theory, practical applications of this approach remain uncommon. This paper aims to bridge this gap, illustrating the potential of complex systems theory to transform our engagement with intractable problems and pave the way for more robust, holistic solutions. By synthesizing insights from mathematics, physics, and social sciences, we present a transdisci- plinary approach that promises to revolutionize how we conceptualize and address society’s most challenging issues.

The extraction of cell cultures from fresh tissue is a process that requires significant computa-tional resources and is associated with substantial overheads. The objective of our research is to de-vise a rapid, straightforward, and efficient technique for the cultivation of neuronal cells derived from frozen biological material. We utilized freshly isolated hippocampus and cerebral cortex tissue from rats, in addition to whole brain tissue. This tissue underwent digestion and processing to yield a cellular suspension. This suspension was subsequently cryopreserved using a variety of cryopro-tectants: CTS™ Synth-a-Freeze™, SpermFreeze®, and a medium supplemented with 10% DMSO. CTS™ Synth-a-Freeze™ is a commercially available cryoprotectant typically employed in the preservation of cellular cultures, while the addition of 10% DMSO to the medium is a conventional technique for the cryopreservation of cells to mitigate damage. The innovative aspect of our meth-odology is the application of SpermFreeze®, a product used for the cryopreservation of sperm in in vitro clinics. We postulated that SpermFreeze® might enhance the viability and quality of the cryo-preserved neuronal cells, given the delicate and energetically demanding nature of both sperm and neuronal cells. The ultimate objective was to ascertain whether a cryoprotectant formulated for sperm could augment the post-thawing efficacy of our nervous system cells. This investigation intro-duces an innovative methodology for the optimization of neuronal cell isolation and cryopreserva-tion from animal-derived tissues.

Recent advancements in gut microbiome research have highlighted the complex interplay between gut microbiota and various physiological and pathological processes, showing that gut microbiota plays a vital role in human health and disease. Imbalances in the gut microbiota, known as dysbiosis, have been associated with a range of health conditions, including gastrointestinal disorders, metabolic diseases, etc. In response to these findings, probiotics, prebiotics, synbiotics, and postbiotics have emerged as a promising therapeutic strategy to modulate gut microbiota composition and functionality. This review paper explores the latest research on how gut microbiota impacts host physiology, immune responses, and overall well-being. Furthermore, the paper delves into the therapeutic potential of probiotics, postbiotics, prebiotics, and synbiotics in therapeutic applications and curing various diseases. The paper also addresses the challenges and opportunities in the field, highlighting the need for personalized approaches to probiotic therapy and the importance of considering factors such as strain specificity, dosing, and safety.Overall, this review aims to provide a comprehensive overview of the evolving landscape of gut microbiota and probiotics, prebiotics, synbiotics, and postbiotics as novel therapeutic agents. It underscores the potential of harnessing the gut microbiome to improve health, prevent diseases, and complement traditional medical interventions. As research in this field continues to expand, a deeper understanding of the gut microbiota and probiotics, prebiotics, synbiotics, and postbiotics promises new avenues for preventive and therapeutic healthcare strategies.

Now day; the interest for the synthesis of heterocyclic compounds containing hydroquinoline fragments has increased tremendously due to their wide variety of pharmaceutical and industrial applications. This work details the synthesis of linear and fused heterocyclic systems containing hydroquinoline fragments and the pharmacological activity spectra of the synthesized compounds was predicted by in silico method using Prediction of Activity Spectra of Substances (PASS) program. 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5a was reacted for three hours with a system of hydroxylammonium chloride/pyridinium chloride/toluene to produce 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-nitrile 7. N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde 6b and iodine reacted at room temperature in aqueous ammonia water, followed by aq. treatment with Na2S2O3 and produced N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-nitrile 8. 30-60% 2-phenyl-1,3-oxazol-5(4H)-ones 9a,b; 10a,b were synthesized via the condensation reaction of N-alkylhydroquinoline-6-carbaldehydes 5a,b; 6a,b with hippuric acid in acetic acid. When activated 7-methylazolopyrimidines 11a,b were reacted with N-alkyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehydes 6a,b, the reaction produced 60–70% yield of 7-[(E)-2,2,4-trimethylhydroquinolin-6-ylidenemethyl]azolo[1,5-a]pyrimidin-6-yl carboxylic acids 12a,b. The condensation reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3h with dimethylacetylenedicarboxylate (DMAD) and ethylacetoacetate afforded methyl (Z)-2-(5,7,7,8-tetramethyl-2-oxo-7,8-dihydrofuro[3,2-g]quinolin-3(2H)-ylidene)acetate 16 and 4,6,8,8,9-pentamethyl-8,9-dihydro-2H-pyrano[3,2-g]quinolin-2-one 17, respectively. The condensation reaction of 6-formyl-7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 5e with methylene active compounds ethylcyanoacetate/dimethyl-3-oxopentanedioate/ ethylacetoacetate/diethylmalonate/Meldrum’s acid afforded 3-substituted dihydroquinoline containg coumarins 19 & 21. A pentacyclic coumarin 22 was obtained via the random condensation reaction of malononitrile with 5e in the presence of catalytic amount of piperidine in ethanol. The potential biological activities of the synthesized compounds were evaluated using PASS computer program. According to the prognosis, (E)-4-(N-alkylhydroquinolin-6-yl)-3-buten-2-ones, 13a, b & 14 showed high probability of being active (Pa) as the Gluconate 2-dehydrogenase inhibitor, Anti-allergic, Anti-asthmatic, and Anti-arthritic with the Pa value of 0.849-0.870. It was also found out that hydroquinolinecarbonitrile compounds 7 & 8 have a propensity to act as a good progesterone antagonists, anti-allergic, anti-asthmatic, and anti-arthritic (Pa = 0.276-0.827). Among the coumarin moieties containing hydroquinolines, compounds 17, 19a, and 19c were predicted to be good progesterone antagonists with the Pa values of 0.710, 0.630 and 0.615; respectively.

Currently, Pythagorean fuzzy sets (PFSs) have been widely applied in various fields due to their substantial advantages in expressing and dealing with uncertainty. However, measuring the similarity and difference between PFSs effectively remains an unresolved issue. Inspired by Tanimoto similarity, we propose a novel set of similarity and distance measures for PFSs. We delve into the theoretical properties of the proposed measures and compare it with existing PFSs measures. Numerous numerical examples validate their rationality and effectiveness. Furthermore, our experimental findings suggest that in contrast to existing measures, the introduced measures successfully circumvent various counter-intuitive issues encountered by current measures, and yield more pronounced outcomes in the discrimination of different fuzzy sets. This enhances the uniqueness and superiority of our measures. Finally, we developed two decision models based on the proposed measures and validated their applicability in three applications.

Sarcocystis sp. are coccidian protozoans belonging to the Apicomplexa phylum. As other members of this phylum, they are obligate intracellular parasites having a complex cellular machinery for the invasion of host cells. Sarcocystis spp. display dixenous life cycles, involving a predator and a prey as definitive and intermediate hosts, respectively. Specifically, these parasites develop sarcocysts in the tissues of their intermediate hosts, ranging in size from microscopic to visible to the naked eye, depending on the species. When definitive hosts consume sarcocysts, infective forms are produced in the digestive system and discharged into the environment via feces. Consumption of oocyst-contaminated water and pasture by the intermediate host completes the parasitic cycle. More than 200 Sarcocystis spp. have been described infecting wildlife, domestic animals, and humans, some of which are of economic or public health importance. Interestingly, Old World camelids (dromedary, domestic Bactrian camel, and wild Bactrian camel) and New World or South American camelids (llama, alpaca, guanaco, and vicuña) can each be infected by two different Sarcocystis species: Old World camelids by S. cameli (producing micro- and macroscopic cysts) and S. ippeni (microscopic cysts); and South American camelids by S. aucheniae (macroscopic cysts) and S. masoni (microscopic cysts). Large numbers of Old and New World camelids are bred for meat production, but the finding of macroscopic sarcocysts in carcasses significantly hampers meat commercialization. This review tries to compile the information that is currently accessible regarding the biology, epidemiology, phylogeny, and diagnosis of Sarcocystis spp. infecting Old and New World camelids. In addition, knowledge gaps will be identified to encourage research that will lead to the control of these parasites.

Gallbladder diseases are very common and their diagnosis is based on clinical-laboratory evaluation and imaging techniques. Considering the different imaging diagnostic tools, ultrasound (US) has the advantage of high accuracy combined with easy availability. Therefore, when a gallbladder disease is suspected, US can readily assist the clinician in the medical office or in the emergency department. The high performance of US in the diagnosis of gallbladder diseases is mainly related to its anatomic location. The most frequent gallbladder pathological condition is gallstones disease, easily diagnosed by US examination. Acute cholecystitis (AC), a possible complication of gallstone disease, can be readily recognized, due to its specific sonographic features. Additionally, a number of benign, borderline or malignant gallbladder lesions may be detected by US evaluation. The combined use of standard B-mode US and additional sonographic techniques, such as contrast-enhanced ultrasonography (CEUS), may provide a more detailed study of gallbladder lesions. Multiparametric US (combination of multiple sonographic tools) can improve the diagnostic yield during gallbladder examination.

