Search Results (543)

Background: Monkeypox (Mpox) is a re-emerging zoonotic disease caused by the monkeypox virus (MPXV). Transmission occurs primarily through direct contact with lesions or contaminated materials, with sexual transmission playing a significant role in recent outbreaks. In 2022, Mpox triggered a major global outbreak and was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO), prompting renewed interest in effective control strategies. Methods: This study developed a compartmental SEIR-based model to assess the epidemiological impact of key interventions, including vaccination and isolation, while incorporating critical epidemiological parameters. Sensitivity analyses were conducted to examine (1) disease dynamics in relation to the basic reproduction number, and (2) how different parameters influence the curve of symptomatic infections. Real-world continental-scale data were used to validate the model and identify the parameters that most significantly affect epidemic progression and potential control of Mpox. Results: Results showed that the basic reproduction number was most influenced by the recovery rate, vaccination rate, vaccine effectiveness, and transmission rates of symptomatic and asymptomatic individuals. In contrast, the progression of symptomatic cases was highly sensitive to the case fatality rate and incubation rate. Conclusions: These findings highlight the importance of integrated public health strategies combining vaccination, isolation, and early transmission control to mitigate future Mpox outbreaks. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

According to the World Health Organization (WHO), globally, cervical cancer ranks as the fourth most common cancer in women, with around 660,000 new cases in 2022. In the same year, about 94 percent of the 350,000 deaths caused by cervical cancer occurred in low- and middle-income countries. This paper focuses on the dynamics of HPV by modeling the interactions between four compartments, as follows: S(t), the number of susceptible females; I(t), females infected with HPV; X(t), females infected with HPV but not yet affected by cervical cancer (CCE); and V(t), females infected with HPV and affected by CCE. A compartmental model is formulated to analyze the progression of HPV, ensuring all key mathematical properties, such as existence, uniqueness, positivity, and boundedness of the solution. The equilibria of the model, such as the HPV-free equilibrium and HPV-present equilibrium, are analyzed, and the basic reproduction number, $R_0$, is computed using the next-generation matrix method. Local and global stability of these equilibria are rigorously established to understand the conditions for disease eradication or persistence. Sensitivity analysis around the reproduction number is carried out using partial derivatives to identify critical parameters influencing $R_0$, which gives insights into effective intervention strategies. With appropriate positivity, boundedness, and numerical stability, a new stochastic non-standard finite difference (NSFD) scheme is developed for the proposed model. A comparison analysis of solutions shows that the NSFD scheme is the most consistent and reliable method for a stochastic fractional delay model. Graphical simulations are presented to provide visual insights into the development of the disease and lend the results to a more mature discourse. This research is crucial in highlighting the mathematical rigor and practical applicability of the proposed model, contributing to the understanding and control of HPV progression. Full article

DROSHA protein is widely known for its essential role in the microRNA (miRNA/miR) biogenesis pathway where, together with its co-factor DGCR8, it forms the “Microprocessor” complex and catalyzes the primary miRNA (pri-miRNA) processing in the nucleus. Nevertheless, DROSHA also seems to participate in several miRNA-independent cellular mechanisms, such as transcriptional regulation, RNA processing and genome integrity maintenance. Hence, the present study aims to further investigate novel miRNA-independent activities of DROSHA protein, with potentially regulatory roles in the oncogenesis of human cancer cells. Our results reveal a new, strong profile of microprocessor-independent DROSHA localization at the Golgi apparatus in several human cancer cell lines of different tissue origin, with hepatic carcinoma, thyroid cancer, urothelial bladder cancer, colon carcinoma and melanoma being the cellular model systems herein examined. Notably, oncogenic activity, malignancy grade and metastatic capacity are shown to be strongly associated with DROSHA’s compartmentalization at Golgi, a phenotype that does not seem to rely on p53 protein’s functionality. Taken together, through employment of advanced confocal laser scanning microscopy (CLSM) and molecular modeling, we herein unveil the ability of DROSHA, but not AGO2 and DICER, to reside at Golgi, where DROSHA can physically interact with the GM130 Golgi-specific component, thus indicating DROSHA’s engagement in non-canonical and miRNA-independent—but also Golgi apparatus-dependent—novel mechanisms that can be tightly coupled with malignancy dynamics and beneficially utilized as potential biomarkers and therapeutic targets for human cancer. Full article

