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Objectives: This study aimed to elucidate the connection between osteoclastic forkhead transcription factor O1 (FoxO1) and periodontitis and explore the underlying mechanism by which FoxO1 knockdown regulates osteoclast formation. Materials and Methods: A conventional ligature‐induced periodontitis model was constructed to reveal the alterations in the proportion of osteoclastic FoxO1 in periodontitis via immunofluorescence staining. Additionally, RNA sequencing (RNA‐seq) was performed to explore the underlying mechanisms of FoxO1 knockdown‐mediated osteoclastogenesis, followed by western blotting, quantitative polymerase chain reaction, and enzyme‐linked immunosorbent assay. Results: FoxO1+ osteoclasts were enriched in the alveolar bone in experimental periodontitis. Moreover, FoxO1 knockdown led to impaired osteoclastogenesis with low expression of osteoclast differentiation‐related genes, accompanied by an insufficient osteoclast maturation phenotype. Mechanistically, RNA‐seq revealed that the nuclear factor kappa B (NF‐κB) and nucleotide‐binding oligomerization domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were inhibited in FoxO1‐knockdown osteoclasts. Consistent with this, MCC950, an effective inhibitor of the NLRP3 inflammasome, substantially attenuated osteoclast formation. Conclusions: FoxO1 knockdown contributed to the inhibition of osteoclastogenesis by effectively suppressing NF‐κB signaling and NLRP3 inflammasome activation. This prospective study reveals the role of FoxO1 in mediating osteoclastogenesis and provides a viable therapeutic target for periodontitis treatment. [ABSTRACT FROM AUTHOR]

The Raman spectroscopy analysis technique has found extensive applications across various disciplines due to its exceptional convenience and efficiency, facilitating the analysis and identification of diverse substances. In recent years, owing to the escalating demand for high-efficiency analytical methods, deep learning models have progressively been introduced into the realm of Raman spectroscopy. However, the application of these models to portable Raman spectrometers has posed a series of challenges due to the computational intensity inherent to deep learning approaches. This paper proposes a lightweight classification model, named RepDwNet, for identifying 28 different types of biological blood. The model integrates advanced techniques such as multi-scale convolutional kernels, depth-wise separable convolutions, and residual connections. These innovations enable the model to capture features at different scales while preserving the coherence of feature data to the maximum extent. The experimental results demonstrate that the average recognition accuracy of the model on the reflective Raman blood dataset and the transmissive Raman blood dataset are 97.31% and 97.10%, respectively. Furthermore, by applying structural reparameterization to compress the well-trained model, it maintains high classification accuracy while significantly reducing the parameter size, thereby enhancing the speed of classification inference. This makes the model more suitable for deployment in portable and mobile devices. Additionally, the proposed model can be extended to various Raman spectroscopy classification scenarios. [ABSTRACT FROM AUTHOR]

Tardigrades, with over 1450 species, are important organisms in ecological understanding and are valuable biological models (e.g., due to their extremotolerant capabilities). While their biodiversity is better known in Europe and North America, Central and South America have only recently started making significant contributions. Through a comprehensive review of scientific literature, biological collections, web portal consultations, and the addition of new records, this study clarifies the current knowledge of tardigrade biodiversity in Colombia. Past research started in the early 20th century, but most data are unreliable due to information gaps and the absence of specimens in biological collections. The last decade has witnessed a resurgence in tardigrade research in Colombia, leading to new species descriptions and a more robust understanding of their biodiversity. Nevertheless, the majority of the territory remains unexplored. A total of 43 known species from our analysis are present in Colombia: 26 records accepted by the literature and 17 questioned in the literature but representing distinct taxa surely present in Colombia. Other species records are considered doubtful. Our study recommends considering mostly scientific records based on verifiable material deposited in scientific collections (highlighting their importance in studying and safeguarding biodiversity) and encourages future researchers to contribute while adhering to legal requirements. [ABSTRACT FROM AUTHOR]

In recent years, fractional calculus (FC) has filled in a hole in traditional calculus in terms of the effect of memory, which lets us know things about the past and present and guess what will happen in the future. It is very important to have this function, especially when studying biological models and integral equations. This paper introduces developed mathematical strategies for understanding a direct arrangement of fractional integro-differential equations (FIDEs). We have presented the least squares procedure and the Legendre strategy for discussing FIDEs. We have given the form of the Caputo concept fractional order operator and the properties. We have presented the properties of the shifted Legendre polynomials. We have shown the steps of the technique to display the solution. Some test examples are given to exhibit the precision and relevance of the introduced strategies. Mathematical outcomes show that this methodology is a comparison between the exact solution and the methods suggested. To show the theoretical results gained, the simulation of suggested strategies is given in eye-catching figures and tables. Program Mathematica 12 was used to get all of the results from the techniques that were shown. [ABSTRACT FROM AUTHOR]

Dynamical system models typically involve numerous input parameters whose "effects" and orthogonality need to be quantified through sensitivity analysis, to identify inputs contributing the greatest uncertainty. Whilst prior art has compared total-order estimators' role in recovering "true" effects, assessing their ability to recover robust parameter orthogonality for use in identifiability metrics has not been investigated. In this paper, we perform: (i) an assessment using a different class of numerical models representing the cardiovascular system, (ii) a wider evaluation of sampling methodologies and their interactions with estimators, (iii) an investigation of the consequences of permuting estimators and sampling methodologies on input parameter orthogonality, (iv) a study of sample convergence through resampling, and (v) an assessment of whether positive outcomes are sustained when model input dimensionality increases. Our results indicate that Jansen or Janon estimators display efficient convergence with minimum uncertainty when coupled with Sobol and the lattice rule sampling methods, making them prime choices for calculating parameter orthogonality and influence. This study reveals that global sensitivity analysis is convergence driven. Unconverged indices are subject to error and therefore the true influence or orthogonality of the input parameters are not recovered. This investigation importantly clarifies the interactions of the estimator and the sampling methodology by reducing the associated ambiguities, defining novel practices for modelling in the life sciences. Author summary: In order to gain new insight into a biological system, one often uses mathematical models to predict possible responses from the system. One vital step when using such models is to gain knowledge of the uncertainty associated with the model responses, for any input changes. Utilising two non-linear and stiff cardiovascular models as test cases, we investigate the effects of different choices made when quantifying the uncertainty of mathematical models. Leveraging efficient solving of the mathematical model, we show that in order to truly quantify the effects of inputs on a set of outputs, one must ensure converged estimates of the inputs' influence. Our detailed study provides a robust workflow of good modelling practice for biological systems, thus ensuring a true interpretation of the uncertainty associated with model inputs. [ABSTRACT FROM AUTHOR]

Computational biological models have proven to be an invaluable tool for understanding and predicting the behaviour of many biological systems. While it may not be too challenging for experienced researchers to construct such models from scratch, it is not a straightforward task for early stage researchers. Design patterns are well-known techniques widely applied in software engineering as they provide a set of typical solutions to common problems in software design. In this paper, we collect and discuss common patterns that are usually used during the construction and execution of computational biological models. We adopt Petri nets as a modelling language to provide a visual illustration of each pattern; however, the ideas presented in this paper can also be implemented using other modelling formalisms. We provide two case studies for illustration purposes and show how these models can be built up from the presented smaller modules. We hope that the ideas discussed in this paper will help many researchers in building their own future models. [ABSTRACT FROM AUTHOR]

