Search Results (6,328)

The role of endoplasmic reticulum (ER) stress in atherosclerosis has long been recognized, but whether it acts as a uniform pathological signal across all cell types has remained unclear. With the advancement of single-cell sequencing technology (scRNA-seq), we can analyze this problem at the resolution of a single cell subpopulation. In this review, we have synthesized the recent evidence from single-cell studies and proposed the “cell type-specific differential response” mode. We believe that endoplasmic reticulum stress does not universally have a pro-atherosclerotic effect. On the contrary, it shows a differential pattern in different atherosclerotic-related cell subpopulations. For example, endoplasmic reticulum stress is activated in monocytes but inhibited in certain macrophage subsets and endothelial cell subsets and dynamically regulated during phenotypic transitions in smooth muscle cells. We explored the underlying mechanisms of this heterogeneity, its impact on plaque progression, and the theoretical basis of subpopulation targeted treatment strategies. Ultimately, we concluded that recognizing the cellular heterogeneity of endoplasmic reticulum stress is the foundation for understanding and precisely intervening in atherosclerotic diseases. Full article

Background/Objectives: OS is characterized by marked tumor heterogeneity, stemness-associated phenotypes, metastatic potential, and poor prognosis. FZD4 is an important Wnt signaling receptor involved in stem cell regulation and tumor progression, but its role and microRNA-mediated regulation in OS remain unclear. The aim of this study was to investigate the relationship between FZD4 expression, OS stemness, malignant progression, and upstream microRNA regulation. Methods:Human OS single-cell RNA sequencing data were analyzed using Seurat, CytoTRACE, and Monocle2. Tumor cell subpopulations, developmental potential, and pseudotime trajectories were evaluated. Functional enrichment analyses were performed to identify pathways associated with high FZD4 expression. MicroRNA–mRNA interaction analysis was used to predict upstream regulatory microRNAs, and immunohistochemistry, Western blotting, and in vitro and in vivo experiments were performed for validation. Results: FZD4 was mainly enriched in OS tumor cell subpopulations and was significantly associated with poor prognosis. Tumor cells with high FZD4 expression showed increased developmental potential, stemness features, and enrichment in early developmental states. Functional enrichment analysis indicated activation of epithelial–mesenchymal transition, angiogenesis, inflammatory response, KRAS signaling, hypoxia, glycolysis, and Wnt-related pathways. Clinical validation confirmed elevated expression of FZD4, OCT4, and SOX2 in OS tissues. FZD4 knockdown inhibited OS cell stem-like phenotypes and malignant behaviors, proliferation, and migration, while miR-424-5p suppressed these malignant phenotypes by targeting FZD4. Importantly, rescue experiments demonstrated that restoration of FZD4 substantially reversed the inhibitory effects of miR-424-5p mimics on sphere formation, migration/invasion, proliferation, and stemness-associated cell populations. Conclusions: Our findings identify miR-424-5p as an upstream suppressor of FZD4 and demonstrate that the miR-424-5p/FZD4 axis regulates stem-like and malignant phenotypes of OS cells, at least partly through Wnt/β-catenin signaling. This axis may represent a potential therapeutic target for OS. Full article

Bio-inspired optimization algorithms have become an effective class of techniques for addressing challenging continuous optimization problems. In this work, we introduce the Parallel Enzyme Action Optimization (PEAO) algorithm, a parallel bio-inspired optimization approach that incorporates a multi-strategy communication mechanism among cooperative subpopulations. The population is partitioned into multiple subpopulations that evolve concurrently, promoting a more effective exploration of the search space. Furthermore, PEAO integrates adaptive search factors, local search procedure and communication strategies to improve solution quality while reducing the risk of premature convergence. In addition, a K-means-based population initialization procedure and a convergence-driven stopping criterion based on successive improvements in the best objective-function value are incorporated to reduce unnecessary objective-function evaluations and improve the overall efficiency of the optimization process. Full article