As of the end of 2022, despite the disruptions caused by the COVID-19 pandemic, the global HIV epidemic persists, with 39 million individuals living with the virus and 1.3 million new infections reported in that year. Opportunistic infections associated with AIDS claimed the lives of over 630,000 people in 2022, contributing to a cumulative death toll exceeding 40.4 million since the disease's emergence in 1981. Although advances in HIV diagnosis and antiretroviral therapy have transformed the disease into a manageable chronic condition, issues like drug resistance, low compliance, and high treatment costs persist. Until a vaccine becomes available, a comprehensive approach involving prevention and therapy is essential, particularly for high-risk populations. Research shows that prevention strategies are more cost-effective than treatment. The development of antiretroviral drugs has also spurred the creation of antivirals for other infections. The emergence of COVID-19 vaccines has opened new avenues for HIV vaccine development, as lessons from vaccine platform technologies like mRNA, viral vectors, and protein subunits can be applied to HIV. This review explores the most promising prophylactic and therapeutic HIV vaccine trials, emphasizing the need for a multi-pronged approach combining vaccines with non-vaccine strategies. Though significant progress is anticipated, the road to a viable HIV vaccine remains long, especially for high-risk populations, such as medical workers, blood transfusion recipients, and drug users. The combinatorial approach, capitalizing on various aspects of immunity, may hold the key to defeating HIV in the future.

In an era marked by rapid technological progress and global dynamics, the Neo-Language Acquisition and Learning Theory challenges conventional language acquisition paradigms through its conceptualization of 'Grit: The Unyielding Will to Connect,' emphasizing determination, motivation, and adaptability as the primary drivers of language learning, transcending age-related constraints and critical periods. This theory also underscores 'Self-Preservation: Language as the Canvas of Reality,' as language plays a pivotal role in preserving and conveying our individual and collective experiences. Recent global events have underscored the theory's relevance, prompting a reevaluation of language education in response to changing circumstances. Moreover, 'Techno-Training: Language Acquisition and Learning in the Digital Age' is integral to the theory, as it recognizes the influence of technology on modern language education. Beyond traditional methods, these three reshape our fundamental understanding of said theory. Drawing from historical evidence, psychological principles, and contemporary applications, they supported the conceptualization of the theory itself. Overall, the Neo-Language Acquisition and Learning Theory revolutionizes language education, spotlighting the power of motivation, determination, and adaptability to navigate the evolving landscape of language learning and acquisition.

Esterases are hydrolases that catalyze the hydrolysis of esters into the corresponding acids and alcohols. The development of fluorescent probes for detecting esterases is of great importance due to their wide spectrum of biological and industrial applications. These probes can provide a rapid and sensitive method for detecting the presence and activity of esterases in various samples, including biological fluids, food products, and environmental samples. Fluorescent probes can also be used for monitoring the effects of drugs and environmental toxins on esterase activity, as well as to study the functions and mechanisms of these enzymes in several biological systems. Additionally, fluorescent probes can be designed to selectively target specific types of esterases, such as those found in pathogenic bacteria or cancer cells. In this review, we summarize the recent fluorescent probes described for the visualization of cell viability and some applications for in vivo imaging. On the other hand, Positron Emission Tomography (PET) is a nuclear-based molecular imaging modality of great value to study the activity of enzymes in vivo. We provide some examples of PET probes for imaging acetylcholinesterases and butyrylcholinesterases in brain, which are valuable tools for diagnosing dementia and monitoring the effects of anticholinergic drugs on the central nervous system.

Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine is the cornerstone of lupus treatment. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, azathioprine, cyclosporine and tacrolimus. Cyclophosphamide and mycophenolate mofetil may also be used. However, despite conventional immunosuppressive treatment flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression, increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.

(1) Background: Artificial intelligence (AI) has existed in some form for decades, but recent rapid advances in a subset called machine learning (ML) — and more specifically deep learning (DL), a neural network-based approach — have made headlines for the potential to revolutionize and automate multiple large sectors of society, including scientific research and the healthcare field. Furthermore, large language models (LLMs) — which are built on DL — could lead to a more seamless, natural interaction between humans and computers. (2) Methods: We reviewed numerous publications on this subject from recent years. (3) Results: We found these studies collectively show that AI is positively disrupting both biomedical research and medical practice, such as optical imaging in surgery guidance. (4) Conclusions: However, we recommend caution in over-reliance on AI in the laboratory or the clinic due to anticipated risks and current limitations.

Several methods of processing wood into strong, durable products for the construction industry provide transformative opportunities to substitute for less sustainable building materials. Carbon storage is a further advantage, with the added possibility of combustion for bioenergy at end of life. Intense research activity in this area is expected to open up new markets for wood fiber during the lifetime of trees now being planted. Here, wood-derived materials are classified according to the particle size, from metres to nanometres, into which the wood is fragmented before reconstitution. Materials made by densifying or chemically modifying solid wood with no fragmentation are already in production for exterior doors, window frames and cladding, with improved uniformity and stability compared with unmodified wood. Pre-commercial developments promise further gains in durability and strength. Emerging developments extend these process technologies to wood that has been chipped or stranded or pulped, retaining the above advantages over raw timber for weather-facing applications and adding processability by moulding or extrusion. Crucially, the raw material does not then need to be sawn timber but can be bioenergy-grade wood biomass. This will facilitate afforestation strategies that combine the aims of carbon sequestration and biodiversity.

Cancer is a complex disease, considered a major public health problem worldwide. Among the types of cancer, melanoma, and leukemias present high mortality rates in Brazil and worldwide. Currently, conventional cytotoxic treatments cause severe side effects by the non-selectivity between normal cells and cancer cells. Therefore, molecules of natural origin with more efficient anticancer properties and that present fewer adverse effects are of extreme importance for cancer therapy and improvement in patients’ quality of life. This study isolated, identified, and characterized the chemical structure of a new anthraquinone present in the extract of the roots of Senna velutina. In addition, we sought to evaluate the anticancer potential of this molecule against melanoma and leukemic cell lines and identify the pathways of cell death involved. To this end, a novel anthraquinone was isolated from the barks of the roots of S. velutina, analyzed by HPLC-DAD, and its molecular structure was determined by NMR. Subsequently, their cytotoxic activity was evaluated by the MTT method against non-cancerous, melanoma, and leukemic cells. The migration of melanoma cells was evaluated by the scratch assay. By flow cytometry technique, the apoptosis process, caspase-3 activation, analysis of mitochondrial membrane potential, and measurement of ROS were evaluated. In addition, the pharmacological cell death inhibitors NEC-1, RIP-1, BAPTA, Z-VAD, and Z-DEVD were used to confirm the related cell death mechanisms. With the results, it was possible to elucidate the novel compound characterized as 2'-OH-Torosaol I. In normal cells, the compound showed no cytotoxicity in PBMC but reduced the cell viability of all melanoma and leukemic cell lines evaluated. 2'-OH-Torosaol I inhibited chemotaxis of B16F10-Nex2, SK-Mel-19, SK-Mel28 and SK-Mel-103. The cytotoxicity of the compound was induced by apoptosis via the intrinsic pathway with reduced mitochondrial membrane potential, increased levels of reactive oxygen species, and activation of caspase-3. In addition, the inhibitors demonstrated the involvement of necroptosis and CA+ in the death process and confirmed caspase-dependent apoptosis death as one of the main programmed-cell death pathways induced by 2'-OH-Torosaol I. Taken together, the data characterize the novel anthraquinone 2'-OH-Torosaol I, demonstrating its anticancer activity and potential application in cancer therapy.

Insulin resistance, as a common pathological process of many metabolic diseases, including diabetes and obesity, has attracted much attention due to its relevant influencing factors. To date, studies have mainly focused on the mechanisms between mitochondrial stress and insulin resistance, and they are now pursued as a very attractive therapeutic target due to their extensive involvement in many human clinical settings. In view of the complex pathogenesis of diabetes, natural drugs have become new players in diabetes prevention and treatment because of their wide targets and few side effects. In particular, plant phenolics have been paid more attention because of their close relationship with oxidative stress. In this review, we briefly review the mechanisms by which mitochondrial stress leads to insulin resistance. Moreover, we list some cytokines and genes that have recently been found to play roles in mitochondrial stress and insulin resistance. Furthermore, we describe several natural drugs that are currently widely used and give a brief overview of their therapeutic mechanisms. Finally, we suggest possible ideas for future research related to the unique role that natural drugs play in the treatment of insulin resistance through the above targets.

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 7 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. We focused on articles hypothesizing the identification and study of compounds that induce proliferation and osteogenic differentiation of the two d-DSC populations, representing an interesting issue for regenerative medicine. The reconstruction of bone defects in fact is still a challenge for personalized medicine.

Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune cells infiltration. The cytokine profile of these cells shows clear proinflammatory and profibrotic characteristics. Furthermore, the production of inflammatory mediators by non-immune cells, in response to several stimuli, can be involved in the fibrotic process. It is now established that defects in the abilities of non-immune cells to mediate immune regulation may be involved in the pathogenicity of a series of inflammatory diseases. The convergence of several, not yet well identified, factors results in the aberrant activation of non-immune cells, such as epithelial cells, endothelial cells and fibroblasts, that producing pro-inflammatory molecules, exacerbate the inflammatory condition leading to the excessive and chaotic secretion of extracellular matrix proteins. However, the precise cellular mechanisms involved in this process have not yet been fully elucidated. In this review we explore the latest discoveries on the mechanisms that initiate and perpetuate the vicious circle of abnormal communications between immune and non-immune cells, responsible for fibrotic evolution of inflammatory autoimmune diseases.

We approximate the trigonometric function sine and cosine on the interval . This analysis provides two formulas to approximate sine and cosine. At first, we try to derive the formula which involves a square root, and then we derive another formula that does not require any use of a square root. Nevertheless, after deriving the procedure which requires no square root, we further try to increase its accuracy and then derive another formula that approximates trigonometric functions more accurately on the interval [0, pi/2]. So, this analysis provides mainly two types of procedures. One uses square roots, whereas the other does not. We also focus on ensuring the accuracy of these trigonometric functions in the interval [0,pi/2]. This accuracy analysis is portrayed using the graph. This graph shows the difference between the values generated by the functions defined here and the actual value of these functions. So, these graphs also indicate the error of these functions on that interval. Finally, we compare our approximation with the approximation formula of the 7th-century Indian Mathematician Bhaskara I.

Plants are constantly exposed to a variety of different environmental stresses, including drought, salinity, and elevated temperatures. These stress cues are assumed to aggravate in the future driven by the global climate change scenario which we are currently experiencing. These stressors have largely detrimental effects on plant growth and development and, therefore, put global food security in jeopardy. For this reason, it is necessary to expand our understanding of the underlying mechanisms by which plants respond to abiotic stresses. Especially boosting our insight into the ways by which plants balance their growth and their defense programs appears to be of paramount importance, as this may lead to novel perspectives that can pave the way to increase agricultural productivity in a sustainable manner. In this review, our aim was to present a detailed overview of different factettes of the crosstalk between the antagonistic plant hormones abscisic acid (ABA) and auxin, two phytohormones that are the main drivers of plant stress responses, on the one hand, and plant growth, on the other.

Community-based case managers in health have been compared to glue which holds the dynamic needs of clients to a disjointed range of health and social services. However, case manager roles are difficult to understand due to poorly defined roles, confusing terminology, and low visibility in New Zealand. This review aims to map the landscape of case management work to advance workforce planning by clarifying the jobs, roles, and relationships of case managers in Aotearoa New Zealand (NZ). Our scoping and mapping review includes peer-reviewed articles, grey literature sources, and interview data from 15 case managers. Data was charted iteratively until convergent patterns emerged and distinctive roles identified. A rich and diverse body of literature describing and evaluating case management work in NZ (n=148) is uncovered with at least 38 different job titles recorded. 18 distinctive roles are further analysed with sufficient data to explore the research question. Social ecology maps highlight diverse interprofessional and intersectoral relationships. Significant innovation and adaptations are evident in this field, particularly in the last five years. Case managers also known as health navigators, play a pivotal but often undervalued role in NZ health care, through their interprofessional and intersectoral relationships. Their work is often unrecognised which impedes workforce development and the promotion of person-centred and integrated health care.

Pandemic scenario has significantly changed several factors of life, including teaching, and learning at university. The development of suitable teaching materials to support university studies is mandatory to overcome distance learning difficulties and improve traditional teaching methodologies. This work explains a novel method for the preparation of teaching materials for medical sciences, but also plausible for other learning fields. An encephalon was extracted and prepared by using this methodology for teaching purposes. More than 200 students evaluated several factors of the material prepared this way, indicating a better understanding (up to 80%) of theoretical contents related to this human section, together with a high usability and good physical appearance

In the search for new 2D materials beyond graphene with similar exemplary properties Stanene the new graphene relative was successfully synthesized and characterized in 2016 [14]. This new material which consists of atomically thin tin (Sn) atoms arranged in a hexagonal lattice has shown great promise in gas sensing applications in its pristine, doped and functionalized forms as evidenced by the recent research outputs following its discovery. Researchers have discovered that with its exotic properties it is highly efficient in the detection of the environmentally harmful gases like SO2, NO2, CO2, NH3 and can serve as a multifunctional gas sensor. In this focused and up-to-date review we aim to group the literature on first principles studies of stanene regards to its application for gas sensing and critically examine the success/failures of its multifunctional gas sensing properties as compared to graphene. We systematically present and discusses how structural deformations, defects and doping effect the gas sensing performance. Despite the impressive progress in the field of gas sensing with stanene shown by first principles calculations, many challenges in large scale synthesis, device fabrication and commercialization need to be addressed. The current review can help understand the current status and drawbacks of stanene and identify future directions in this field.

Sustainable urban design or planning is not a LEGO-like assembly of prefabricated elements, but an embryo-like growth with persistent differentiation and adaptation towards a coherent whole. The coherent whole has a striking character – called living structure – that consists of far more small substructures than large ones. To detect the living structure, natural streets or axial lines have been previously adopted to be topologically represent an urban environment as a coherent whole. This paper develops a new approach to detecting the underlying living structure of urban environments. The approach takes an urban environment as a whole and recursively decomposes it into meaningful subwholes at different levels of hierarchy or scale ranging from the largest to the smallest. We compared the new approach to natural street and axial line approaches and demonstrated, through four case studies, that the new approach is better and more powerful. Based on the study, we further discuss how the new approach can be used not only for understanding, but also for effectively designing or planning the living structure of an urban environment to be more living or more livable.

Exogenous miRNAs derived from dietary substances have been shown to be orally transferred to the mammalian system and proven to remain active to regulate host-gene expression. This way they have become an active area of research as functional food components and aspects for dietary supplementation. They are being studied as a new class of metabolically targeted therapeutics that work through diet manipulation and may hold promise for a therapeutic approach in reducing the risk of life-threatening diseases. However, a substantial amount of evidence also defies this dietary miRNA concept in terms of their absorption, bioavailability, cellular uptake and its physiological effects in the mammalian system. But recent advances in the identification of some unique sequence and structural characteristics of dietary miRNAs and a deeper understanding of their stability in host peripheral blood for its cellular uptake have strengthened the whole concept. The review comprehensively summarizes the mechanism for miRNA extracellular transport, absorption through the gastrointestinal tract (GI), stability in peripheral blood, and cellular uptake in mammalian cells. It recapitulates the shreds of evidence, related to the influence of dietary miRNAs on gene expression based on the source of the origin (plant vs animal), and compares their cross-kingdom behaviour in terms of their unique sequence and stem-loop structure properties that help them to get stabilized in the mammalian system. The review also summarizes the parameters required for maintaining the sustainable uptake and bioavailability of the dietary miRNAs with existing examples of successful in-vivo and in-vitro delivery of dietary miRNA for augmented therapy. Lastly, it provides an overview of the available and required databases, webserver, and tools that can be used for the successful identification of potential dietary miRNA candidates.

New experimental and clinical findings question the historic view of hydrocephalus and its 100-year-old classification. In particular, real-time MRI evaluation of CSF flow and detailed insights into brain water regulation on the molecular scale indicate the existence of at least three main mechanisms that determine the dynamics of neurofluids. (i) Inspiration is a major driving force (ii) Adequate filling of brain ventricles by balanced cerebrospinal fluid upsurge is sensed by cilia (iii) The perivascular glial network connects the ependymal surface to the pericapillary Virchow-Robin spaces. Hitherto, these aspects have not been considered a common physiologic framework improving knowledge and therapy for severe disorders of normal-pressure and post-haemorrhagic hydrocephalus, spontaneous intracranial hypotension and spaceflight disease.

Cervical cancer (CC) is the most common cancer in women worldwide and is almost always associated with repeated infections by human papillomavirus (HPV). Screening by traditional tests combined with biomarker identification techniques for low- or high-grade injuries, are becoming increasingly important in diagnosis and prognosis, avoiding countless deaths. This article explores existing literature on the main serum biomarkers and the identification of biomarkers associated with the oncogenesis of HPV expression in the identification of pre-cancerous lesions and of CC for an effective treatment, with reduction of recurrence, as well as we explain strategies for the development of biomarkers based on DNA, proteins and other markers. We also describe how markers of chromosomal instability host DNA, promoting hypo- or hypermethylation of DNA, as well as polymorphisms and epigenetic events in the p53 gene. Finally, we discuss changes in gene expression using cDNA microarray techniques and changes in the expression of proteins and markers identified through mass spectrometry.

In this paper, we provide alternative proofs to some results proposed in the article "New inequalities involving circular, inverse circular, hyperbolic, inverse hyperbolic and exponential functions" authored by Yogesh J. Bagul.