Due to factors such as climate change, natural disasters, and deforestation, most measurement processes and initial data may have errors. Therefore, models with imprecise parameters are more realistic. This paper constructed a new predator-prey model with an interval biological coefficient by using the interval number as the model parameter. First, the stability of the solution of the fractional order model without a diffusion term and the Hopf bifurcation of the fractional order α were analyzed theoretically. Then, taking the diffusion coefficient of prey as the key parameter, the Turing stability at the equilibrium point was discussed. The amplitude equation near the threshold of the Turing instability was given by using the weak nonlinear analysis method, and different mode selections were classified by using the amplitude equation. Finally, we numerically proved that the dispersal rate of the prey population suppressed the spatiotemporal chaos of the model. [ABSTRACT FROM AUTHOR]

This paper presents an analytical solution to the model. By solving the system of nonlinear reaction-diffusion equations using Akbari–Ganji's method (AGM), we can derive the semi-analytical expressions for substrate and oxidized and reduced mediator concentrations. These models provide information about enzyme electrode mechanisms and their kinetics. These modeling results can be helpful for sensor design, optimization, and determining how the electrode will react. Further, we studied the effects of many physical and biological parameters on model prediction. The mathematical equations, which are nonlinear partial differential equations, are solved using AGM. Also, we derived the semi-analytical results for concentrations for saturated and unsaturated kinetics. It is verified that the proposed solution is validated by comparing it with numerical solutions. [ABSTRACT FROM AUTHOR]

We examine a biological population model of fractional order (FBPM) in this paper using the Riccati-Bernoulli sub-ODE approach. Many scenarios in computational biology make use of this fundamental fractional model. Of particular note is that our study's FBPM uses fractional derivatives to track changes in the density populations. The study is concerned with the construction of new solitary wave solutions for the FBPM, a system of two nonlinear fractional ordinary differential equations. In this investigation, we use the conformable derivative as the fractional derivative. The Backlund transformation is the foundation of the solution process. We create a variety of families of soliton wave solutions and explain different physical behaviours that are inherent in the problems we explore. In particular, we apply the suggested methods to investigate rational, periodic, and hyperbolic solutions. The solutions found in various classes provide insightful information about the underlying physical mechanisms. To sum up, our current methods are superior instruments for analyzing different families of solutions in fractional-order issues. [ABSTRACT FROM AUTHOR]

Many studies have shown that personalized exergames have a positive effect on promoting regular and proper exercise. However, there is no consensus on the design characteristics and evaluation of exergames. This systematic review of published research literature aimed to explore the general characteristics, personalization characteristics, and evaluation of personalized exergames for middle-aged and older people. We screened published studies in the Web of Science, Scopus, PubMed, ACM, and IEEE Xplore databases, extracted data, and performed a thematic analysis according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. Three main themes and nine subthemes were generated from 24 included papers. Moreover, a personalization model (FACTS) and evaluation system (PMSS) of exergames were developed. Personalized exergames had potential positive effects on motivating middle-aged and older people to exercise and improve their health, particularly physical, mental, and social health. However, more fine-grained studies on personalized exergames are necessary in the future. [ABSTRACT FROM AUTHOR]

In this paper, we propose an efficient Newton linearized numerical method for the nonlinear time-fractional parabolic equations with distributed delay based on the Galerkin finite element method in space and the nonuniform L1 scheme in time. The term of distributed delay is approximated by using the compound trapezoidal formula. For the constructed numerical scheme, we mainly focus on the unconditional convergence and superconvergence without any time–space ratio restrictions, the key of which is the use of fractional discrete Grönwall inequality and time–space error splitting technique. Numerical tests for several biological models, including the fractional single-species population model with distributed delay, the fractional diffusive Nicholson's blowflies equation with distributed delay, and the fractional diffusive Mackey-Glass equation with distributed delay, are conducted to confirm the theoretical results. Finally, combined with the nonunifom Alikhanov scheme in time and the FEM in space, we extend a higher-order Newton linearized numerical scheme for the nonlinear time-fractional parabolic equations with distributed delay and give some numerical tests for some biological models. [ABSTRACT FROM AUTHOR]

Objective. In this paper, we present MONAS (MicrOdosimetry-based modelliNg for relative biological effectiveness (RBE) ASsessment) toolkit. MONAS is a TOPAS Monte Carlo extension, that combines simulations of microdosimetric distributions with radiobiological microdosimetry-based models for predicting cell survival curves and dose-dependent RBE. Approach. MONAS expands TOPAS microdosimetric extension, by including novel specific energy scorers to calculate the single- and multi-event specific energy microdosimetric distributions at different micrometer scales. These spectra are used as physical input to three different formulations of the microdosimetric kinetic m odel, and to the generalized stochastic microdosimetric model (GSM2), to predict dose-dependent cell survival fraction and RBE. MONAS predictions are then validated against experimental microdosimetric spectra and in vitro survival fraction data. To show the MONAS features, we present two different applications of the code: (i) the depth-RBE curve calculation from a passively scattered proton SOBP and monoenergetic 12C-ion beam by using experimentally validated spectra as physical input, and (ii) the calculation of the 3D RBE distribution on a real head and neck patient geometry treated with protons. Main results. MONAS can estimate dose-dependent RBE and cell survival curves from experimentally validated microdosimetric spectra with four clinically relevant radiobiological models. From the radiobiological characterization of a proton SOBP and 12C fields, we observe the well-known trend of increasing RBE values at the distal edge of the radiation field. The 3D RBE map calculated confirmed the trend observed in the analysis of the SOBP, with the highest RBE values found in the distal edge of the target. Significance. MONAS extension offers a comprehensive microdosimetry-based framework for assessing the biological effects of particle radiation in both research and clinical environments, pushing closer the experimental physics-based description to the biological damage assessment, contributing to bridging the gap between a microdosimetric description of the radiation field and its application in proton therapy treatment with variable RBE. [ABSTRACT FROM AUTHOR]

Successful bioinspired design depends on practitioners' access to biological data in a relevant form. Although multiple open-access biodiversity databases exist, their presentation is often adapted to life scientists, rather than bioinspired designers. In this paper, we present a new tool, "Bioinspire-Explore", for navigating biodiversity data in order to uncover biological systems of interest for a range of sectors. Bioinspire-Explore allows users to search for inspiring biological models via taxa (species, genera, etc.) as an entry point. It provides information on a taxon's position in the "tree of life", its distribution and climatic niche, as well as its appearance. Bioinspire-Explore also shows users connections in the bioinspiration literature between their taxon of interest and associated biological processes, habitats, and physical measurements by way of their semantic proximity. We believe Bioinspire-Explore has the potential to become an indispensable resource for both biologists and bioinspired designers in different fields. [ABSTRACT FROM AUTHOR]