Most existing studies on anthropogenic N and P inputs in the Yangtze River Basin focus on the middle-lower main stem and large lake regions, while long-term fine-scale assessments of small and medium plateau tributaries in the upper reaches remain limited. This study was based on the Net Anthropogenic Nitrogen and Phosphorus Input (NANI) & (NAPI) models to systematically quantify total anthropogenic N/P inputs and their sources, and to characterize spatiotemporal dynamics. The random forest model was employed to disentangle and quantify key driving factors; additionally, the multiple linear regression (MLR) model was employed to construct prediction equations, and key-factor scenarios were set to predict N and P input evolution trends under reduced fertilizer application and population change. Results indicate that: (1) from 2009 to 2023, the mean annual NANI and NAPI in the study area were (8741.97 ± 1715.37) kg·km⁻²·yr⁻¹ and (2016.01 ± 610.68) kg·km⁻²·yr⁻¹, respectively, exhibiting an overall “first increase, then decrease” trend. Their spatial distribution patterns were highly coupled. The spatial distribution was highly heterogeneous, with high values concentrated in the central dam regions and low values in mountainous areas. (2) Across all sub-basins, food and feed N input and fertilizer application were the primary sources of NANI, accounting for 50.87% and 43.94% of the total on average, respectively, while food and feed P input and fertilizer application dominated NAPI with average shares of 31.31% and 68.69%. (3) Population size, fertilizer application intensity, and livestock/poultry breeding volume were the primary drivers of regional NANI and NAPI. (4) Scenario prediction results show that fertilizer reduction significantly reduces N and P inputs, whereas population growth does not directly elevate N and P loads. Overall, N and P inputs in the Longchuan River Basin are dominated by human activities, with spatiotemporal variations closely linked to agricultural activity intensity and population distribution. These findings provide scientific support for targeted precise zonal N/P control in the Longchuan River Basin, and also offer a reference for non-point source pollution control research and management policy-making in similar plateau basins of the upper Yangtze River. Full article

This study develops and analyzes a nonlinear tumor–immune–chemotherapy model to investigate how chemotherapy influences tumor suppression in the presence of heterogeneous tumor subpopulations and immune responses. The model incorporates two tumor cell populations with different immunogenic characteristics, innate and adaptive immune responses, and a dynamic chemotherapy effect. We analytically identify the equilibrium points and assess the conditions for their stability in the presence of chemotherapy. A bifurcation analysis with respect to the chemotherapy tumor killing rate of the less immunogenic tumor reveals Hopf bifurcations, indicating transitions to oscillatory behavior and complex tumor–immune dynamics under varying treatment intensities. The effects of chemotherapy dosing and drug potency are investigated through six-month numerical treatment simulations to evaluate tumor suppression and long-term system behavior under different treatment scenarios. An optimal control problem is then formulated to determine chemotherapy schedules that reduce tumor burden while limiting drug exposure. Numerical results indicate that the optimal chemotherapy protocol produces faster and more efficient tumor reduction than a constant-dose treatment strategy. Overall, this study provides a treatment-focused dynamical framework for understanding how chemotherapy interacts with tumor heterogeneity and immune response, providing theoretical insight into treatment-dependent tumor–immune dynamics and chemotherapy scheduling. Full article