Counterfeiting and theft have always been problems that incur high costs and results in considerable losses for the international markets. In this research paper, we will address the issue of counterfeiting while using RFID technology in retailer systems or other industries by presenting a new anti-counterfeiting and anti-theft system for the retailer market. This system will address the two above mentioned issues and provide a solution that can save the retailer systems millions of dollars yearly. This proposed system will achieve the objective of preventing or minimising the counterfeiting and theft of tagged products. At the same time, it will provide a strong indication for suspiciously sold or obtained items. Furthermore, we conducted a security analysis to prove the correctness of our protocol on the basis of the strand spaces.

Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its copy number alteration (CNA) and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2 and 12p13.31 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.

This study proposes a new algorithm termed rain cell identification and tracking (RCIT) to identify and track rain cells from high resolution weather radar data. Previous algorithms have limitations when tracking non-consequent rain cells owing to their use of maximum correlation coefficient methods and their lack of an alternative way to handle the variation stages of rain cells during their life cycles. To address these deficiencies, various methods are implemented in the new algorithm. These include the particle image velocimetry (PIV) method for motion estimation and the rain cell matching rule to obtain the stage changes of rain cells. High resolution (5-min and 1-km) radar reflectivity data from three rainy days over the German federal state North Rhine Westphalia (NRW) are used to evaluate the proposed algorithm. The performance of the new algorithm is compared with a radar reflectivity map and verified by two object-oriented methods: structure–amplitude–location (SAL) and geometric index. The verification results suggest that the performance of the new algorithm is good. Application of the RCIT algorithm to the selected cases shows that the inner structure of rainfall events in the experimental region present extreme value distributions, with most rainfall events having a short duration with less intensity. The new algorithm can effectively capture the stage changes of rain cells during their life cycles. The proposed algorithm can serve as the basis for further hydro-meteorological applications such as spatial and temporal analysis of rainfall events and short-term flood forecasting.

A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of antinflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represent a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.

As the global demand for water increases, so does the quantity of wastewater requiring treatment. Due to a relatively low carbon footprint, compared with conventional wastewater treatment technologies, anaerobic digestion (AD) was identified in the 1970s as a forerunner in the push for sustainability, when interest in sustainable technologies and renewable energy sources was first sparked. AD technology development ultimately resulted in the discovery of the ‘anaerobic granule’. It is a spontaneously-forming bio-aggregate of microbial cells capable of digesting pollutants and producing methane-rich biogas as a renewable source of bioenergy. The high settling velocity of such granules meant that AD systems could be operated as high-rate treatment processes, because the active, relatively-slow-growing, pollutant-removing biomass would be retained inside, and not washed out of, even bioreactors operated at extremely high volumetric loading rates. In the intervening years the emergence of the anaerobic ammonium oxidising (anammox) granule, aerobic granule, hydrogenic granule, oxygenic photogranule, and many other functionally-specialised granules, has opened new opportunities in wastewater treatment biotechnology. Whilst environmental engineering based around wastewater treatment is still a growing field of research and implementation, the granule (in all forms) is starting to catch the attention of microbial ecologists. It is a self-immobilised biofilm, with many of the properties of ‘conventional’ biofilms formed in Nature. However, as a single entity, a granule represents an entire community of microorganisms, competing or functioning cooperatively or in syntrophy. Together, inside a bioreactor, granules perform side-by-side arguably representing a meta-organism. Granules are gaining traction as the perfect samples for high-throughput studies on fundamental ecological concepts. Granular biofilms can be used to test hypotheses around drivers of diversity, community assembly, biofilm formation and maturation, community expansion and succession, community stress response, among others. This review outlines the history of three of the most influential types of granules: the anaerobic (methanogenic), aerobic and anammox granule. The main biochemical processes found in each type; their primary characteristics; and the typical makeup of the microbial community underpinning the processes are compared. Finally, the adoption of granules as the perfect ‘playground’ for experiments in microbial ecology is reviewed.

One of creators of quantum mechanics P. Jordan in his work on quantum biology claimed that life's missing laws were the rules of chance and probability of the quantum world. The article presents author’s results of studying frequencies (or probabilities) of nucleotides on so-called epi-chains of long DNA sequences of various eukaryotic and prokaryotic genomes. DNA epi-chains are algorithmically constructed subsequencies of DNA nucleotide sequences. According to the algorithm of construction of any epi-chain of the order n, the epi-chain is such nucleotide subsequence, in which the numerations of adjacent nucleotides differ by natural number n (n = 1, 2, 3, 4,…). Correspondingly each epi-chain of order n ≥ 2 contains n times less nucleotides than the original DNA sequence. The presented results unexpectedly discover that in long single-stranded and double-stranded DNA of any tested genome its DNA epi-chains of different orders n (values n are not too large) have practically identical frequencies (or probabilities) of each kind of nucleotides. These data allow considering DNA as a regular rich set of epi-chains, which can play a certain role in genetic and epigenetic phenomena as the author belives. Appropriate rules of nucleotide frequencies on epi-chains of long DNA sequences are formulated for further their tests on a wider set of genomes. These results testify on existence of long-range coherence in long DNA and remind the Fröhlich's theory of long-range coherence in biological systems. The phenomenological data are discussed from different standpoints: the DNA double helices and helical antennas with circular polarizations of electromagnetic waves; relations with the Fröhlich's theory; numerical analysis of DNA epi-chains under binary representations of nucleotides. Results are useful for developing quantum and algebraic biology.

Genetic testing allows for identification of germline DNA variations which are associated with a significant increase in risk of developing breast and ovarian cancer. Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as Variants of Uncertain Clinical Significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottle neck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.

This article analyses from a post-Marxist view, particularly, an ecological and gender-oriented perspective, the perception and attitudes of the Mexican people by gender, political affiliation and income level towards such current environmental issues as global warming, water shortage, water pollution and the influence of economic growth on the environment, among others. It highlights the influence of political ideology on the environment and of gender awareness on conservation and a more positive attitude towards ecological issues, despite women having usually been excluded from the administrative and decision-making arenas. A new theoretical model is proposed related to the Responsibility Footprints, a new concept more critical than the neoliberal Corporate Social Responsibility. The data for this study come from the 2012 International Social Survey Program. The results analysed brought to light some relevant questions for designing public policies that will greatly bolster initiatives to prompt better female professional involvement in the conservation of natural resources.

This paper addresses the problem of assessing and optimizing acoustic positioning system for underwater target localization with range measurements only. We present a new three-dimensional assessment model to assess the optimal geometric beacon formation whether meet user needs. For the sake of mathematical tractability, it is assumed that the measurements of the range between the target and beacons are corrupted with white Gaussian noise with variance is distance-dependent. Then by adopting dilution of precision (DOP) parameters in the assessment model, the relationship between DOP parameters and positioning accuracy is derived. In addition, the optimal geometric beacon formation that will yield the best performance is achieved by minimizing the values of geometric dilution of precision (GDOP) on condition that the position of target is known and fixed. Next, in order to make sure whether the estimate positioning accuracy over interesting region satisfy the precision needed by the users, geometric positioning accuracy (GPA), horizonal positioning accuracy (HPA) and vertical positioning accuracy (VPA) are utilized to assess the optimal geometric beacon formation. Simulation examples are designed to illustrate the exactness of the conclusion. Unlike other work which only use GDOP to optimize the formation and cannot assess the performance of the specified dimensions, this new three-dimensional assessment model can assess the optimal geometric beacon formation in each dimension for any point in three-dimensional space, which can provide users with guidance advices to optimize performance of every specified dimension.

Globally, humans are struggling with the double threat of communicable and non-communicable diseases, which are presenting new challenges to public health. Public health problems are generally studied and addressed at primary, secondary and tertiary levels. Most effective results are seen with primary interventions. Public health is becoming more aware of the importance of environment-gene interactions in the ontology of health and disease using epigenetics. Epigenetics is the study of altered gene expression without change in base pairs. Be it physical, social, behavioral, or economic factors; they all influence quality of life and health of individuals and populations. That environments are changing the human health phenotype and these changed phenotypes are heritable is of concern for the future of the human race. Knowing the causes of non-communicable human diseases using epigenetics will contribute to the development of new policies to encourage prevention using primary public health initiatives. Research and application of epigenetics shows great promise for improving population health. Continued advances in epigenetics will enhance how we understand and address the way environments are affecting the human health phenotype. For some time, health systems have been and continue to be tertiary in nature. Epigenetic changes can provide information necessary to better understand how social determinants of health can be used to build societies focused on equitable health for all people, rather than continuing to focus on treatment of diseases in the tertiary phase that leads to health disparities. Understanding mechanisms of social determinants of disease, will allow society to evolve in a health-oriented rather than a disease-oriented world. For this reason, we must enhance and apply epigenetics (physical, social, behavioral, economic) research to policy development. We will discuss how bringing social determinants together with biology can be used as new tools for public health policy.