The gut microbiota (GM), as a forgotten organ, refers to the microbial community that resides in the gastrointestinal tract and plays a critical role in a variety of physiological activities in different body organs. The GM affects its targets through neurological, metabolic, immune, and endocrine pathways. The GM is a dynamic system for which exogenous and endogenous factors have negative or positive effects on its density and composition. Since the mid-twentieth century, laboratory animals are known as the major tools for preclinical research; however, each model has its own limitations. So far, two main models have been used to explore the effects of the GM under normal and abnormal conditions: the isolated germ-free and antibiotic-treated models. Both methods have strengths and weaknesses. In many fields of host-microbe interactions, research on these animal models are known as appropriate experimental subjects that enable investigators to directly assess the role of the microbiota on all features of physiology. These animal models present biological model systems to either study outcomes of the absence of microbes, or to verify the effects of colonization with specific and known microbial species. This paper reviews these current approaches and gives advantages and disadvantages of both models. [ABSTRACT FROM AUTHOR]

For patients who had testicular tissue cryopreserved before receiving gonadotoxic therapies, transplantation of testicular tissues and cells has been recommended as a potential therapeutic option. There are no studies that indicate the generation of sperm after human immature testicular tissue (ITT) or spermatogonial stem cells (SSCs) transplantation. The use of releasing scaffolds and localized drug delivery systems as well as the optimizing transplantation site can play an effective role in increasing the efficiency and improving the quality of testicular tissue and cell transplantation in animal models. Current research is focused on optimizing ITT and cell transplantation, the use of releasing scaffolds, and the selection of the right transplantation site that might restore sperm production or male infertility treatment. By searching the PubMed and Google Scholar databases, original and review papers were collected. Search terms were relevant for SSCs and tissue transplantation. In this review, we'll focus on the potential advantages of using scaffolds and choosing the right transplantation site to improve transplantation outcomes. [ABSTRACT FROM AUTHOR]

Analysis of the method of using sonography during surgery in animals with polycystic kidney disease is an urgent task since firstly, sonography is a safe and non-invasive method of examination, which allows determining the structural features of the kidneys before, during, and after surgery. Secondly, from the standpoint of improving the results of surgery, sonography helps to clarify the localisation of cysts and determine their size. Thirdly, an important factor in the use of sonography is the reduction of pain and the risk of postoperative complications. In addition, due to this method of kidney examination, it is possible to more accurately determine the optimal route of access to cysts, which helps to reduce tissue injury and ensures rapid recovery of the animal after surgery. The purpose of the study is to analyse in detail and describe the method of using sonography during surgery in animals with polycystic kidney disease. The study focuses on the need to determine how sonography affects reducing the duration of surgery, improving the quality of cyst removal, and reducing the risk of complications during abdominal surgery. The approach in this study is based on the analysis of scientific papers on this subject, in particular on the experience of veterinarians who have already used sonography during abdominal operations in animals with polycystic kidney disease. Thus, special techniques of sonography and surgical treatment of kidney cysts include dopplerography, colour dopplerography, 3D and 4D sonography, elastography, introperative sonography, intraperitoneal sonography, and duplex scanning of renal arteries and veins. Surgical methods of treatment include extraction of individual cysts, drainage of cysts, resection, and nephrectomy. The use of sonography at different stages of surgical intervention helps to optimise the operation process, reduce the risk of complications, and contribute to the introduction of new approaches in the treatment of animals with polycystic kidney disease, which will substantially improve their quality of life [ABSTRACT FROM AUTHOR]

Epigenetics in the form of DNA methylation and other processes is an established property of genotypes and a focus of empirical research. Yet, there remain fundamental gaps in the evolutionary theory of epigenetics. To support a comprehensive understanding of epigenetics, this paper investigates theoretically the combined effects of deleterious mutation and epimutation with and without inbreeding. Both spontaneous epimutation and paramutation are considered to cover a broader range of epigenetic phenomena. We find that inbreeding generally reduces the amount of segregating deleterious genetic and epigenetic variation at equilibrium, although interestingly inbreeding can also increase the amount of deleterious genetic or epigenetic variation. Furthermore, we also demonstrate that epimutation indirectly can cause increased or decreased deleterious genetic variation at equilibrium relative to classic expectations, which is particularly evident when paramutation is occurring. With the addition of deleterious epimutation, there may be significantly increased purging of deleterious variation in more inbred populations and a significantly increased amount of segregating deleterious variation in more outbred populations, with notable exceptions. [ABSTRACT FROM AUTHOR]

Neurological disorders (NDs) are diseases that seriously affect the health of individuals worldwide, potentially leading to a significant reduction in the quality of life for patients and their families. Herbal medicines have been widely used in the treatment of NDs due to their multi-target and multi-pathway features. Ginkgo biloba leaves (GBLs), one of the most popular herbal medicines in the world, have been demonstrated to present therapeutic effects on NDs. However, the pharmacological mechanisms of GBLs in the treatment of neurological disorders have not been systematically summarized. This study aimed to summarize the molecular mechanism of GBLs in treating NDs from the cell models, animal models, and clinical trials of studies. Four databases, i.e., PubMed, Google Scholar, CNKI, and Web of Science were searched using the following keywords: "Ginkgo biloba", "Ginkgo biloba extract", "Ginkgo biloba leaves", "Ginkgo biloba leaves extract", "Neurological disorders", "Neurological diseases", and "Neurodegenerative diseases". All items meeting the inclusion criteria on the treatment of NDs with GBLs were extracted and summarized. Additionally, PRISMA 2020 was performed to independently evaluate the screening methods. Out of 1385 records in the database, 52 were screened in relation to the function of GBLs in the treatment of NDs; of these 52 records, 39 were preclinical trials and 13 were clinical studies. Analysis of pharmacological studies revealed that GBLs can improve memory, cognition, behavior, and psychopathology of NDs and that the most frequently associated GBLs are depression, followed by Alzheimer's disease, stroke, Huntington's disease, and Parkinson's disease. Additionally, the clinical studies of depression, AD, and stroke are the most common, and most of the remaining ND data are available from in vitro or in vivo animal studies. Moreover, the possible mechanisms of GBLs in treating NDs are mainly through free radical scavenging, anti-oxidant activity, anti-inflammatory response, mitochondrial protection, neurotransmitter regulation, and antagonism of PAF. This is the first paper to systematically and comprehensively investigate the pharmacological effects and neuroprotective mechanisms of GBLs in the treatment of NDs thus far. All findings contribute to a better understanding of the efficacy and complexity of GBLs in treating NDs, which is of great significance for the further clinical application of this herbal medicine. [ABSTRACT FROM AUTHOR]