Carcass traits, which reflect growth performance and muscle development, are economically important in beef cattle, yet their genetic determinants remain poorly characterized. Both single-population Genome-wide association studies (GWAS) methods, such as BLINK, and cross-population meta-analysis approaches are widely used to identify genetic variants, yet their comparative performance in genomic prediction for complex traits in structured populations remains underexplored. Few studies have directly compared these methods in genomic prediction. To address this gap, this study aims to (i) identify positional candidate genes associated with carcass traits and (ii) evaluate the context-dependent advantages of Covariate Adjustment (CA) and meta in genomic prediction. In this study, we analyzed carcass weight (CW), live weight (LW), and dressing percentage (DP) in 279 crossbred Angus cattle genotyped with the PHR0105_Bt140K_v1.0 SNP chip. GWAS was performed on the full population using BLINK, and results from three subpopulations were combined via meta-analysis, with significance thresholds for both approaches determined by a shuffle-based method. Candidate genes located within ±10 kb of significant SNPs were associated with different carcass traits, including STRIT1, SEL1L3, NOC4L and ANK1 for DP; SNCA and DNAH5 for CW; and GYPC, GPR158, and GUCY1A1 for LW. Prediction accuracy under MAS and MABLUP showed meta slightly outperformed BLINK in MAS, while BLINK was better with covariate adjustment; after incorporating kinship in MABLUP, meta achieved higher accuracy and population partitioning was negligible. Overall, MABLUP yielded the highest accuracy (0.52–0.79) versus MAS (0.37–0.54) in all traits. These findings provide a methodological basis for selecting appropriate GWAS strategies in structured populations and highlight candidate genes. Full article

Background/Objectives: Interindividual pharmacokinetic (PK) variability remains a daunting challenge for effective and safe drug therapy. Despite the widespread use of direct oral anticoagulants (DOACs) and calcium channel blockers (CCBs), a substantial number of adverse drug reactions have been reported for both classes. Herein, this study aimed to assess and analyze the PK variability of DOACs and CCBs across diverse clinical and demographic profiles under both single- and multiple-dose conditions. Methods: A PubMed search identified clinical PK studies reporting maximum plasma concentration (C_max) and/or area under the concentration-time curve (AUC). The coefficient of variation (CV%) was calculated and used as a measure of PK variability. A CV% < 40% indicated low-to-moderate variability, and a CV% > 40% was defined as high variability. Results: A total of 264 studies were included following systematic screening, and the dataset was further characterized according to population features and clinical context. Among DOACs, edoxaban exhibited the lowest PK variability, whereas dabigatran showed the highest. CCBs demonstrated a broad variability spectrum, ranging from predictable agents (amlodipine and felodipine) to highly variable compounds (nisoldipine, isradipine, nimodipine, diltiazem, and verapamil). Studies evaluating drug–drug interactions, ethnicity, and specific drug-related factors were associated with increased PK variability. Conclusions: These findings suggest that fixed-dose strategies may not be universally appropriate for DOACs and CCBs, particularly in high-risk subgroups where altered exposure may lead to sub- or supratherapeutic concentrations and compromise clinical outcomes. Therefore, clinicians should avoid evaluating individual risk factors in isolation and instead consider the patient’s complete profile when selecting and adjusting pharmacotherapy. Full article

Coordinating production–living–ecology (PLE) land use requires an accurate account of how PLE functions interact, yet most studies treat these interactions as static attributes and report their thresholds in isolation. We instead treat them as dynamic states conditioned by their driving factors. For the karst region of southwest China, we identified the leading natural and the leading anthropogenic factors of the PLE functions with Geodetector, fixed one natural and one anthropogenic conditioning axis for each function pair by a pair-level rule, and reconstructed the 2010 and 2019 Pareto frontier of each pair along those two gradients; curve tipping points distinguished reversal-type from buffer-type thresholds, from which regulation zones follow directly. Production–ecology and living–ecology are trade-offs over the fitted range, whereas the production–living boundary rises over most of the production range. Total benefit at the equal-weight reference optimum rose in all three pairs (0.552 to 0.636, 0.701 to 0.726, and 0.823 to 0.872), with no decrease in any of 1000 block bootstrap resamples. Boundaries also differed between areas of rising and of falling constraint function, but the two groups are unbalanced in terms of elevation and population density, so this contrast is reported as a descriptive comparison only. Along the elevation gradient the living–ecology interaction shows one reversal-type threshold in each year, at 595 and 756 m, whose confidence intervals define a precautionary management envelope of 498 to 939 m; along the population density gradient no threshold survived at the sub-watershed scale. The framework gives an operable basis for differentiated regulation in fragile regions. Full article