Indocyanine green (ICG) is a fluorescent agent which is characterized by a wide range of applications in the proper visualization of the operating field, differentiation of vital structures, and localization of lesions to be excised. An investigation and overview of novel approaches of indocyanine green in modern gynecological oncology was conducted, including ovarian cancer surgery with its compartmental approach and compartmental surgery in endometrial cancer. Ureteral visualization and perfusion, lymphography, lymph node transfers, or the localization of anastomotic leakage in bowel surgery are examples of applications aimed at reducing the risk of surgical complications and improving the patients’ quality of life. The general use of indocyanine green in lymph node detection, subcategorized and analyzed, is constantly improved and reviewed. A therapeutic approach with macromolecules is being tested in preclinical models. Early results could suggest the future application of indocyanine green not only in broad-sense imaging but also as a cytotoxic agent conjugated with macromolecules. Further studies on the application of indocyanine green in laparoscopy, open surgery, and finally as a curative cytotoxic agent are needed. Full article

Agri-food supply chains have experienced notable changes in recent decades, with tomatoes (Solanum lycopersicum) maintaining their status as a key global crop in terms of both production and consumption. These supply chains comprise a complex network of stakeholders—including producers, processors, distributors, and retailers—who collectively ensure the delivery of tomatoes from farms to consumers. This study develops mathematical models of agri-food tomato supply chains (AFTSCs) and examines their behavior through stability analysis and dynamic simulations based on a compartmental approach. Furthermore, the environmental impact is evaluated using a sustainability index, to which the waste diversion rate is introduced. This metric is defined as the proportion of diverted waste (i.e., materials recycled, reused, or composted) relative to the total waste generated, thereby enabling the quantification of sustainability performance within the system. Finally, a sensitivity analysis is conducted on the proposed dynamical models to validate and reinforce the findings. Full article

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite, and abnormal NAD⁺ metabolism has been linked to numerous human diseases. The nicotinamide mononucleotide adenylyl transferases (NMNATs) catalyze NAD⁺ production through both de novo and salvage pathways. NMNATs are multi-functional enzymes with NAD⁺ synthesis activity and chaperone activity. Interestingly, NMNATs are involved in neuroprotection, and whether these neuroprotective effects require NAD⁺ synthesis activity appears to vary depending on the context. Nevertheless, NMNATs can modulate cellular processes primarily through supporting NAD⁺ homeostasis. In this review, we discuss the roles of NMNATs in NAD⁺ homeostasis, their functional domains, and how their subcellular localizations influence the compartmentalized NAD⁺ pools. We present an integrative framework to help understand the diverse impacts of NMNATs in human diseases, with a focus on neurological disorders caused by different insults. To address knowledge gaps, we integrate the regulation of NMNATs in both human and model organisms. We also discuss the current understanding and limitations of NMNAT activators and inhibitors to help evaluate their translational significance as therapeutic targets for NAD⁺ modulation. Full article

Progressive multiple sclerosis (PMS) represents a distinct clinical and biological entity characterized by compartmentalized neuroinflammation, chronic glial activation, and resistance to conventional immunotherapies. Unlike relapsing MS, PMS is sustained by resident CNS immune networks, where activated microglia and astrocytes orchestrate persistent cytokine signaling—particularly involving TNF-α, IL-1β, and IL-6—through self-amplifying feedback loops. In this narrative review, we explore how these cytokines interact with oxidative stress, iron accumulation, mitochondrial dysfunction, and impaired autophagy to drive neurodegeneration. Human-based evidence is integrated with insights from experimental models to clarify translational mechanisms. We also highlight fluid biomarkers (e.g., GFAP, NfL) and imaging modalities (e.g., TSPO-PET, QSM) that reflect glial activity and disease progression in vivo. Age, sex hormones, and immunosenescence are discussed as modulators of cytokine expression. Finally, we review emerging therapeutic strategies that target glial metabolism and cytokine networks rather than peripheral immune cells, offering a systems-based framework for future PMS interventions and personalized disease monitoring. Full article