Several mathematical models of two competing viruses (or viral strains) that have been published in the literature assume that the infection rate is determined by bilinear incidence. These models do not show co-existence equilibrium; moreover, they might not be applicable in situations where the virus concentration is high. In this paper, we developed a mathematical model for the co-dynamics of two competing viruses with saturated incidence. The model included the latently infected cells and three types of time delays: discrete (or distributed): (i) The formation time of latently infected cells; (ii) The activation time of latently infected cells; (iii) The maturation time of newly released virions. We established the mathematical well-posedness and biological acceptability of the model by examining the boundedness and nonnegativity of the solutions. Four equilibrium points were identified, and their stability was examined. Through the application of Lyapunov's approach and LaSalle's invariance principle, we demonstrated the global stability of equilibria. The impact of saturation incidence, latently infected cells, and time delay on the viral co-dynamics was examined. We demonstrated that the saturation could result in persistent viral coinfections. We established conditions under which these types of viruses could coexist. The coexistence conditions were formulated in terms of saturation constants. These findings offered new perspectives on the circumstances under which coexisting viruses (or strains) could live in stable viral populations. It was shown that adding the class of latently infected cells and time delay to the coinfection model reduced the basic reproduction number for each virus type. Therefore, fewer treatment efficacies would be needed to keep the system at the infection-free equilibrium and remove the viral coinfection from the body when utilizing a model with latently infected cells and time delay. To demonstrate the associated mathematical outcomes, numerical simulations were conducted for the model with discrete delays. [ABSTRACT FROM AUTHOR]

INTRODUCTION The aim of the study is the regulatory effect of MicroRNA-210 (MiR-210) on cigarette smoke extract (CSE)-induced mouse lung epithelial type II cells (MLE-12) apoptosis and determine whether the MiR-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via Shh signaling pathway. METHODS Expression of MiR-210 in CSE-induced MLE-12 was assessed by qRT-PCR. The emphysema mouse model and MiR-210 knockdown mice were each established by inhaling cigarette smoke or intratracheal lentiviral vector instillation. The Sonic hedgehog (Shh), Ptch1, Gli1, B-cell lymphoma-2 (Bcl-2), and Caspase 3 protein expressions were detected by Western blotting. mRNA expressions of MiR-210, Shh, Ptch1, and Gli1 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Apoptotic ratios in mice and CSE-induced HPVEC were assessed using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays and flow cytometry. RESULTS Our results showed that MiR-210 mRNA levels were significantly down-regulated in the CSE-induced MLE 12. MLE 12 apoptosis with down-regulated Shh, Ptch1, Gli1, and Bcl-2 expression, increased Caspase 3 expression in the emphysema mouse model and CSE-induced MLE 12. Knockdown MiR-210 can facilitate cell apoptosis and emphysema via the Shh signaling pathway in mice. In vitro, MiR-210 can attenuate the apoptosis of CSE-exposed MLE 12. Moreover, MiR-210 regulated the Shh pathway and promoted its expression. CONCLUSIONS MiRNA-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via the Shh signaling pathway. The present study reveals that MiRNA-210 may be a key regulator of cellular apoptosis and could be explored as a potential therapeutic target in the future. [ABSTRACT FROM AUTHOR]

Essential soil functions such as plant productivity, C storage, nutrient cycling and the storage and purification of water all depend on soil biological processes. Given this insight, it is remarkable that in modeling of these soil functions, the various biological actors usually do not play an explicit role. In this review and perspective paper we analyze the state of the art in modeling these soil functions and how biological processes could more adequately be accounted for. We do this for six different biologically driven processes clusters that are key for understanding soil functions, namely i) turnover of soil organic matter, ii) N cycling, iii) P dynamics, iv) biodegradation of contaminants v) plant disease control and vi) soil structure formation. A major conclusion is that the development of models to predict changes in soil functions at the scale of soil profiles (i.e. pedons) should be better rooted in the underlying biological processes that are known to a large extent. This is prerequisite to arrive at the predictive models that we urgently need under current conditions of Global Change. [ABSTRACT FROM AUTHOR]

INTRODUCTION Macrophages play an important role in chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) impairs autophagy in alveolar macrophages from COPD patients, and autophagic impairment leads to reduced clearance of protein aggregates, dysfunctional mitochondria, and defective bacterial delivery to lysosomes. However, the exact function of lung macrophage autophagy in the pathogenesis of CS-induced COPD remains largely unknown. METHODS Western blot detected the expression of autophagy-related proteins induced by CSE. The model of COPD mice was established by CS exposure combined with CSE intraperitoneal injection. Double immunofluorescence was used to measure the CD206+LC3B+ cells. The morphological changes and effects on lung function were observed. Masson staining detected the changes in collagen fibers in lung tissue. The expression levels of E-cadherinb and N-cadherinb were detected by immunohistochemistry. Western blot detected the expression of ATP6V1E1 in lung tissue. RESULTS At 24 hours of exposure to CSE, the expression levels of LC3B (microtubuleassociated protein 1A/1B-light chain 3B) and P62 (nucleoporin 62) were highest at 1% CSE and AGT5 (nucleoporin 62) at 2.5% CSE; at 48 hours, the expression levels of LC3B, P62 and AGT5 were highest at 2.5% CSE, and as the intervention time increased. CD206+LC3B+ cells were significantly higher in the COPD group. Enhanced macrophage autophagy may promote emphysema formation and aggravate lung function damage. The expression of E-cadherinb in lung tissue of the COPD group was decreased, and N-cadherinb expression was increased; the expression of E-cadherinb was increased, and N-cadherinb expression was decreased in ATG5myeΔ COPD mice. The expression of ATP6V1E1 in the lung tissue was increased in the COPD group; ATP6V1E1 expression was decreased in the lung tissues of ATG5myeΔ COPD mice. CONCLUSIONS CSE enhanced macrophage autophagy, leads to increased lung function impairment and collagenous fiber in lung tissue, as well as promotes epithelialmesenchymal transition, and eventually leads to small airway remodeling, which may be achieved through the ATG5/ATP6V1E1 pathway. [ABSTRACT FROM AUTHOR]

INTRODUCTION Apoptosis and chronic inflammation are the main phenotypes in chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke exposure is the leading risk factor for COPD, which causes aberrant airway epithelial structure and function. As a non-classical calpain, the molecular function of calpain5 (CAPN5) in COPD remains unclear. This study investigated the role of CAPN5 in mediating cigarette smoke extract (CSE)-induced apoptosis and inflammation. METHODS Immunohistochemistry (IHC) and Western blotting (WB) were performed to detect the location and expression of CAPN5. In vitro, BEAS-2B cells were transfected with CAPN5 siRNA or CAPN5 plasmid, followed by phosphatebuffered saline (PBS) or cigarette smoke extract (CSE) treatment. The protein expression levels of CAPN5, NF-κB p65, p-p65, IκBα, p-IκBα and apoptosis proteins (BCL-2, BAX) were measured by WB. Flow cytometry (FCM) was performed to analyze the cell apoptosis index. RESULTS CAPN5 was mainly expressed in the airway epithelium and significantly decreased in the COPD-smoker and emphysema-mouse groups. Silencing CAPN5 significantly decreased the protein expression of BCL-2, IκBα, and increased p-p65 and BAX protein expression. Additionally, an increased apoptosis index was detected after silencing CAPN5. Moreover, overexpression of CAPN5 partly inhibited IκBα degradation and p65 activation, and reduced CSE-induced inflammation and apoptosis. CONCLUSIONS These combined results indicate that CAPN5 could protect against CSEinduced apoptosis and inflammation, which may provide a potential therapeutic target for smoking-related COPD. [ABSTRACT FROM AUTHOR]