Cardiomyopathies (CMPs) are a group of myocardial disorders that are characterized by structural and functional abnormalities of the heart muscle. These abnormalities occur in the absence of coronary artery disease (CAD), hypertension, valvular disease, and congenital heart disease. CMPs are an increasingly important topic in the field of cardiovascular diseases due to the complexity of their diagnosis and management. In 2023, the ESC guidelines on cardiomyopathies were first published, marking significant progress in the field. The growth of techniques such as cardiac magnetic resonance imaging (CMR) and genetics has been fueled by the development of multimodal imaging approaches. For the diagnosis of CMPs, a multimodal imaging approach, including CMR, is recommended. CMR has become the standard for non-invasive analysis of cardiac morphology and myocardial function. This document provides an overview of the role of CMR in CMPs, with a focus on tissue mapping. CMR enables the characterization of myocardial tissues and the assessment of cardiac functions. CMR sequences and techniques, such as late gadolinium enhancement (LGE) and parametric mapping, provide detailed information on tissue composition, fibrosis, edema, and myocardial perfusion. These techniques offer valuable insights for early diagnosis, prognostic evaluation, and therapeutic guidance of CMPs. The use of quantitative CMR markers enables personalized treatment plans, improving overall patient outcomes. This review aims to serve as a guide for the use of these new tools in clinical practice.

The aim of this cross-sectional study was to assess the influence of the maturity status on speed, explosive power and change of direction (COD) in 13-year-old football players. Ninety-eight male players (age: 13.1 ± 1.0 y) were divided into late, average, and early maturation groups. Physical fitness testing included the following variables: 10 and 30-meter sprint time and maximum speed in the 20-30 m segment of the 30-meter sprint test, the T-test time, countermovement jump height and horizontal distance in the triple jump. The data showed a significant effect of maturity status on performance in three parameters: in maximum speed in the 20-30 m section (p = 0,024), however, the only significant differences were found between the early-maturation group and average-maturation group (p = 0.033); in the COD (p = 0.024), where significant differences were confirmed between the late-maturation group and the average-maturation group (p = 0.033); in the unilateral triple jump distance of the dominant and non-dominant (p = 0,007 and p = 0.001, respectively) lower limb. For both limbs, significant differences between the late-maturation group and average maturation group (p = 0.005 and p = 0.013, respectively) as well as the late-maturation group and early-maturation group (p = 0.007 and p = 0.045, respectively) were proved. These results indicate that maximal speed, COD speed and unilateral lower limb reactive strength are moderated by biological age in football players aged 13 years.

The Sanaga River Valley is a deep-seated structure of about 220 km in width, bounded on its northern and southern sides by 025-0550 fault zones. Its internal structure has been very little described before this study. It is characterized by the presence of surface features where a thick stratum of shale and argillaceous sandstones have been documented. The use of electrical resistivity tomography for near-surface imaging and hydrogeological prospecting within shale succession is widespread. However, several methods of spatial modeling of resistivity contours are generally proposed for the interpretation of inverse resistivity model sections. To determine the most appropriate method for interpreting resistivity tomographies in the context of subsoil marked by significant heterogeneity, logarithmic contour intervals, and linear contour interval processing were implemented on data collected over five areas. The data consists of outcrops data, cuttings samples from groundwater boreholes, and resistivity sections ranging in length from 240 to 1000 m. Well-control of the inverse resistivity model sections derived from both processes shows that the linear contour intervals modeling gives a more realistic picture of the reservoir size of the wa-ter-bearing sand in both shale and argillaceous sandstone succession. The sedimentary architecture over Sanaga fault breccia is marked by vertical intrusion anomalies up to 80 m high. The shape of these anomalies, as well as the very low resistivity values that characterize them, suggests that they could be related to mud intrusion.

SARS-CoV-2 was identified as the pathogenic agent causing the COVID-19 pandemic. Among the proteins codified by this virus, the Spike is one of the most external and exposed. A fragment of the Spike protein, named the Receptor Binding Protein (RBD) interacts with the ACE2 receptors of human cells, allowing the entrance of the viruses. RBD has been proposed as an interesting protein for the development of diagnosis tools, treatment and prevention of the disease. In this work, a method for recombinant RBD production using Pichia pastoris as a cell factory in a Stirred Tank Bioreactor (SRTB) up to 7 L was developed. Using a basal saline medium with glycerol, methanol and compressed air in a four stages procedure, around 500 mg/L of raw yRBD (RBD produced by yeasts) and 206 mg/L of purified (>95%) RBD were obtained. Thereby, the proposed method represents a feasible, simple, scalable and cheap procedure for the obtention of RBD for diagnosis kits and vaccines formulation

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin releasing factor (CRF)-CRF1 receptor and GABAergic signaling dysregulation occurring in alcohol dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch clamp electrophysiology to examine the effects of alcohol dependence on the CRF-modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had less CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.

Introduction Early prediction of long term outcomes in patients resuscitated after cardiac arrest (CA) is still challenging. Guidelines suggested a multimodal approach combining multiple predictors. We evaluated whether the combination of the electroencephalography (EEG) reactivity, somatosensory evoked potentials (SSEPs) cortical complex and Gray to White matter ratio (GWR) on brain computed tomography (CT) at different temperatures could predict survival and good outcome at hospital discharge and after six months. Methods We performed a retrospective cohort study including consecutive adult, non-traumatic patients resuscitated from out-of-hospital CA who remained comatose on admission to our intensive care unit from 2013 to 2017. We acquired SSEPs and EEGs during the treatment at 36°C and after rewarming at 37°C, Gray to white matter ratio (GWR) was calculated on the brain computed tomography scan performed within six hours of the hospital admission. We primarily hypothesized that SSEP was associated with favorable functional outcome at distance and secondarily that SSEP provides independent information from EEG and CT. Outcomes were evaluated using the Cerebral Performance Category (CPC) scale at six months from discharge. Results Of 171 resuscitated patients, 75 were excluded due to missing of data or uninterpretable neurophysiological findings. EEG reactivity at 37 °C has been shown the best single predictor of good outcome (AUC 0.803) while N20P25 was the best single predictor for survival at each time point. (AUC 0.775 at discharge and AUC 0.747 at six months follow up) Predictive value of a model including EEG reactivity, average GWR, and SSEP N20P25 amplitude was superior (AUC 0.841 for survival and 0.920 for good outcome) to any combination of two tests or any single test. Conclusion Our study, in which life-sustaining treatments were never suspended, suggests SSEP cortical complex N20P25, after normothermia ad off sedation, is a reliable predictor for survival at any time. When SSEP cortical complex N20P25 is added into a model with GWR average and EEG reactivity, the predictivity for good outcome and survival at distance is superior than each single test alone.

All humans will experience the process of birth, old age, illness, and death. However, when faced with life-sustaining decisions, the families of patients are often faced with medical decisions as surrogates. In recent years, the families of patients have started to value the importance of the right to palliative care, although this often requires lengthy discussions. Therefore, this study explored the predictability of factors that affect the feeling experienced by patients’ families when signing Do-Not-Resuscitate Consent. This study used a cross-sectional study and interviewed 90 family members using a structural questionnaire. The study hypotheses were tested using a t-test, one-way analysis of variance, product–moment correlation, and hierarchical regression analysis. Attribute variables of family members, such as gender and whether they live with the patient, are predictors that affect the family member’s feeling experience when signing Do-Not-Resuscitate Consent. The emotional support from medical professionals to family members helps the family member to express their negative feelings on signing Do-Not-Resuscitate Consent; more informational support information provided to family members by medical professionals can alleviate negative feelings felt by family members when signing Do-Not-Resuscitate Consent. This study identified that family members’ knowledge about Do-Not-Resuscitate acquired from medical professionals is relatively low. It is suggested that critical care units regularly conduct training on hospice palliative care, implement standard care procedures of hospice palliative care at critical care units, and provide detailed medical information about advanced decisions to family members so as to reduce their emotional stress. This will ensure that intensive care units can also achieve the goal of critically ill hospice palliative care.

With the advent of Web 3.0, the swift advancement of technology confronts an imminent threat from quantum computing. Security protocols safeguarding the integrity of Web 2.0 and Web 3.0 are growing more susceptible to both quantum attacks and sophisticated classical threats. The article introduces our novel long-distance free-space quantum secure direct communication (LF QSDC) as a method to safeguard against security breaches in both quantum and classical contexts. Differing from techniques like quantum key distribution (QKD), LF QSDC surpasses constraints by facilitating encrypted data transmission sans key exchanges, thus diminishing the inherent weaknesses of key-based systems. The distinctiveness of this attribute, coupled with its quantum mechanics base, protects against quantum computer assaults and advanced non-quantum dangers, harmonizing seamlessly with the untrustworthy tenets of the Web 3.0 age. The focus of our study is the technical design and incorporation of LF QSDC into web 3.0 network infrastructures, highlighting its efficacy for extended-range communication. LF QSDC is based on the memory DL04 protocol and enhanced with our novel Quantum-Aware Low-Density Parity Check (LDPC), Pointing, Acquisition, and Tracking (PAT) technologies, and Atmospheric Quantum Correction Algorithm (AQCA). Utilizing this method not only bolsters the security of worldwide Web 3.0 networks but also guarantees their endurance in a time when quantum and sophisticated classical threats exist simultaneously. Consequently, LF QSDC stands out as a robust security solution, well-suited for Web 3.0 systems amidst the constantly evolving digital environment.

