Search Results (52)

The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without relying on cytotoxicity, co-culture systems, or molecular profiling. Tumor cells were monitored using IncuCyte^® S3 (Sartorius) real-time imaging under ex vivo neutral conditions. No dendritic cell components or immune co-cultures were used in this mode. All results are derived from direct tumor cell responses to structurally active formulations. Using eight human tumor lines, we captured proliferative behavior, cell death rates, and secretomic profiles to assign each case into stimulatory, inhibitory, or neutral categories. A structured decision-tree logic supported the classification, and a Functional Stratification Index (FSI) was computed to quantify the response magnitude. Inhibitory lines showed early divergence and high IFN-γ/IL-10 ratios; stimulatory ones exhibited a proliferative gain under balanced immune signaling. The results were reproducible across independent batches. This system enables quantitative phenotypic screening under standardized, marker-free conditions and offers an adaptable platform for functional evaluation in immuno-oncology pipelines where traditional cytotoxic endpoints are insufficient. This approach has been codified into the STIP (Structured Traceability and Immunophenotypic Platform), supporting reproducible documentation across tumor models. This platform contributes to upstream validation logic in immuno-oncology workflows and supports early-stage regulatory documentation. Full article

Fractional calculus plays a central role in modeling memory-dependent processes and complex dynamics across various fields, including control theory, fluid mechanics, and bioengineering. This study introduces an efficient and stable fractional-order iterative method based on the Caputo derivative for solving nonlinear equations. By employing a Taylor series expansion, a local convergence analysis shows that for $\gamma \in (0,1]$, the method achieves a convergence order of $2\gamma +1$. To address challenges related to memory effects and instability in existing approaches, the proposed scheme incorporates parameter optimization through chaos and bifurcation analysis. Dynamical plane analysis reveals that parameter values within chaotic regimes lead to divergence, while those in stable regions converge uniformly. The method’s performance is evaluated using a set of nonlinear models drawn from biomedical engineering, including enzyme kinetics with inhibition, extended glucose–insulin regulation, drug dose–responses, and lung volume–pressure dynamics. Comparative results demonstrate that the proposed approach outperforms existing methods in terms of iteration count, residual error, CPU time, convergence order, fractal behavior, and memory efficiency. These findings underscore the method’s applicability to complex systems characterized by nonlinearity and memory effects in scientific and engineering contexts. Full article

(1) Objectives: Understanding the genetic basis of muscle development and meat quality traits in divergent pig breeds is crucial for advancing precision breeding strategies. (2) Methods: This study investigated transcriptome differences in the longissimus dorsi muscle between Chinese Congjiang Xiang (CX) and Landrace (LAN) pigs. RNA sequencing was performed on muscle tissues from ten individuals of each breed, generating 874.5 million raw reads with an average mapping rate of 89.3% to the pig reference genome. (3) Results: Transcriptional profiling revealed distinct expression patterns with 785 genes exclusively expressed in CX pigs and 457 genes unique to LAN pigs, while 7099 co-expressed genes were shared by both breeds. Differential expression analysis identified 2459 significantly different genes (|log2FC| ≥ 1, adjusted p-value < 0.05), with 1745 up-regulated and 714 down-regulated in CX pigs. Among the most significantly up-regulated genes in CX pigs were flavor-associated genes (ELOVL5/6, FASN, DGAT2, ALDH1A3, PPAR-γ) with log2FC values ranging from 1.21 to 3.88. GO and KEGG pathway analyses revealed that up-regulated genes in CX pigs were significantly enriched in immune response pathways (adjusted p-value < 0.01), while down-regulated genes were primarily associated with myosin complex formation and PPAR signaling pathway. PPI network analysis identified PPAR-γ as a central hub gene with 16 direct interactions to other flavor-related genes. (4) Conclusions: These findings demonstrate that the superior meat flavor characteristics of indigenous Chinese pigs are driven by enhanced expression of lipid metabolism genes and distinctive immune-related pathways, providing specific molecular targets for breeding programs aimed at improving meat quality while maintaining production efficiency in commercial breeds. Full article