Accumulated degree-days are among the most significant indicators in ecological and geographical modeling of the distribution of biological objects. The present paper analyzes several existing methods for calculating accumulated degree-days, proposes an improved calculation method, and presents a set of the global maps of accumulated degree-days constructed using the improved method. The produced maps are publicly available and can be used for ecological and geographical analysis and modeling. [ABSTRACT FROM AUTHOR]

The paper addresses a computational method to simulate more accurate models for population growth with immigration, focusing on integral equations (IEs) featuring a delay parameter in the time variable. The proposed method utilizes Legendre wavelets within the Galerkin scheme as a orthonormal basis. Legendre wavelets are known for their localized functions, offering suitable precision and stability in simulating time-delay biological models. This approach employs the composite Gauss-Legendre (CGL) quadrature rule to compute integrals appeared in the scheme. An error bound analysis demonstrates a convergence rate of order 2 − M k. Additionally, various numerical examples are presented to show the efficiency, accuracy and validate the theoretical error estimate of the novel technique. [ABSTRACT FROM AUTHOR]

INTRODUCTION The use of e-cigarettes (ECs) has reached unprecedented levels, due to a variety of reasons, including the misconception regarding their safety. Thus, there have been efforts to characterize the effects of EC exposure, including in the context of thirdhand EC (THEC) on a host of disorders, such as cardiovascular disease (CVD). METHODS To address this issue, we sought to characterize the effects of THEC on platelet function and thrombus formation, using a novel mouse exposure protocol that resembles real life scenarios. To assess these effects, a host of related in vivo (i.e. tail bleeding time, and ferric chloride injury induced thrombosis model) assays and in vitro platelet specific (e.g. aggregation, and dense granule secretion) investigative assays were conducted. RESULTS Our in vivo characterization demonstrated that THEC exposed mice exhibited a prothrombotic phenotype reflected by their shortened tail bleeding (THEC: 37 ± 15 seconds, versus clean air: 183 ± 56 s) and occlusion times (THEC: 188 ± 39 s, versus clean air: 519 ± 70 s), relative to those exposed to clean air. Importantly, we found no difference in the platelet counts between the THEC and clean air mice. As for the underlying mechanism, separate experiments revealed significantly enhanced platelet aggregation, dense and alpha granule secretion, as well as integrin/GPIIb-IIIa activation and phosphatidylserine exposure in response to thrombin and ADP agonist stimulation. CONCLUSIONS Taken together, these results provide evidence that THEC does have the capacity to increase the risk of thrombotic disease, which should increase awareness regarding its underappreciated negative health effects. [ABSTRACT FROM AUTHOR]

This paper presents an analytical solution of the differential equations describing the pulsatory liposome dynamics. We consider a unilamellar liposome filled with an aqueous solution of osmotic solute inserted in a hypotonic aqueous medium. Due to the osmosis process the liposome has a cyclic evolution. The lipid vesicle swells to a critical size, at which point a transbilayer pore suddenly appears. Part of the internal solution leaks through this pore. The liposome relaxes and returns to the initial size. The swelling starts again and the liposome goes through a periodical process. The swelling of the liposome is described by a differential equation. The appearance of the pore changes the evolution of the liposome. The internal solution comes out through the pore and the liposome starts its deflation (relaxation). The evolution of the pore has two phases: first, the radius of the pore increases to its maximum value, then the radius decreases until it disappears, and the liposome reaches its initial size. During each cycle, the liposome will release a quantity (a pulse) of the solution from its interior. All the processes which contribute to the liposome relaxing and its coming back to the initial size are described by three differential equations. This system of differential equations can be integrated using numerical methods. The functions - which model our biological engine in three stages, are as follows: R(t) - the liposome radius, r(t) - the pore radius, C(t) - solute concentration, Q(t) - the osmotic solute amount inside the liposome. The graphs representing these functions contain important linear portions, which suggested a solution using analytical methods. Based on some analytical methods, we solve these equations, and their explicit solutions are validated by comparing with numerical results of previous studies. [ABSTRACT FROM AUTHOR]

The first "R" from animal research ethics prescribes the replacement of animal experiments with animal-free alternatives. However, the question of when an animal-free method qualifies as an alternative to animal experiments remains unresolved. Drawing lessons from another debate in which the word "alternative" is central, the ethical debate on alternatives to germline genome editing, this paper develops a general account of when something qualifies as an alternative to something. It proposes three ethically significant conditions that technique, method, or approach X must meet to qualify as an alternative to Y: (1) X must address the same problem as Y, under an appropriate description of that problem; (2) X must have a reasonable chance of success, compared to Y, in solving the problem; and (3) X must not be ethically unacceptable as a solution. If X meets all these conditions, its relative advantages and disadvantages determine whether it is preferable, indifferent, or dispreferable as an alternative to Y. This account is then applied to the question of whether animal-free research methods qualify as alternatives to animal research. Doing so breaks down the debate around this question into more focused (ethical and other) issues and illustrates the potential of the account. [ABSTRACT FROM AUTHOR]

This canine in vivo study assessed the effect of recombinant human platelet-derived growth factor (rhPDGF) on the healing of periapical tissues following apical surgery. From a total of 96 premolar teeth, 64 teeth from six beagle dogs (2 years old) were classified as experimental and were randomly assigned to four experimental groups (16 teeth per group). After having the pulp extirpated, leaving teeth open to the oral cavity for 1 week, and sealing with an immediate restorative material for 8 weeks, nonsurgical endodontic treatment was performed. A split-mouth design was used, and intra-animal randomization of treatment sides was applied to the groups as follows: apical curettage + 1.5-mm root-end resection (Group 1); apicoectomy + mineral trioxide aggregate (MTA) root-end filling (Group 2); apicoectomy + MTA root-end filling + rhPDGF (Group 3); and apical curettage + rhPDGF (Group 4). The animals were sacrificed 24 months after apical surgery, and histologic and µCT analyses were performed for bone volume loss (BVL). Group 1 showed partial resolution of the periapical lesions without signs of tissue regeneration (BVL: 49.09 ± 10.97 mm3). Group 2 had minimal bone regeneration and showed cementum reformation in 9 teeth, with no direct attachment to the MTA (BVL: 35.34 ± 10.97 mm3). Group 3 showed regeneration of all damaged apical tissues without direct contact between the cementum and MTA (BLV: 4.51 ± 1.55 mm3). Group 4 showed regeneration of PDL, bone, and cementum and attachment of functional cementum fibers (BVL: 2.82 ± 2.3 mm3). The difference in BVL was statistically significant only for Groups 1 and 2 (P < .05). rhPDGF may help regenerate apical tissue structures following apical surgery. [ABSTRACT FROM AUTHOR]

Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE 2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms. [Display omitted] • WJW treatment GUs potential mechanism is by inhibiting inflammation, oxidative stress injury and apoptosis signaling pathways. • Integrated network pharmacology and metabolomics identified the key targets of WJW in the treatment of GUs, namely TNF, AKT1, PTGS2 and MAPK1. • The active components in WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. • This paper provides a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms. [ABSTRACT FROM AUTHOR]