Abstract: Circumcision is a long-standing and frequently performed surgical procedure which holds significant cultural significance among AmaXhosa people in South Africa. Due to cultural reasons in some parts of Africa, the integration of medical male circumcision with traditional manhood initiation rituals still lacks acceptance. This study examined the level of knowledge and acceptance of voluntary male medical circumcision (VMMC) among young males in a selected high school in the Nyandeni District of the Eastern Cape Province, South Africa. A descriptive, quantitative, cross-sectional study was conducted, and a self-administered questionnaire was used to obtain information on sociodemographic characteristics, knowledge of VMMC, percep-tions of VMMC, and circumcision practices. One Hundred participants were recruited from both grades 11 and 12, and 82% of the participants indicated that they had received information about VMMC. Most of the respondents (88%) preferred traditional male circumcision (TMC) and only 12% of respondents preferred VMMC. The participants displayed a good understanding of the distinction between VMMC and TMC. However, results from the study showed that most re-spondents exhibited low acceptability towards VMMC. These findings highlight the need to develop evidence-based strategies to enhance learners’ knowledge and acceptance of VMMC.

This research paper aimed to explore the impact of childhood and adolescent experiences on the leadership development of Emirati women in the United Arab Emirates (UAE). Using a qualitative research methodology, the study utilized in-depth narrative semi-structured interviews, document analysis, and diary writing to understand the complex issue of leadership development. Findings indicate that childhood and adolescent experiences, including family upbringing, education, culture, and societal expectations, have significant impacts on the leadership development of Emirati women. Specifically, family upbringing and cultural values shape Emirati women's leadership aspirations and behaviors, while education and societal expectations provide opportunities and barriers for women's leadership development. The implications of these findings for policymakers and practitioners seeking to promote women's leadership development in the UAE are discussed.

Transcatheter Aortic Valve Implantation (TAVI) now represents the mainstay in the treatment of severe aortic stenosis. Owing to its exceptional procedural efficacy and safety, TAVI has been extended to include patients at lower surgical risk, thus now encompassing a diverse patient population receiving this treatment. Yet, long-term outcomes also depend on optimal medical therapy for secondary vascular prevention, with antithrombotic therapy serving as a cornerstone. Leveraging data from multiple randomized controlled trials, current guidelines generally recommend single antithrombotic therapy, with either single antiplatelet therapy (SAPT) or oral anticoagulation (OAC) alone in those patients without, or with atrial fibrillation respectively. Yet, individualization of this pattern, as well as specific case uses, may be needed based on individual-patient characteristics and concurrent procedures. This review aims to discuss the evidence supporting antithrombotic treatments in patients treated with TAVI, indications for a standardized treatment, as well as specific considerations for an individualized approach to treatment.

A new-type vibration sensor based on a fiber Bragg grating combining with a special structure-packaged design is proposed for monitoring the mechanical vibration signals. Three different sensing structures including the film squeeze type, new film squeeze type and elastic tape squeeze type are proposed for measuring the vibration signals with the frequency range from tens to thousands of Hz. In the comparison of experimental results, the new film squeeze structure has a nice sensing performance in the range from 100 to 1000 Hz with the sensitivity of 35 mV/V. For the elastic tape squeeze structure, the elastic tape is designed to encapsulate the optical fiber with a good frequency response from 1100 to 3100 Hz. In addition, by using the new film squeeze structure to measure the steady-state and non-steady-state vibration signals, the spectral components of sensing signals are analyzed by using the wavelet transformation for confirming the testing signals. These vibration fiber sensors can be applied in the measurement of high-end manufacture-facility vibration or earthquake vibrations etc.

In modern agriculture, decision-making is deeply intertwined with data, yet essential agricultural knowledge remains encased within dense scientific texts such as journals, manuals, and free-text reports. This necessitates specialized search systems capable of distilling and delivering precise information in response to specific queries from agricultural users. This study introduces AgriQuery, a sophisticated agent designed to field natural language questions from the agricultural sector by exploring vast troves of scientific documents. A comprehensive review and analysis of farmers' information needs have been conducted, leading to the creation of an information retrieval test collection that includes actual queries, a vast array of scientific documents segmented into passages, and a set of ground truth relevance assessments that map these passages to corresponding queries. We explore and benchmark several information retrieval models, highlighting the efficacy of advanced neural ranking models in this context. AgriQuery's proposed deployment architecture features a client interface on the Telegram platform and a backend model on standard hardware. This test collection aims to catalyze further research into matching natural language queries with scientific text answers, with implications extending beyond agriculture.

Any material object vibrating or rotating excites in spacetime around gravitational waves. Atomic nucleus being highly dynamical object also excites continuously micro gravitational waves which might form around the nucleus specific structure resembling optical diffraction grating and which gives huge effect to nuclear elastic scattering cross sections. The close similarity between the nuclear diffractive scattering and the optical Debye-Sears Effect is shown.

From the critical premises that underpin the debate between archeology and architecture, evi-dence emerges, namely that the musealization of building or urban remains of the past is even more harmful, for the purposes of its real understanding, than that of any other artefact. In a country, Italy, that has archeological presences more than any other, architecture must contribute to overcoming the consolidated aporia that the Contemporary, understood not only as a period but also and above all as its “forms and functions”, it’s structurally in opposition to the conser-vation of the archeological heritage. What is presented is an attempted exercise for “inhabiting archaeology”, that is, trying to re-grant inclusive usability to a historical fragment, which has lost the elements necessary for its habitability. The set of questions, doubts and steps have been high-lighted more than the final “figure” of the project: an essential form directly connected with the primordial principles of its constitution, for a project that protects and encourages to visit the complex, trying to offer new perspectives, new narratives and new connections that translate into the possibility of being – for those who visit this place – the protagonists of a unique experience made of history, memory and continuous discoveries.

We show how the Poincar\'e--Riemann--Hilbert boundary-value problem enables us to construct effective estimates of the potential in the Schr\"odinger equation. The apparatus of the three-dimensional inverse problem of quantum scattering theory is developed for this. It is shown that the unitary scattering operator can be studied as a solution of the Poincar\'e--Riemann--Hilbert boundary-value problem. This allows us to go on to study the potential in the Schr\"odinger equation

Glaucoma is a group of ocular diseases that causes irreversible blindness worldwide and is characterized by a multifactorial degeneration of optic nerve and retinal ganglion cells (RGCs), leading to vision loss. One of the significant risk factors in glaucoma pathogenesis is glia-driven neuroinflammation. Impairment of mitochondrial dynamics and bioenergetics is associated with glaucomatous neurodegeneration and is linked to neuroinflammation. Apolipoprotein A-I binding protein (AIBP) binds to toll-like receptor 4 (TLR4) and facilitates the removal of excess cholesterol from the plasma membrane in activated cells, suggesting the regulation of cholesterol-driven inflammation by inhibiting the TLR4-associated lipid rafts. AIBP is localized in mitochondria and regulates mitophagy by ubiquitination of mitofusin 1 and 2. We observed elevated intraocular pressure-induced AIBP deficiency in glaucomatous neurodegeneration. We also observed that AIBP deficiency activated TLR4 in Müller glia, triggered mitochondrial dysfunction in both RGCs and Müller glia and impaired visual function. In mouse models of glaucoma, AIBP treatment protects RGCs by reducing inflammatory responses. Here, our review focuses on investigating the role of AIBP in the retina and examining the underlying mechanism by which AIBP contributes to the pathogenesis of glaucoma, aiming to provide new insight into the therapeutic potential for the treatment of glaucoma.

In view of the diminishing contribution of natural products from plants to the discovery of new chemical structures, the aim of this study was to compile the articles from 2021 to 2022, assessing: (1) which classes of compounds these new structures belong to; (2) which plants and families these compounds belong to and (3) assessing the degree of novelty of the compound with an already known structure. The review was elaborate following the Preferred Reporting Items for System-atics Reviews and Meta-analyses (PRISMA) statement checklist for guide reporting of systematic reviews. A total of 464 articles were selected for the new compounds of natural origin survey. We included 117 complete articles in this review and reported approximately 109 new structures elucidated during the years 2021 and 2022. Many of the compounds showed small structural var-iations in relation to already known molecules. For some, however, this small modification was decisive for the biological activity reported, demonstrating the importance of descriptive phytochemical studies.

Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy, characterized by ventricular chamber dilatation and systolic dysfunction, in the absence of coronary artery disease, arterial hypertension, valvular or congenital diseases. DCM is a heterogeneous group of disorders of the myocardium caused by genetic factors, environmental factors, or a combination of both. DCM affects mainly men aged between 20 and 50 years, being considered one of the main causes of heart failure (HF) and the main indication for heart transplantation. Guideline-based HF treatment is the mainstay of management for patients with DCM. In recent years, gene therapy and induced pluripotent stem cells have become promising strategies. In this review, we summarize the relevant clinical issues, and current treatment of DCM patients, including the role of genetic evaluation.