Background/Objectives: Osteosarcoma (OS) is an aggressive bone malignancy with a complex tumor microenvironment (TME) that influences therapeutic outcomes and resistance. How neoadjuvant chemotherapy (NACT) reshapes the OS TME at single-cell resolution remains largely undefined. This study aimed to characterize cellular heterogeneity in the OS TME after NACT and identify chemokine-mediated intercellular crosstalk driving chemoresistance. Methods: Single-cell RNA sequencing was performed on surgical specimens from 12 OS patients (6 treatment-naive and 6 post-NACT). After quality control, 77,616 cells (36,214 from naive patients, 41,402 from post-NACT samples) were analyzed through the Seurat pipeline. Unsupervised clustering, differential expression analysis, and cell–cell communication network construction were performed, and candidate signaling axes were validated using transwell assays and Western blotting. Results: Cells were classified into 10 major cell types. Osteoblasts, identified as malignant cells, were partitioned into 11 subpopulations with marked transcriptional heterogeneity and differential PI3K/Akt pathway activity. Post-NACT, stromal and vascular components underwent molecular and functional remodeling, shaping an immune-activated microenvironment. Mononuclear phagocytes resolved into three discrete clusters—monocytes, macrophages, and dendritic cells—with differentiation gradients. Endothelial cells maintained robust CXCL2 expression throughout the therapeutic course. Functional validation via transwell assays and Western blotting confirmed that endothelial-derived CXCL2 promoted macrophage chemotaxis via CXCR2, with corresponding CXCR2 upregulation in macrophages. Conclusions: Collectively, these findings suggest the complex cellular and transcriptional heterogeneity of the OS microenvironment and its chemokine-driven molecular remodeling after NACT, indicating that TME dynamics may be a determinant of therapeutic response and chemoresistance. Full article

Essential oils (EOs) are promising natural antimicrobial agents, although their mechanisms of action are not yet fully understood. This study investigated the antimicrobial mechanisms of cinnamon (Cinnamomum verum) and oregano (Origanum vulgare) EOs against Listeria monocytogenes Scott A and Staphylococcus aureus DSM 20231^T by combining conventional plate counting with multiparameter flow cytometry. Bacterial cells were exposed to different sub-lethal or lethal EO concentrations, and culturability and three complementary physiological endpoints—viability, membrane permeability, and membrane potential—were monitored during treatment and after stress removal. Oregano EO, rich in carvacrol, rapidly reduced bacterial culturability and induced extensive membrane damage and cell death in both species. In contrast, cinnamon EO, characterized by trans-cinnamaldehyde as its main constituent, produced a slower antimicrobial response, with more limited membrane permeabilization and a greater recovery after stress removal. Discrepancies between culturability and flow-cytometric viability revealed transient VBNC-like populations, while post-stress recovery demonstrated that loss of culturability was reversible under some conditions. Overall, cinnamon EO-induced injury was at least partially repairable, particularly in L. monocytogenes, whereas damage caused by oregano EO at the highest tested concentration was essentially irreversible. These findings clarify the distinct antimicrobial effect of the two EOs and support their rational application as natural food preservatives. Full article