The Morison's equation continues to be an important approximation of the load effect of waves on structures. However, such forces can evolve with time due to marine growth and the evolution of long term growth within the Morison equation is challenging. Incorporation of long term marine growth gives rise to two timescales associated with the Morison equation. A short time scale is associated with the period of a wave, while a long time scale is associated with the change in geometry of the structure due to marine growth. This paper proposes a new modification of the Morison's equation where these multiple time scales of change are addressed. The proposed method allows for a better understanding of how the force predicted by the Morison equation changes over time. The approach allows considering marine growth as an integral part of the Morison equation, expanding the capability to handle a significantly wider range of conditions related to lifetime performance of marine infrastructure, like wind turbines. The proposed approach is compatible with ecological processes and consequently the sampling of randomness over time is physically and biologically viable. The proposed approach allows incorporation of changes in the geometry of these structures through simple biological sampling and subsequently provides a way of updating Morison's equation to provide more accurate force estimates. This ecologically compatible geometry allows for forces estimates closer to reality, departing from the existing and simplistic smooth and rough regimes which are typically used as binary parameters. • Modified Morison's equation with slow marine growth and fast hydrodynamic timescales. • Accommodation of ecological/biological growth models and site-specific monitoring. • A gradual evolution of marine growth effects replacing unrealistic sudden changes. • Demonstration of negligible second order effects making proposed model efficient. • Numerical implementation of models for real-life data and scenarios. [ABSTRACT FROM AUTHOR]

• In this paper, we found that senescent mice develop pathologies such as obesity lipid metabolism disorders. • The expression of miR-743b-3p was elevated in senescent mice, which inhibited the expression of PPM1K. • MiR-743b-3p regulates BCAA levels in senescent hepatocytes by targeting PPM1K causing abnormal lipid deposition. Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. In this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. We found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). These results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing. [Display omitted] [ABSTRACT FROM AUTHOR]

First-order compartment models are common tools for modelling many biological processes, including pharmacokinetics. Given the compartments and the transfer rates, solutions for the time-dependent quantity (or concentration) curves can normally be described by a sum of exponentials. This paper investigates cases that go beyond simple sums of exponentials. With specific relations between the transfer rate constants, two exponential rate constants can be equal, in which case the normal solution cannot be used. The conditions for this to occur are discussed, and advice is provided on how to circumvent these cases. An example of an analytic solution is given for the rare case where an exact equality is the expected result. Furthermore, for models with at least three compartments, cases exist where the solution to a real-valued model involves complex-valued exponential rate constants. This leads to solutions with an oscillatory element in the solution for the tracer concentration, i.e., there are cases where the solution is not a simple sum of (real-valued) exponentials but also includes sine and cosine functions. Detailed solutions for three-compartment cases are given. As a tentative conclusion of the analysis, oscillatory solutions appear to be tied to cases with a cyclic element in the model itself. [ABSTRACT FROM AUTHOR]

A clinical, evidence-based model to inform clients and their parents about the nature of stuttering is indispensable for the field. In this paper, we propose the Erasmus Clinical Model of Stuttering 2.0 for children who stutter and their parents, and adult clients. It provides an up-to-date, clinical model summary of current insights into the genetic, neurological, motoric, linguistic, sensory, temperamental, psychological and social factors (be it causal, eliciting, or maintaining) related to stuttering. First a review is presented of current insights in these factors, and of six scientific theories or models that have inspired the development of our current clinical model. Following this, we will propose the model, which has proven to be useful in clinical practice. The proposed Erasmus Clinical Model of Stuttering visualizes the onset and course of stuttering, and includes scales for stuttering severity and impact, to be completed by the (parent of) the person who stutters. The pathway of the model towards stuttering onset is based on predisposing and mediating factors. In most children with an onset of stuttering, stuttering is transient, but if stuttering continues, its severity and impact vary widely. The model includes the circle of Engel (1977), which visualizes unique interactions of relevant biological, psychological, and social factors that determine the speaker's experience of stuttering severity and its impact. Discussing these factors and their interaction with an individual client can feed into therapeutic targets. The model is supplemented by a lifeline casus. • A new clinical, evidence-based model to inform children who stutter and their parents, and adult clients about stuttering. • The onset and development of stuttering is visualized in a Figure. • Biological, psychological, and social factors are related to the speaker's experience of stuttering severity and impact. • A hypothetical lifeline casus illustrates the model. [ABSTRACT FROM AUTHOR]

Spiking Neural Networks (SNNs) have become one of the most prominent next-generation computational models owing to their biological plausibility, low power consumption, and the potential for neuromorphic hardware implementation. Among the various methods for obtaining available SNNs, converting Artificial Neural Networks (ANNs) into SNNs is the most cost-effective approach. The early challenges in ANN-to-SNN conversion work revolved around the susceptibility of converted SNNs to conversion errors. Some recent endeavors have attempted to mitigate these conversion errors by altering the original ANNs. Despite their ability to enhance the accuracy of SNNs, these methods lack generality and cannot be directly applied to convert the majority of existing ANNs. In this paper, we present a framework named DNISNM for converting ANN to SNN, with the aim of addressing conversion errors arising from differences in the discreteness and asynchrony of network transmission between ANN and SNN. The DNISNM consists of two mechanisms, Data-based Neuronal Initialization (DNI) and Signed Neuron with Memory (SNM), designed to respectively address errors stemming from discreteness and asynchrony disparities. This framework requires no additional modifications to the original ANN and can result in SNNs with improved accuracy performance, simultaneously ensuring universality, high precision, and low inference latency. We verify it experimentally on challenging object recognition datasets, including CIFAR10, CIFAR100, and ImageNet-1k. Experimental results show that the SNN converted by our framework has very high accuracy even at extremely low latency. [ABSTRACT FROM AUTHOR]

Recently, the area devoted to fractional calculus has given much attention by researchers. The reason behind such huge attention is the significant applications of the mentioned area in various disciplines. Different problems of real world processes have been investigated by using the concepts of fractional calculus and important and applicable outcomes were obtained. Because, there has been a lot of interest in fractional differential equations. It is brought on by both the extensive development of fractional calculus theory and its applications. The use of linear and quadratic perturbations of nonlinear differential equations in mathematical models of a variety of real-world problems has received a lot of interest. Therefore, motivated by the mentioned importance, this research work is devoted to analyze in detailed, a class of fractal hybrid fractional differential equation under Atangana- Baleanu- Caputo ABC derivative. The qualitative theory of the problem is examined by using tools of non-linear functional analysis. The Ulam-Hyer's (U-H) type stability criteria is also applied to the consider problem. Further, the numerical solution of the model is developed by using powerful numerical technique. Lastly, the Wazewska-Czyzewska and Lasota Model, a well-known biological model, verifies the results. Several graphical representations by using different fractals fractional orders values are presented. The detailed discussion and explanations are given at the end. [ABSTRACT FROM AUTHOR]

Background: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. Methods: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P <.05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P <.01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. Conclusion: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans. [ABSTRACT FROM AUTHOR]