Flavone derivatives have emerged as promising antiviral agents, with baicalein demonstrating the potent inhibition of the SARS-CoV-2 main protease (Mpro). In this study, the unique electronic and structural properties of 3-hydroxyflavone (3-HF) were investigated using the density functional theory (B3PW91/cc-pVTZ), providing insights into its potential as a bioactive scaffold. Among mono-hydroxyflavone (n-HF) isomers, 3-HF exhibits an extensive intramolecular hydrogen-bonding network linking the phenyl B-ring to the A- and γ-pyrone C-rings, enabled by the distinctive C3-OH substitution. Despite a slight non-planarity (dihedral angle: 15.4°), this hydrogen-bonding network enhances rigidity and influences the electronic environment. A ¹³C-NMR chemical shift analysis revealed pronounced quantum mechanical effects of the C3-OH group, diverging from the trends observed in other flavones. A natural bond orbital (NBO) analysis highlighted an unusual charge distribution, with predominantly positive charges on the γ-pyrone C-ring carbons, in contrast to the typical negative charges in flavones. These effects impact C1s orbital energies, suggesting that the electronic structure plays a more significant role in ¹³C-NMR shifts than simple ring assignments. Given the established antiviral activity of hydroxylated flavones, the distinct electronic properties of 3-HF may enhance its interaction with SARS-CoV-2 Mpro, making it a potential candidate for further investigation. This study underscores the importance of quantum mechanical methods in elucidating the structure–activity relationships of flavones and highlights 3-HF as a promising scaffold for future antiviral drug development. Full article

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A₁₆₅/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis. Full article

Accurately determining the exposure time to an infectious pathogen, together with the corresponding incubation period, is vital for identifying infection sources and implementing targeted public health interventions. However, real-world outbreak data often include outliers—namely, tertiary or subsequent infection cases not directly linked to the initial source—that complicate the estimation of exposure time. To address this challenge, we introduce a robust estimation framework based on a three-parameter Weibull distribution in which the location parameter naturally corresponds to the unknown exposure time. Our method employs a $\gamma$-divergence criterion—a robust generalization of the standard cross-entropy criterion—optimized via a tailored majorization–minimization (MM) algorithm designed to guarantee a monotonic decrease in the objective function despite the non-convexity typically present in robust formulations. Extensive Monte Carlo simulations demonstrate that our approach outperforms conventional estimation methods in terms of bias and mean squared error as well as in estimating the incubation period. Moreover, applications to real-world surveillance data on COVID-19 illustrate the practical advantages of the proposed method. These findings highlight the method’s robustness and efficiency in scenarios where data contamination from secondary or tertiary infections is common, showing its potential value for early outbreak detection and rapid epidemiological response. Full article

Gene duplication, as a prevalent phenomenon in the tree of life, provides a potential substrate for evolution. However, its role in the Aurantioideae remains unclear. In this study, we systematically identified, for the first time, a comprehensive landscape of five types of gene duplication in the genomes of 26 species within Aurantioideae, focusing on dissecting the duplication patterns, their potential evolutionary significance, and their impact on gene function and expression. Our results showed that the tandem duplication (TD) was a predominant duplication type and confirmed a shared ancient whole-genome duplication (γWGD) event within Aurantioideae. Ka/Ks indicated that all duplication types are under purifying selection pressure, with TD and proximal duplication (PD) undergoing rapid functional divergence. Gene Ontology (GO) enrichment analysis revealed functional specialization among different duplication types, collectively contributing to genome evolution. In addition, comparing the gene expression differentiation of the five gene duplication types between the outer and inner pericarps of Citrus maxima ‘Huazhouyou’, it was found that the proportion of gene expression differentiation in the exocarp was generally higher, suggesting tissue-specific functional roles for duplicated genes in the peel. Furthermore, gene conversion events revealed that Citrus sinensis and Citrus maxima ‘Huazhouyou’ experienced more gene conversion events, supporting that C. sinensis originated through hybridization with C. maxima as the maternal parent. Finally, the comparative analysis of gene families among 26 species in Aurantioideae revealed that small gene families (1–3 members) accounted for a substantial proportion in all species, indicating a lack of recent large-scale genome duplication events in this subfamily. These findings fill a gap in the understanding of gene duplication in Aurantioideae and provide a theoretical foundation for exploring the evolutionary mechanisms and breeding improvements within this group. Additionally, our study offers new insights into the contribution of gene duplication to functional diversification and ecological adaptation in other plants. Full article