Background: Secondary hair germ (SHG)-associated epithelial cells are a key progenitor population that contribute to hair follicle regeneration during early anagen. Although SHG-associated cells become activated during early anagen and contribute to the formation of regenerating follicular structures, the morphologically recognizable SHG compartment becomes less apparent as lower hair follicle structures develop during mid-anagen. However, the transcriptional changes accompanying the transition from SHG-associated states toward lower hair follicle-associated states remain poorly characterized. This study aimed to characterize the transcriptional changes associated with this transition and identify a proliferative intermediate transcriptional state during early anagen. By integrating single-cell transcriptomic analysis with regulatory and cell–cell communication analyses, we sought to improve the understanding of cellular state transitions and microenvironmental changes during early hair follicle regeneration. Methods: Hematoxylin and eosin staining (H&E) was performed to examine histological changes in mouse dorsal skin on days 0, 5, 10, 15, 20, 25, and 30 of the hair cycle. In parallel, previously published single-cell RNA sequencing data from mouse dorsal skin during early anagen were reanalyzed. Hair follicle epithelial cells were extracted and reclustered to identify cell subpopulations with distinct transcriptional characteristics. Cell types were annotated based on canonical marker genes and subpopulation-specific expression patterns. Differential expression analysis, functional enrichment analysis, cell-cycle analysis, developmental potential assessment, trajectory inference, transcription factor regulon analysis, and cell–cell communication analysis were further performed to characterize the relationships among hair germ cells, proliferative lower hair follicle-like cells (PR-loHF), and lower hair follicle cells. Results: Proliferative lower hair follicle-like cells (PR-loHF) were identified as a transcriptionally defined intermediate state associated with the transition from secondary hair germ (SHG)-associated cells toward lower hair follicle-associated cells. PR-loHF exhibited enrichment of biological programs associated with cell-cycle activity, epithelial remodeling, extracellular matrix organization, and developmental regulation. Moreover, compared with SHG-associated and lower hair follicle-associated states, PR-loHF exhibited distinct transcription factor regulon activity and cell–cell communication patterns, further supporting its characterization as a transcriptionally distinguishable intermediate state. Conclusions: PR-loHF represents a proliferative intermediate transcriptional state emerging during the transition from secondary hair germ (SHG)-associated cells toward lower hair follicle-associated states, providing new insights into transcriptional transitions and microenvironmental regulation during early hair follicle regeneration. Full article

Background/Objectives: Cancer cell migration is a hallmark of cancer and is associated with metastasis. While large-scale functional screens have identified regulators of migration, less is known about how intrinsic transcriptional heterogeneity drives highly migratory phenotypes within individual cancer models or whether these transcriptional changes are conserved across different models of varying tissues of origin. This study aims to define shared and cell line-specific transcriptional programs associated with cancer cell migration and analyze their relevance to patient datasets. Methods: Five cancer cell lines across three cancer types (breast, colorectal, and melanoma) were subjected to transwell-based migratory sorting to isolate highly and weakly migratory subpopulations. Bulk RNA sequencing, differential gene expression analysis, Gene Ontology (GO) enrichment, and upstream regulator prediction were performed. Public tumor datasets were analyzed to evaluate gene expression and its association with patient survival. Results: EVA1A was consistently upregulated in all highly migratory (HM) subpopulations. Multiple GO terms were enriched across all cell lines, often driven by distinct gene signatures, indicating convergence at the level of biological processes despite transcriptional divergence. TEAD4 was predicted as an upstream regulator, and increased TEAD4 nuclear localization was observed in four of the five HM subpopulations. EVA1A and TEAD4 expression were elevated in tumors relative to normal tissues, with cancer type-dependent survival outcomes. Conclusions: Migratory selection was accompanied by extensive transcriptional change within each model, yet across five models spanning three tissue types these changes converged on shared biological processes rather than shared genes. Migration-associated phenotypes may therefore be better defined by pathway-level than single-gene analyses, and the clinical relevance of regulatory nodes such as TEAD4 appears conditional on cancer type. Full article