A good theory of mathematical beauty is more practical than any current observation, as new predictions about physical reality can be self-consistently verified. This belief applies to the current status of understanding deep neural networks including large language models and even the biological intelligence. Toy models provide a metaphor of physical reality, allowing mathematically formulating the reality (i.e., the so-called theory), which can be updated as more conjectures are justified or refuted. One does not need to present all details in a model, but rather, more abstract models are constructed, as complex systems such as the brains or deep networks have many sloppy dimensions but much less sti dimensions that strongly impact macroscopic observables. This type of bottom-up mechanistic modeling is still promising in the modern era of understanding the natural or artificial intelligence. Here, we shed light on eight challenges in developing theory of intelligence following this theoretical paradigm. Theses challenges are representation learning, generalization, adversarial robustness, continual learning, causal learning, internal model of the brain, next-token prediction, and the mechanics of subjective experience. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Static 3-dimensional (3D) printing became attractive for operative planning in cases that involve difficult anatomy. An interactive (low cost, fast) 3D print allowing deliberate surgical practice can be used to improve interventional simulation and planning. Background: Endovascular treatment of complex aortic aneurysms is technically challenging, especially in case of narrow aortic lumen or significant aortic angulation (hostile anatomy). The risk of complications such as graft kinking and target vessel occlusion is difficult to assess based solely on traditional software measuring methods and remain highly dependent on surgeon skills and expertise. Methods: A patient with juxtarenal AAA with hostile anatomy had a 3-dimensional printed model constructed preoperatively according to computed tomography images. Endovascular graft implantation in the 3D printed aorta with a standard T-Branch Cook (Cook® Medical, Bloomington, IN, USA) was performed preoperatively in the simulation laboratory enabling optimized feasibility, surgical planning and intraoperative decision making. Results: The 3D printed aortic model proved to be radio-opaque and allowed simulation of branched endovascular aortic repair (BREVAR). The assessment of intervention feasibility, as well as optimal branch position and orientation was found to be useful for surgeon confidence and the actual intervention in the patient. There was a remarkable agreement between the 3D printed model and both CT and X-ray angiographic images. Although the technical success was achieved as planned, a previously deployed renal stent caused unexpected difficulty in advancing the renal stent, which was not observed in the 3D model simulation. Conclusion: The 3D printed aortic models can be useful for determining feasibility, optimizing planning and intraoperative decision making in hostile anatomy improving the outcome. Despite already offering satisfying accuracy at present, further advancements could enhance the 3D model capability to replicate minor anatomical deformities and variations in tissue density. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends. Methods: This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references. Results: A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood-brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024. Conclusion: This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations. [ABSTRACT FROM AUTHOR]

Background: Cellular senescence features irreversible growth arrest and secretion of multiple proinflammatory cytokines. Cyclic GMP-AMP synthase (cGAS) detects DNA damage and activates the DNA-sensing pathway, resulting in the upregulation of inflammatory genes and induction of cellular senescence. This study aimed to investigate the effect of cGAS in regulating senescence of nucleus pulposus (NP) cells under inflammatory microenvironment. Methods: The expression of cGAS was evaluated by immunohistochemical staining in rat intervertebral disc (IVD) degeneration model induced by annulus stabbing. NP cells were harvested from rat lumbar IVD and cultured with 10ng/ml IL-1β for 48 h to induce premature senescence. cGAS was silenced by cGAS specific siRNA in NP cells and cultured with IL-1β. Cellular senescence was evaluated by senescence-associated beta-galactosidase (SA-β-gal) staining and flow cytometry. The expression of senescence-associated secretory phenotype including IL-6, IL-8, and TNF-a was evaluated by ELISA and western blotting. Results: cGAS was detected in rat NP cells in cytoplasm and the expression was significantly increased in degenerated IVD. Culturing in 10ng/ml IL-1β for 48 h induced cellular senescence in NP cells with attenuation of G1-S phase transition. In senescent NP cells the expression of cGAS, p53, p16, NF-kB, IL-6, IL-8, TNF-α was significantly increased while aggrecan and collagen type II was reduced than in normal NP cells. In NP cells with silenced cGAS, the expression of p53, p16, NF-kB, IL-6, IL-8, and TNF-α was reduced in inflammatory culturing with IL-1β. Conclusion: cGAS was increased by NP cells in degenerated IVD promoting cellular senescence and senescent inflammatory phenotypes. Targeting cGAS may alleviate IVD degeneration by reducing NP cell senescence. [ABSTRACT FROM AUTHOR]

Background: Salvia miltiorrhiza (Danshen, DS) and Radix Paeoniae Rubra (Chishao, CS) herbal pair (DS-CS) is a famous traditional Chinese combination which has been used as antithrombotic formular for centuries. However, there is still lack of sufficient scientific evidence to illustrate its underlying mechanisms. The purpose of this study is to investigate the antithrombotic effects of DS-CS extract in zebrafish and explore its possible mechanism of action. Methods: The quality of traditional Chinese medicines DS and CS granules was evaluated using High Performance Liquid Chromatography (HPLC). Subsequently, the therapeutic effect of the DS-CS combination and its components, Salvianolic Acid A (SAA) and Paeoniflorin (PF), in various concentrations on thrombosis was experimentally validated. Moreover, the interaction between DS-CS and the thrombosis disease targets was analyzed through network pharmacology, predicting the potential antithrombotic mechanism of DS-CS. Molecular docking and in vivo zebrafish experiments were conducted to validate the predicted targets, with qRT-PCR utilized for target validation. Results: DS-CS exhibited anti-thrombotic effect in zebrafish with concentrations ranging from 25 to 300 μg/mL. The co-administration of PF and SAA at 25 μg/mL each revealed a synergistic antithrombotic effect exceeding that of individual components when contrasted with PHZ treatment. Protein–protein interaction (PPI) analysis identified key genes, including Albumin (ALB), Proto-oncogene tyro-sine-protein kinase Src (SRC), Matrix metalloproteinase-9 (MMP9), Caspase-3 (CASP3), Epidermal growth factor receptor (EGFR), Fibroblast growth factor 2 (FGF2), Vascular endothelial growth factor receptor 2 (KDR), Matrix metalloprotein-ase-2(MMP2), Thrombin (F2), and Coagulation factor Xa (F10), associated with the antithrombotic action of PF and SAA. Furthermore, KEGG pathway analysis indicated involvement of lipid metabolism and atherosclerosis pathways. Molecular docking revealed strong binding of PF and SAA to pivotal hub genes, such as SRC, EGFR, and F10. The experimental findings demonstrated that DS-CS could upregulate the mRNA expression levels of EGFR while inhibiting F10 and SRC mRNA levels, thereby ameliorating thrombotic conditions. Conclusion: This research provided valuable insights into the potential mechanisms underlying the antithrombotic activity of DS-CS. Our findings suggested that PF and SAA could be the key active ingredients responsible for this activity. The antithrombotic effects of DS-CS appeared to be mediated through the regulation of mRNA expression of SRC, EGFR, and F10. These results enhanced our understanding of DS-CS's therapeutic potential and lay the groundwork for future studies to further elucidate its mechanisms of action. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma (CCA) is a type of liver cancer with few treatment options and low survival rates in advanced stages. Our study developed a mouse model to study this cancer type by implanting CCA cells into the liver of mice. We used advanced imaging techniques (MRI and PET scans) to monitor tumor growth and metabolism over four weeks. We observed that tumors became visible early and grew steadily over time. PET scans showed increasing tumor activity, and blood tests revealed liver damage. Most mice developed lung metastases after four weeks. Our research shows that combining MRI and PET scans effectively tracks CCA progression in mice, providing valuable insights into cancer development and investigating potential treatments. Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [18F]FDG-PET, and dynamic [18F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: We studied canine mammary tumors to better understand similar human breast cancer using a technique called liquid biopsy, which analyzes blood samples to detect disease, focusing on the detection of tiny particles called small extracellular vesicles. These structures are very interesting because they can carry proteins that may indicate the presence of cancer. In this study, we collected blood from healthy dogs, dogs with benign and malignant CMTs, and those in remission and also with recurrence. We found no differences in the size or amount of the vesicles among the groups but identified specific proteins that could serve as markers for cancer. These proteins could potentially help in the diagnosis, prognosis and monitoring of mammary cancer. (Background). Canine mammary tumors (CMTs) have emerged as an important model for understanding pathophysiological aspects of human disease. Liquid biopsy (LB), which relies on blood-borne biomarkers and offers minimal invasiveness, holds promise for reflecting the disease status of patients. Small extracellular vesicles (SEVs) and their protein cargo have recently gained attention as potential tools for disease screening and monitoring. (Objectives). This study aimed to isolate SEVs from canine patients and analyze their proteomic profile to assess their diagnostic and prognostic potential. (Methods). Plasma samples were collected from female dogs grouped into CMT (malignant and benign), healthy controls, relapse, and remission groups. SEVs were isolated and characterized using ultracentrifugation (UC), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Proteomic analysis of circulating SEVs was conducted using liquid chromatography–mass spectrometry (LC–MS). (Results). While no significant differences were observed in the concentration and size of exosomes among the studied groups, proteomic profiling revealed important variations. Mass spectrometry identified exclusive proteins that could serve as potential biomarkers for mammary cancer. These included Inter-alpha-trypsin inhibitor heavy chain (ITIH2 and ITI4), phosphopyruvate hydratase or alpha enolase (ENO1), eukaryotic translation elongation factor 2 (eEF2), actin (ACTB), transthyretin (TTR), beta-2-glycoprotein 1 (APOH) and gelsolin (GSN) found in female dogs with malignant tumors. Additionally, vitamin D-binding protein (VDBP), also known as group-specific component (GC), was identified as a protein present during remission. (Conclusions). The results underscore the potential of proteins found in SEVs as valuable biomarkers in CMTs. Despite the lack of differences in vesicle concentration and size between the groups, the analysis of protein content revealed promising markers with potential applications in CMT diagnosis and monitoring. These findings suggest a novel approach in the development of more precise and effective diagnostic tools for this challenging clinical condition. [ABSTRACT FROM AUTHOR]