In this paper, we conduct a thorough investigation of the surface and curvature tensions, $\sigma$ and $\gamma$, of three-flavor cold quark matter using the Nambu–Jona–Lasinio (NJL) model with vector interactions. Our approach ensures both local and global electric charge neutrality, as well as chemical equilibrium under weak interactions. By employing the multiple reflection expansion formalism to account for finite size effects, we explore the impact of specific input parameters, particularly the vector coupling constant ratio ${\eta }_V$, the radius R of quark matter droplets, as well as the charge-per-baryon ratio $\xi$ of the finite size configurations. We focus on the role of the contributions of each term of the NJL Lagrangian to the surface and curvature tensions in the mean field approximation. We find that the total surface tension exhibits two different density regimes: it remains roughly constant at around $100\mathrm{MeV}{\mathrm{fm}}^{-2}$ up to approximately 2–4 times the nuclear saturation density, and beyond this point, it becomes a steeply increasing function of $n_B$. The total surface and curvature tensions are relatively insensitive to variations in R but are affected by changes in $\xi$ and ${\eta }_V$. We observe that the largest contribution to $\sigma$ and $\gamma$ comes from the regularized divergent term, making these quantities significantly higher than those obtained within the MIT bag model. Full article

This study employed headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME-GC-MS) and liquid chromatography–mass spectrometry (LC-MS) for non-targeted metabolomics analyses to examine the impact of mixed fermentation with various lactic acid bacteria (LAB) on the flavor compounds and metabolites of peach and apricot mixed juice (PAMJ), specifically focusing on the alterations of volatile compounds and non-volatile metabolites, as well as their metabolic pathways during the fermentation process. A total of 185 volatiles were identified using HS-SPME-GC-MS analysis, revealing significant differential metabolites, including eugenol, benzaldehyde, and γ-decalactone etc. The results indicated that lactic fermentation significantly enhanced the overall flavor of the juice toward the end of the fermentation process. In the interim, untargeted metabolomics utilizing LC-MS identified 1846 divergent metabolites, with 564 exhibiting up-regulation and 1282 demonstrating down-regulation. The metabolic pathway study performed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed significant changes in the metabolic levels of amino acids and saccharides after the lactic fermentation of PAMJ. Primarily associated with amino acid metabolism and starch and sucrose metabolism pathways. This work establishes a theoretical foundation for advancing fermented fruit juices with superior quality. Full article

In this paper, we propose a global numerical method for approximating Caputo fractional derivatives of order $\alpha$$\left(D^{\alpha }f\right)\left(y\right)=\frac{1}{\Gamma (m-\alpha )}{\int }_0^y{(y-x)}^{m-\alpha -1}{f}^{\left(m\right)}\left(x\right)dx,y>0$, with $m-1<\alpha \le m,m\in \mathbb{N}.$ The numerical procedure is based on approximating $f^{\left(m\right)}$ by the m-th derivative of a Lagrange polynomial, interpolating f at Jacobi zeros and some additional nodes suitably chosen to have corresponding logarithmically diverging Lebsegue constants. Error estimates in a uniform norm are provided, showing that the rate of convergence is related to the smoothness of the function f according to the best polynomial approximation error and depending on order $\alpha$. As an application, we approximate the solution of a Volterra integral equation, which is equivalent in some sense to the Bagley–Torvik initial value problem, using a Nyström-type method. Finally, some numerical tests are presented to assess the performance of the proposed procedure. Full article

This paper deals with the stability and occurrence of Hopf bifurcation of a distributed delay differential cobweb model using the chain trick technique. This is a generalized form of the fixed delay cobweb model to which it is compared using the same parameter values. The results from the delay distribution showed that whenever less weight $(\gamma =0.146)$ is put on past prices, the current equilibrium price is adjusted upwards while the reverse is observed when a higher weight $(\gamma =0.186)$ is put on the previous price. It is also observed that if the initial price is set below/above the equilibrium price, the price adjustment either affects the consumers or benefits the suppliers. However, the fixed delay cobweb model does not display the consumers or suppliers benefits of the price dynamics in either direction. These are unique, underlying patterns in price dynamics discovered when using a distributed delay model compared to traditional fixed delay cobweb models. Furthermore, our model challenges the traditional cobweb model’s requirement for divergence, as it is based on the weight assigned to past prices rather than the relationship between the elasticities of supply and demand, which is the determining factor in the classical model. Based on these insights, we recommend that future price adjustment models incorporate distributed delays, as they reveal more intricate price dynamics and provide a more comprehensive understanding of market behavior than fixed delay models. Full article