Background: Optimal tracheostomy timing remains controversial due to conflicting evidence across published systematic reviews. To clarify this ambiguity within specific patient populations (critically ill, traumatic brain injury, stroke, trauma, COVID-19, and spinal cord injury), an umbrella review of systematic reviews was conducted comparing early versus late tracheostomy or prolonged intubation. Additionally, potential benefits in clinical outcomes were evaluated across a mixed-etiology cohort of mechanically ventilated patients. Methods: MEDLINE, Embase, Cochrane Library, and Web of Science were searched from inception through July 2024. Systematic reviews evaluating the impact of tracheostomy timing on mechanical ventilation duration, ventilator-associated pneumonia risk, ICU/hospital length of stay, and mortality were included. Two authors independently extracted data using a standardized form. Methodological quality was assessed via AMSTAR 2 and certainty of evidence via GRADE. Random-effects meta-analyses were conducted for each outcome, stratified by study design (RCTs vs. non-RCTs), with subgroup analyses exploring patient subpopulations. Results: Evidence was synthesized from 9 systematic reviews (24 unique RCTs, 54 non-RCTs). In RCTs, moderate certainty evidence suggests that early tracheostomy reduces ventilator-associated pneumonia (OR 0.66, 95% CI 0.46 to 0.94, p = 0.02) and mechanical ventilation duration (MD −3.76 days, 95% CI −6.01 to −1.52, p < 0.001) compared to late tracheostomy or prolonged intubation. Early tracheostomy may reduce ICU length of stay (MD −6.64 days, 95% CI −9.92 to −3.35, p < 0.001, low certainty). The effect of early tracheostomy on hospital length of stay and mortality remains uncertain. Conclusions: Early tracheostomy shows potential to reduce ventilator-associated pneumonia and mechanical ventilation duration in mixed-etiology cohorts. It may also be associated with shorter ICU length of stay, while its effect on mortality and hospital stay remains uncertain. Future research should establish standardized definitions of tracheostomy timing and prioritize high-quality, etiology-specific RCTs in underrepresented cohorts (e.g., traumatic brain injury, stroke, spinal cord injury). Full article

Endometrial cancer (EC) is a common gynecologic malignancy arising from the epithelial cells of the endometrium. The marked cellular heterogeneity of EC and features of its tumor immune microenvironment (TIME) contribute to disease complexity and have been associated with poor prognosis. This study integrates single-cell RNA sequencing, spatial transcriptomics, and Mendelian randomization (MR) to identify candidate genes associated with EC. Single-cell analysis identified MM0 as a putative stemness-associated transcriptional subpopulation with the highest CytoTRACE-inferred score; irGSEA indicated enrichment of proliferation- and stress-response pathways. Spatial data were analyzed with RCTD, MISTy, and stLearn to estimate spatial associations and pathway activities. MR and colocalization analyses integrating eQTL data and EC GWAS summary statistics prioritized DNAJA4, HSPA6, and LMNA as candidate genes with potential causal associations with EC risk. The expression patterns of these candidate genes were further examined in patient-derived samples. In Ishikawa cells cultured under high-estrogen conditions, siRNA-mediated knockdown of DNAJA4 and HSPA6 significantly suppressed proliferation and migration, accompanied by reduced CDK1 and Cyclin B expression. Collectively, these findings provide insight into EC heterogeneity and support further mechanistic investigation of candidate genes associated with malignant epithelial proliferation. Full article

The Olfactory System is receiving increasing attention in recent years as a potential biomarker for Alzheimer’s disease (AD). Early-stage AD is often associated with a decline in olfactory function, with studies suggesting that olfactory memory deficit may precede cognitive symptoms. We explore the intricate relationship between the Olfactory System and Alzheimer’s disease, examining both the neuroanatomical and physiological changes that occur in the olfactory pathways during the progression of AD. Memory, as a functional feature, was modeled using artificial neural networks, and it was related to the macro-parameters of the network. While these networks cannot completely capture the intricacies and functions of the human brain, they provide a clear understanding of how processes occur within it. Neural networks exhibited memory domains, defined by stable and unstable steady states; the former can be considered a prerequisite for memory storage and recall; the latter can be considered threshold values between stable steady states. Additionally, by introducing division of the neural population into subpopulations, the networks manifested multiple stable states, corresponding to multiple memory domains, which in a qualitative manner suggest hierarchically organized nonlinear complexity and multi-scale self-similarity of memory processes. Full article