Objectives: This study pursued two main purposes. The first aim was to expound on the microscopic factors of radiation-related caries (RRC). Further, it aimed to compare the remineralization effect of different remineralizing agents on demineralized teeth after radiotherapy. Methods: The enamel and dentin samples of bovine teeth were irradiated with different doses of radiation. After analysis of scanning electron microscope (SEM), X-Ray diffraction (XRD), and energy dispersive spectrometer (EDS), the samples irradiated with 50 Gy radiation were selected and divided into the demineralization group, the double distilled water (DDW) group, the Sodium fluoride (NaF) group, the Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group, the NaF + CPP-ACP group, and the Titanium tetrafluoride (TiF4) group. After demineralization, remineralizing agents treatment, and remineralization, the samples were evaluated using SEM, atomic force microscope (AFM), EDS, and transverse microradiography (TMR). Results: A radiation dose of 30 Gy was sufficient to cause damage to the dentinal tubules, but 70 Gy radiation had little effect on the microstructure of enamel. Additionally, the NaF + CPP-ACP group and the TiF4 group significantly promoted deposit formation, decreased surface roughness, and reduced mineral loss and lesion depth of demineralized enamel and dentin samples after radiation. Conclusions: Radiation causes more significant damage to dentin compared to enamel. NaF + CPP-ACP and TiF4 had a promising ability to promote remineralization of irradiated dental hard tissues. Advances in knowledge: This in vitro study contributes to determining a safer radiation dose range for teeth and identifying the most effective remineralization approach for RRC. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a complex cardiovascular syndrome with high mortality. Santalum album L. (SAL) is a traditional Chinese medicine broadly applied for various diseases treatment including HF. However, the potential active compounds and molecular mechanisms of SAL in HF treatment are not well understood. Methods: The active compounds and possible mechanisms of action of SAL were analyzed and validated by a systems pharmacology framework and an ISO-induced mouse HF model. Results: We initially confirmed that SAL alleviates heart damage in ISO-induced HF model. A total of 17 potentially active components in SAL were identified, with Luteolin (Lut) and Syringaldehyde (SYD) in SAL been identified as the most effective combination through probabilistic ensemble aggregation (PEA) analysis. These compounds, individually and in their combination (COMB), showed significant therapeutic effects on HF by targeting multiple pathways involved in anti-oxidation, anti-inflammation, and anti-apoptosis. The active ingredients in SAL effectively suppressed inflammatory mediators and pro-apoptotic proteins while enhancing the expression of anti-apoptotic factors and antioxidant markers. Furthermore, the synergistic effects of SAL on YAP and PI3K-AKT signaling pathways were further elucidated. Conclusions: Mechanistically, the anti-HF effect of SAL is responsible for the synergistic effect of anti-inflammation, antioxidation and anti-apoptosis, delineating a multi-targeted therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Over the last years computer modelling and simulation has emerged as an effective tool to support the total product life cycle of cardiovascular devices, particularly in the device preclinical evaluation and post-market assessment. Computational modelling is particularly relevant for heart valve prostheses, which require an extensive assessment of their hydrodynamic performance and of risks of hemolysis and thromboembolic complications associated with mechanicallyinduced blood damage. These biomechanical aspects are typically evaluated through a fluid-structure interaction (FSI) approach, which enables valve fluid dynamics evaluation accounting for leaflets movement. In this context, the present narrative review focuses on the computational modelling of bileaflet mechanical aortic valves through FSI approach, aiming to foster and guide the use of simulations in device total product life cycle. The state of the art of FSI simulation of heart valve prostheses is reviewed to highlight the variety of modelling strategies adopted in the literature. Furthermore, the integration of FSI simulations in the total product life cycle of bileaflet aortic valves is discussed, with particular emphasis on the role of simulations in complementing and potentially replacing the experimental tests suggested by international standards. Simulations credibility assessment is also discussed in the light of recently published guidelines, thus paving the way for a broader inclusion of in silico evidence in regulatory submissions. The present narrative review highlights that FSI simulations can be successfully framed within the total product life cycle of bileaflet mechanical aortic valves, emphasizing that credible in silico models evaluating the performance of implantable devices can (at least) partially replace preclinical in vitro experimentation and support post-market biomechanical evaluation, leading to a reduction in both time and cost required for device development. [ABSTRACT FROM AUTHOR]

Background: Malaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant's malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice. Methods: The plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences. Results: No toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract. Conclusions: The results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended. [ABSTRACT FROM AUTHOR]