Pleural mesothelioma (PM) comprises three main subtypes: epithelioid, biphasic and sarcomatoid, which have a different impact on prognosis and treatment definition. However, PM subtyping can be complex given the inter- and intra-tumour morphological heterogeneity. We aim to use immunohistochemistry (IHC) to evaluate five markers (Mesothelin, Claudin-15, Complement Factor B, Plasminogen Activator Inhibitor 1, and p21-activated Kinase 4), whose encoding genes have been previously reported as deregulated among PM subtypes. Immunohistochemical expressions were determined in a case series of 73 PMs, and cut-offs for the epithelioid and non-epithelioid subtypes were selected. Further validation was performed on an independent cohort (30 PMs). For biphasic PM, the percentage of the epithelioid component was assessed, and IHC evaluation was also performed on the individual components separately. Mesothelin and Claudin-15 showed a good sensitivity (79% and 84%) and specificity (84% and 73%) for the epithelioid subtype. CFB and PAK4 had an inferior performance, with higher sensitivity (89% and 84%), but lower specificity (64% and 36%). In the biphasic group, all markers showed a different expression when comparing epithelioid with sarcomatoid areas. Mesothelin, Claudin-15 and CFB can be useful in subtype discrimination. PAI1 and PAK4 can improve component distinction in biphasic PM.

Modern drugs have changed epilepsy, which affects people of all ages. But for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people <18y antiseizure medications (ASMs) need separate proof of efficacy and safety (E&S), overall called “pediatric drug development.” This has been corrected to some extent. Authorities accept that ASMs are effective in <18y as well, but they still require "extrapolation of efficacy," as if minors were another species. In our view, the real problem is less that relevant parts of pediatric clinical epilepsy research over the past decades were useless, but that this has hampered research on meaningful challenges. We do not need to show that ASMs work also before the 18th birthday. But we need to learn how to best use ASMs to prevent brain damage in young patients and optimize ASMs use considering a broader range of aspects

Background: Neurosarcoidosis is a great mimic, and its distinction from multiple sclerosis and other disorders can be particularly troublesome. We investigated whether cerebrospinal fluid (CSF) examination could help distinguish these two conditions and propose new diagnostic criteria. Methods: Stringent hierarchical diagnostic criteria were formulated. These were then applied prospectively to 531 neurological patients in whom neurosarcoidosis entered the differential diagnosis. The CSF total protein (TP), white cell count (WCC) and angiotensin-converting enzyme (ACE) levels were measured. The CSF and serum IgG patterns after isoelectric focusing were compared. Not all CSF parameters were measured in every patient. Results: 85/531 (16%) cases examined were diagnosed with neurosarcoidosis. Only 22 of these 85 (26%) met stringent diagnostic criteria. Intrathecal synthesis of oligoclonal IgG was evident in only 1/19 (5%) who fulfilled these criteria compared to 19/59 (32%) cases who did not (p = 0.03). CSF TP levels > 1g/L were more common in patients meeting the stringent criteria compared to the remainder of the patients, i.e. 11/22 (50%) vs 14/58 (24%) (p<0.05). Eleven out of 20 cases (55%) fulfilling stringent criteria had elevated CSF WCCs, and 6/12 cases (50%) had raised CSF ACE, neither significantly different from the remaining cases. Mean CSF TP, WCC, and ACE levels did not differ significantly between any groups of patients. Interpretation: Large elevations in CSF total protein, white cell count, and ACE occur in neurosarcoidosis but are rare in multiple sclerosis. However, the diagnostic use of these tests is limited since minimal changes may occur in both conditions. In contrast, intrathecal synthesis of oligoclonal IgG is a powerful discriminator because it is very uncommon in neurosarcoidosis whilst occurring in 95-98% of cases of multiple sclerosis. This observation implies that the immunopathogenesis of the two disorders is quite different. We suggest caution in diagnosing neurosarcoidosis when intrathecal oligoclonal IgG synthesis is detected. We propose new diagnostic criteria for neurosarcoidosis for future research.

Cancers have been interpreted either as somatic evolution of cheater cells that escape replication regulation or alternatively as non-healing wounds. Both the interpretations have substantial support as well as glaring anomalies but the two have not been put together to make a coherent synthesis. We argue here that mechanisms and pathways to escape the normal regulation of cell proliferation do not need to evolve de novo. Mechanisms to override the normal regulation have already evolved for wound healing and tissue regeneration. Almost all of the hallmarks of cancer are also seen in the wound healing process. This suggests that cancer develops not by any de novo gain of function but by exaptation of pre-evolved wound healing functions. Somatic evolution that makes the wound healing triggers constitutive is not mutation limited but selection limited and the selective forces are dependent on the tissue microenvironment. Some mechanisms for such selection have been suggested. Many more need to be investigated. A series of mechanisms have evolved to minimize the risk of cancers which may fail in an altered lifestyle context. We support our synthesis with multiple lines of evidence and also make differential testable predictions. This evolutionary perspective suggests novel lines of research and also has translatable implications for cancer prevention.

Current sources play an essential role in tissue excitation used in bioelectrical impedance spectroscopy. Most investigations use Howland current sources that, despite their practicality and simplified implementation, have operating frequency limitations and dependence on the load impedance due to theirs narrow output impedance, specially at higher frequencies. The objective of this work is to propose model for a robust current-controlled sinusoidal oscillator. The oscillator is based on fully analog electronics, which enables controlling oscillation phase and amplitude by using a voltage reference. The mathematical model is based on Pyragas control application to the classical harmonic oscillator. From the modelling process, it was build an oscillator topology based on second-generation current carriers and on transconductance amplifiers. The reference signal (Fsync) was a sinusoidal voltage source having a frequency of 1MHz and an amplitude of 1Vpp. The oscillator output current synchronized the oscillations’ phase and amplitude with Fsync, regardless of their magnitude before the control signal acted in the circuit at t≈13.5μs. SPICE simulations using ideal components have confirmed the successful operation of the proposed oscillator. This type of oscillator can be implemented in SOIC, then allowing oscillation control interface with logic circuits.

The efficiency of data sorting algorithms is the key aspect which determines the speed of data processing and searching. The best known efficiency of sorting algorithm has been Log (N) if there are N terms. All of the well-known sorting algorithms use various techniques to sort data. The basis for most of these are comparing the data terms with each other. In this manuscript, we are introducing a new approach for sorting data. This method is postulated to have the highest efficiency ever achieved by any of the sorting algorithms. We achieve this by sorting data without comparing the data terms. Or achieving results of data comparison without comparing the terms explicitly.

Uveal melanoma is the most common primary intraocular malignancy in adults characterized by insidious onset and poor prognosis strongly associated with tumor size and the presence of distant metastases, most commonly in the liver. Contrary to most tumor identification, biopsy followed by pathological exam is not recommended in ophthalmic oncology. Therefore, early and non-invasive diagnosis is essential to enhance patients’ chances for early treatment possibilities. We reviewed imaging modalities currently used in the diagnosis of uveal melanoma, i.e., fundus imaging, ultrasonography (US), optical coherence tomography (OCT), single-photon emission computed tomography (SPECT), positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF). The principle of imaging techniques was briefly explained, along with their role in the diagnostic process and a summary of their advantages and limitations. Further, the experimental data and the advancements in imaging modalities were searched. We described their innovations, showed current usage and research, and explained the possibilities of utilizing them to diagnose uveal melanoma and their potential application in personalized medicine such as theranostics.

We select four important waves of new entrants that knocked on the door of European electricity markets to illustrate how market rules need to be continuously adapted to allow new entrants to come in and push innovation forward. The new entrants that we selected are utilities venturing into neighbouring markets after establishing a strong position in their home market, utility-scale renewables project developers, asset-light software companies aggregating the assets of smaller consumers and producers, and different types of communities. We show that well-intentioned rules designed for certain types of market participants can (unintentionally) become obstacles for new entrants. We conclude that the evolution of market rules illustrates the importance of dynamic regulation. At the start of the liberalisation process the view was that we would deregulate or re-regulate the sector after which the role of regulators could be reduced. But their role has only increased. New players might also present new risks that require intervention by regulators.

GIGANTEA (GI) is a gene involved in multiple biological functions, which were analysed and are partially conserved in a series of mono- and dicotyledonous plant species. The identified biological functions include control over the circadian rhythm, light signalling, cold tolerance, hormone signalling and photoperiodic flowering. The latter function is a central role of GI, as it involves a multitude of pathways, both dependent and independent of the gene CONSTANS(CO) as well as on the basis of interaction with miRNA. The complexity of gene function of GI increases due to the existence of paralogs showing changes in genome structure as well as incidences of sub- and neofunctionalization. We present an updated report of the biological function of GI, integrating late insights into its role in floral initiation, flower development and flower volatile production.

This article presents a new theory on redshift of light from celestial bodies. Lately it has been found that the Hubble constant calculated from different methods discord so much that calls arise for new physics to explain. Also, in addition to many unsolved puzzles like dark matter and source of expansion force, we shall show in this article that the current theory of redshift implies a few hidden, unreasonale assumptions. By assuming photon has temperature and its thermal energy is fully converted to wave energy, this article shows that photon can have a new redshift called Temperature Redshift, which not only is more significant for remote stars or galaxies, but also better fits the observational data, including those used in Hubble constant calculation. As such, if true, this new theory not only adds to our new understanding of photons, but may totally change our current understanding of the Universe, i.e., the Big Bang theory.