Carotenoids are important natural pigments that are responsible for the fruit and flower colors of many plants. The composition and content of carotenoid can greatly influence the color phenotype of plants. However, the regulatory mechanism underling the divergent behaviors of carotenoid accumulation, especially in flower, remains unclear. In this study, a new cultivar Osmanthus fragrans ‘Yanzhi Hong’ was used to study the regulation of carotenoid pigmentation in flower. Liquid chromatograph–mass spectrometer (LC-MS) analysis showed that β-carotene, phytoene, lycopene, γ-carotene, and lutein were the top five pigments enriched in the petals of ‘Yanzhi Hong’. Through transcriptome analysis, we found that the expression of the structural genes in carotenoid pathway was imbalanced: most of the structural genes responsible for lycopene biosynthesis were highly expressed throughout the flower developmental stages, while those for lycopene metabolism kept at a relatively lower level. The downregulation of LYCE, especially at the late developmental stages, suppressed the conversion from lycopene to α-carotene but promoted the accumulation of β-carotene, which had great effect on the carotenoid composition of ‘Yanzhi Hong’. Ethylene response factor (ERF), WRKY, basic helix-loop-helix (bHLH), v-myb avian myeloblastosis viral oncogene homolog (MYB), N-Acetylcysteine (NAC), auxin response factor (ARF), and other transcription factors (TFs) have participated in the flower color regulation of ‘Yanzhi Hong’, which formed co-expression networks with the structural genes and functioned in multiple links of the carotenoid pathway. The results suggested that the cyclization of lycopene is a key link in determining flower color. The modification of the related TFs will break the expression balance between the upstream and downstream genes and greatly influence the carotenoid profile in flowers, which can be further used for creating colorful plant germplasms. Full article

We model compact objects of known stellar mass and radius made of isotropic matter within Einstein’s gravity. The interior solution describing hydrostatic equilibrium we are using throughout the manuscript corresponds to the Tolman IV exact analytic solution obtained a long time ago. The three free parameters of the solutions are determined by imposing the matching conditions for objects of known stellar mass and radius. Finally, using well established criteria, it is shown that, contrary to the Kohler Chao solution, the Tolman IV solution is compatible with all requirements for well-behaved and realistic solutions, except for the relativistic adiabatic index that diverges at the surface of stars. The divergence of the index Γ may be resolved, including a thin crust assuming a polytropic equation of state, which is precisely the case seen in studies of neutron stars. To the best of our knowledge, we model here for the first time the recently discovered massive pulsar PSR J0740+6620 and the strangely light HESS compact object via the Tolman IV solution. The present work may be of interest to model builders as well as a useful reference for future research. Full article

Alzheimer’s disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aβ, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aβ proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aβ substrate. Our examination of BACE1 APP/Aβ proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog is found in cnidarians, while ctenophores, placozoa, and choanoflagellates have genes equally orthologous to BACE1 and BACE2. BACE1 from a cnidarian (Hydra) can cleave APP to release Aβ, pushing back the date of the origin of its function to near the origin of animals. We tested more divergent BACE1/2 genes from a ctenophore (Mnemiopsis) and a choanoflagellate (Monosiga), and neither has this activity. These findings indicate that the specific proteolytic function of BACE1 evolved during the very earliest diversification of animals, most likely after a gene-duplication event. Full article

In this study, the divergent syntheses of (-)-chicanine, (+)-fragransin A₂, (+)-galbelgin, (+)-talaumidin, and (+)-galbacin are detailed. In this approach, an early-stage modified Kowalski one-carbon homologation reaction is utilized to construct the central γ-butyrolactone framework with the two necessary β,γ-vicinal stereogenic centers. The two common chiral γ-butyrolactone intermediates were designed to be capable for assembling five different optically active tetrahydrofuran lignans from commercially available materials in a concise and effective divergent manner in five to eight steps. These five syntheses are among the shortest and highest-yielding syntheses reported to date. Full article