The basal forebrain (BF)-hippocampus (HPC) circuit is indispensable for learning and memory, and in vitro models are essential for dissecting its age-related decline. Nonetheless, current culture methods endure brief survival or confine cells to two dimensions, leaving the circuit’s progressive degeneration refractory to long-term investigation. Here, we developed a simple, three-dimensional (3D) compartmentalized co-culture model that mimics the anatomical organization of BF and HPC neurons. Results demonstrate that basal forebrain cholinergic neurons (BFCNs) co-cultured with primary HPC neurons remain viable for more than two months without exogenous growth factors, significantly promoting BFCNs growth, polarity development, and functional maturation. In this system, BFCNs somata were confined within the hydrogel, whereas cholinergic axons extended toward adjacent hippocampal area, reaching 1681.9 ± 351.8 μm by week 5—significantly longer than in BFCNs monocultures. This model can successfully recapitulate age-dependent progressive neuronal degeneration during long-term culture, validating this long-term co-culture as a platform for studying circuit aging and degeneration. Therefore, this low-cost and highly physiological platform provides a new avenue for in-depth investigations into the mechanisms of neurodegenerative diseases. Full article

Cellular organization relies on both membrane-bound organelles and membraneless biomolecular condensates formed through liquid–liquid phase separation. Recent discoveries reveal intricate coupling between lipid membrane organization and condensate assembly, reshaping our understanding of cellular compartmentalization. This review synthesizes multidisciplinary research using advanced techniques including super-resolution microscopy, fluorescence recovery after photobleaching, and in vitro reconstitution to examine lipid-condensate interactions. Lipid membranes serve as nucleation platforms that reduce critical concentrations for condensate formation by orders of magnitude through membrane anchoring and thermodynamic coupling, creating specialized microenvironments that substantially enhance enzymatic activities. Key regulatory mechanisms include phosphorylation-driven assembly and disassembly, membrane composition effects from cholesterol content and fatty acid saturation, and environmental factors such as calcium and pH. These interactions drive signal transduction through receptor clustering, membrane trafficking via organized domains, and stress responses through protective condensate formation. Dysregulation of lipid-condensate coupling, including aberrant phase transitions and membrane dysfunction, underlies metabolic disorders and neurodegenerative diseases. This coupling represents a fundamental organizing principle with significant therapeutic potential. Current challenges include developing quantitative methods for characterizing condensate dynamics in complex cellular environments and translating molecular mechanisms into clinical applications. Future progress requires interdisciplinary approaches combining advanced experimental techniques, computational modeling, and standardized protocols to advance both fundamental understanding and therapeutic innovations. Full article

The pathogenesis and pathophysiology of Huntington’s disease (HD) are still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. Clinical positron emission tomography studies suggest that phosphodiesterase 10A (PDE10A) declines earlier than dopamine D1 and D2 receptors in HD, indicating that it might serve as a key molecular marker in understanding disease mechanisms. In movement disorders, mutations in the genes encoding PDE10A and G-protein α subunit (Gα_olf), both critical cAMP regulators in striatal spiny projection neurons, have been linked to chorea and dystonia. These observations highlight the potential importance of striatal cyclic AMP (cAMP) signaling in these disorders, but how such dysfunction could come is unknown. Here, we suggest that a key to understanding signaling dysfunction might be to evaluate these messenger systems in light of the circuit-level compartmental organization of the caudoputamen, in which there is particular vulnerability of the striosome compartment in HD. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of Q175 knock-in (Q175KI) HD mice from 3–12 months of age. We demonstrate that the expression of multiple molecules, including Gα_olf, PDE10A, dopamine D1 and D2 receptors, and adenosine A2A receptors, is significantly reduced in the striosomes of Q175KI mice as compared to wildtype controls, across 3, 6, and 12 months of age. By contrast, mu-opioid receptor (MOR1) expression is uniquely upregulated, suggesting a compartment-specific and age-dependent shift in molecular profiles in the Q175KI HD mouse model caudoputamen. These differential changes may serve as a useful platform to determine factors underlying the greater vulnerability of striatal projection neurons in the striosomes than in the matrix in HD. Full article