In theory and applications, it is often inevitable to work with projectors onto convex sets, where a linear transform is involved. In this article, a novel projector is presented, which generalizes previous results in that it admits a broader family of linear transforms, but on the other hand it is limited to box-type convex sets in the transformed domain. The new projector has an explicit formula and it can be interpreted within the framework of proximal optimization. The benefit of the new projector is demonstrated on an example from signal processing, where it was possible to speed up the convergence of a signal declipping algorithm by a factor of more than two.

Accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions and can be repaired using homologous recombination (HR). HR is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here we discuss the current perspective on the RAD51 paralogs in vivo and in vitro function and their relationship with cancer in vertebrate models.

In the context of long-term screening for viruses on Western Palaearctic bats, we tested for the presence of adenovirus 1.392 oropharyngeal swabs and 325 stool samples taken from 27 bat species. Adenoviruses were detected in 12 species of the Vespertilionidae and the Rhinolophidae families. Fifty positive respiratory and 26 positive stool samples were studied. Phylogenetic analyses of partial hexon protein and partial DNA-dependent DNA polymerase genes, indicate all these bat adenoviruses belong to the genus Mastadenovirus but without constituting a monophyletic cluster. According to genetic identities, the new groups are distinct to the previously described Bat mastadenovirus A and B species, and contribute with potentially new members. Our data support that diversity of Bat mastadenovirus is host-dependent and increase the knowledge of potentially pathogenic virus from bats. For human concerns this knowledge is an important Public Health issue due to the active role of bats as viral reservoirs.

In this paper, the modification of two synthetic steps to obtain EMICORON, with respect to the usual protocol, is reported. EMICORON is a benzo[ghi]perylen-diimmide which was synthesized the first time in our laboratory in 2012 and showed to have in-vivo antitumor activities interfering with tumor growth and development by a multi-target mechanism of action. The provided modifications regarded the reaction times and the reaction conditions as well as the work-up procedures and allowed to increase the global yield of the process from 28% to about 40%. Thus, this new procedure may be more suitable in order to get larger amounts of EMICORON for further preclinical studies.

Monochromatic documents claim for much less computer bandwidth for network transmission and storage space than their color or even grayscale equivalent. The binarization of historical documents is far more complex than recent ones as paper aging, color, texture, translucidity, stains, back-to-front interference, kind and color of ink used in handwritting, printing process, digitalization process, etc. are some of the factors that affect binarization. This article presents a new binarization algorithm for historical documents. The new global filter proposed is performed in four steps: filtering the image using a bilateral filter, splitting image into the RGB components, decision-making for each RGB channel based on an adaptive binarization method inspired by Otsu's method with a choice of the threshold level, and classification of the binarized images to decide which of the RGB components best preserved the document information in the foreground. The quantitative and qualitative assessment made with 21 binarization algorithms in three sets of “real world” documents showed very good results.

Corrosion inhibitors are the natural or synthetic compounds that have the ability to inhibit the average of corrosion and reduce the damage of the mild steel. Enormous organic inhibitors nowadays employed in the corrosion domain but excluded due to costly. Comparatively cheap, and stable organic compound, namely 3-((4-nitrobenzylidene)amino)coumarin, have been utilized as an excellent corrosion inhibitor in hydrochloric acid for mild steel. The inhibition efficiency has been figured regarding to weight loss method. The corrosion inhibitor was identified according to spectroscopic techniques namely Fourier transform infrared and nuclear magnetic resonance in addition to micro-elemental analysis. Inhibition efficiency for the studied inhibitor was 71.4% that, at the highest studied concentration.

In this short paper we study some properties of the lines associated with van Aubel’s theorem in the special case when squares are replaced with equilateral triangles constructed on the sides of an arbitrary quadrilateral.

In this paper, we consider the development of algorithms for the solution of first order initial value problems whose solution exhibits exponential behaviour. Method of interpolation and collocation of basis function to give system of nonlinear equations which is solved for the unknown parameters to give a continuous scheme. The discrete methods recovered from the continuous scheme are implemented in block form. The stability properties of the method is verified and numerical experiments show that our method is efficient in handling these problems

Background: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the ApoE gene and plasmatic apolipoprotein E (ApoE) levels as MCI biomarkers in Colombian subjects with MCI and controls. Methods: 100 participants were included (71% women, average age, 70 yrs., range 43-91). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Multivariate logistic regression models adjusted by age and gender were performed to examine the risk association of MCI with plasma ApoE and APOE methylation Results: MCI was diagnosed in 41 subjects (average age, 66.5±9.6 yrs.) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (P<0.05). Higher CpG-227 methylation correlated with lower risk for MCI (P=0.002). Only CpG-227 was significantly correlated with plasmatic ApoE levels (correlation coefficient=-0.665; P=0.008). Conclusion: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns can be used as potential biomarkers to identify early stages of MCI.

: The ichthyofauna of Lake Tanganyika consists of 12 families of fish of which five belong to Siluriformes (catfishes). Studies on siluriforms and their parasites in this lake are very fragmentary. The present study was carried out to help fill the knowledge gap on the monogeneans parasitizing the siluriform fishes of Lake Tanganyika in general and more particularly Clarias gariepinus. The gills of a specimen of Clarias gariepinus (Clariidae) were examined for ectoparasites. We identified the monogenean Gyrodactylus transvaalensis (Gyrodactylidae). This is the first time this parasite was found infecting gills. We are the first to observe a large spine in the male copulatory organ of this species, and to provide measurements of its genital spines; this completes the description of the male copulatory organ which is important in standard monogenean identification. This is the first monogenean species reported on C. gariepinus at Lake Tanganyika and the third known species on a representative of Siluriformes of this lake. It brings the total number of species of Gyrodactylus recorded in Lake Tanganyika to four. Knowing that other locations where this species has been reported are geographically remote from Lake Tanganyika, we propose a “failure to diverge” phenomenon for G. transvaalensis.

Although extracorporeal membrane ventilation offers the possibility for low frequency ventilation, protocols commonly used in patients with acute respiratory distress syndrome (ARDS) and treated with extracorporeal membrane oxygenation (ECMO) vary largely. Whether strict adherence to low frequency ventilation offers benefit on important outcome measures is poorly understood. Background/Objectives: This pilot clinical study investigated the efficacy of low frequency ventilation on ventilator free days (VFDs) in patients suffering from ARDS treated with ECMO therapy. Methods: In this single-center randomized controlled trial, 44 (70% male) successive ARDS patients treated with ECMO (aged 56 ± 12 years, SAPS III 64 (SD ± 14)) were randomly assigned 1:1 to control group (conventional ventilation) or treatment group (low fre-quency ventilation during first 72 hours on ECMO: respiratory rate 4-5/min; PEEP 14-16cm H2O; plateau pressure 23-25 cm H2O, tidal volume: < 4mL/kg). The primary endpoint was VFDs at day 28 of ECMO start. The major secondary endpoint was ICU mortality, 28-day and 90-day mortality. Results Twenty-three (52%) patients could be successfully weaned from ECMO and were discharged from intensive care unit (ICU). Twelve patients in the treatment group and five patients in the control group showed more than one VFD at day 28 after ECMO. VFDs were 3.0 (SD ± 5.5) days in the control group and 5.4 (SD ± 6) days in the treatment group (P = 0.117). Until day 28 after ECMO initiation, patients in the treatment group could be more often successfully weaned from ventilator (OR of 0.164 of 0 VFDs at day 28 after ECMO start; 95% CI 0.036-0.758; P = 0.021). ICU mortality did not differ significantly (36% in treatment group and 59% in control group; P = 0.227). Conclusions: Low frequency ventilation is comparable to conventional protec-tive ventilation in patients with ARDS treated with ECMO. However, low frequency ventilation may support weaning from invasive mechanical ventilation in patients suffering from ARDS treated with ECMO therapy.

There are various approaches to managing polyethylene terephthalate waste, including methods for recycling PET. However, at present, only the cleanest wastes that can already be efficiently recycled using known methods are considered in the scientific literature. The study aims to look at other forms of polyethylene terephthalate waste that pose a challenge: low quality PET flakes, polyester tire cord, PET dust and prepolymer waste. The waste was characterized by FTIR spectroscopy, viscosimetry, differential scanning calorimetry, laser diffraction and sieve analysis. The findings describe the composition and properties of various forms of polyethylene terephthalate waste. Low quality PET flake waste and polyethylene terephthalate dust have been shown to be suitable for all chemical recycling methods. When recycling waste polyester tire cord, it is difficult to completely separate the rubber, so its presence in the final product must be taken into account. The most promising way to process a prepolymer is its depolymerization by hydrolysis, alcoholysis or glycolysis to produce monomers for the synthesis of PET, similar in properties to the primary one.