Graphic design and image processes have a vital role in information technologies and safe, memorable learning activities, which can meet the need for modern and visual aids in the field of education. In this article, the concepts of comparison and competition have been presented using grades or numbers obtained for two different intelligence quotient (IQ) classes of students. The two classes are categorized as learners having textual (un-visualized) and visualized aids. We use the results and outcomes of the random sampling data of the two classes in the parameters of four different, competitive, two-compartmental mathematical models. One of the compartments is for students who only learn through textual learning, and the other one is for students who have access to visualized text resources. Four of the mathematical models were solved numerically, and their grades were obtained by different iterations using the data of the mean of different random sampling tests taken for thirty months; each sampling involved thirty students. The said data are also drawn by using a neural network approach, showing the fitting curves for all the data, the training data, the validation data, and the testing data with histogram, aggression, mean square error, and absolute error. The obtained dynamics are also compared with neural network dynamics. The results of the scenario pointed out that the best results (determined through high grades) were obtained among the students of visual aid learners, as compared to textual and conventional learners. The visualized resources, constructed within the mathematics syllabus domain, may help to upgrade multidimensional mathematical education and the learning activities of intermediate-level students. For this, the findings of the present study are helpful for education policymakers: there is a directive to focus on visual-based learning, utilizing data from various surveys, profile checks, and questionnaires. Furthermore, the techniques presented in this article will be beneficial for those seeking to build a better understanding of the various methods and ideas related to mathematics education. Full article

The discovery of Asgard archaea has reshaped our understanding of eukaryotic origins, supporting a two-domain tree of life in which eukaryotes emerged from Archaea. Building on this revised framework, we propose the Pre-prokaryotic Organismal Lifeforms Existing Today (POLET) hypothesis, which suggests that relic pre-prokaryotic life forms—termed POLETicians—may persist in deep, anoxic, energy-limited environments. These organisms could represent a living bridge to the RNA world and other origin-of-life models, utilizing racemic oligoribonucleotides and peptides, non-enzymatic catalysis, and mineral-assisted compartmentalization. POLETicians might instead rely on radical-based redox chemistry or radiolysis for energy and maintenance. These biomolecules may be racemic or noncanonical, eluding conventional detection. New detection methods are required to determine such life. We propose generalized nanopore sequencing of any linear polymer—including mirror RNAs, mirror DNAs, or any novel genetic material—as a potential strategy to overcome chirality bias in modern sequencing technologies. These approaches, combined with chiral mass spectrometry and stereoisomer-resolved analytics, may enable the detection of molecular signatures from non-phylogenetic primitive lineages. POLETicians challenge the assumption that all life must follow familiar biochemical constraints and offer a compelling extension to our search for both ancient and extant forms of life hidden within Earth’s most extreme environments. Full article

Background/Objectives: Reflecting the interaction between dissolution and absorption, the biphasic dissolution system is an appealing approach for estimating the intestinal absorption of drugs in humans. The study aims to characterize the suitability of the biphasic in vitro dissolution testing to set up an in vitro–in vivo correlation (IVIVC) for the original and generic immediate-release (IR) tablets of a Biopharmaceutics Classification System (BCS) Class II drug, bicalutamide (BIC). Methods: USP apparatus II paddle was used to conduct dissolution testing. A level A IVIVC was obtained between in vitro partitioning and in vivo absorption data of the original drug. The single-compartmental modeling was used for pharmacokinetic (PK) analysis. The generic product’s plasma concentrations were estimated. Results: There was a good correlation between in vitro and in vivo data (r² = 0.98). The area under the concentration–time curve (AUC) and maximum plasma concentration (C_max) ratios for generic/original were 1.04 ± 0.01 and 0.951 ± 0.026 (mean ± SD), respectively. Conclusions: The biphasic dissolution testing may present an in vivo predictive tool for developing generic products of poorly soluble and highly permeable drugs such as BIC, which are characterized by pH-independent poor solubility. Full article

Biomolecular condensates (BCs), formed through liquid–liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies. Full article