Search Results (3,488)

This paper studies a stochastic service system with N-policy, Bernoulli interruption vacations, and a patient server. When the number of waiting customers reaches the threshold N during a vacation, the server interrupts the vacation with probability $p(0\le p\le 1)$, otherwise continuing the vacation until its completion. If the system is empty when a vacation ends, the server waits for a patience period before starting a new vacation. Service station failures occur during service, and interrupted service resumes after repair. We derive the Laplace transform expressions for the transient queue length probabilities and recursive formulas for the stationary queue length distribution. In addition, cost optimization models for the threshold N and the vacation length T are developed, both without and with an average waiting time constraint. Using the Particle Swarm Optimization algorithm, numerical examples under phase-type distributions illustrate how the probability p affects the optimal control policy. Full article

Endoplasmic reticulum (ER) stress is a common state of cellular adversity experienced by tumor cells under unfavorable conditions such as hypoxia, nutrient deprivation, and oncogene activation. As the most conserved signaling branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1α (IRE1α)- X-box-binding protein 1 (XBP1) pathway plays a central role in sustaining tumor cell survival, driving malignant progression, and remodeling the tumor microenvironment (TME). XBP1, the terminal transcription factor of this pathway, finely orchestrates tumor cell fate through both its canonical and non-canonical functions. This review systematically summarizes the dual mechanisms of XBP1 in cancer: within cancer cells, XBP1 promotes proliferation, metastasis, and chemoresistance via metabolic reprogramming, anti-apoptotic proteins, and DNA repair; within immune cells (macrophages, dendritic cells, T cells), XBP1 fosters an immunosuppressive microenvironment, while also modulating cancer-associated fibroblasts, endothelial cells, and osteoclasts. Despite its therapeutic promise, several major unresolved questions remain, including the precise molecular switch governing XBP1’s pro-tumorigenic versus anti-tumorigenic functions, the functional divergence between XBP1u and XBP1s isoforms in different cellular contexts, and the lack of reliable predictive biomarkers for patient stratification. Key translational challenges involve the on-target toxicity of systemic XBP1/IRE1α inhibition due to its essential roles in normal tissues, the cell-type-specific and context-dependent effects that complicate therapeutic outcomes, and the limited selectivity and off-target effects of current inhibitors, as well as compensatory activation of other UPR branches that may drive adaptive resistance. Finally, this review discusses XBP1-targeted therapeutic strategies, including small-molecule inhibitors, nucleic acid-based drugs, immunotherapeutic combination approaches, and XBP1-based tumor vaccines, and provides perspectives on future research directions, aiming to establish a theoretical foundation for the development of more effective and precise XBP1-targeted therapies for tumorigenesis and cancer progression. Full article

CLEC3B (C-type lectin domain family 3 member B), also known as tetranectin (TN), is a secreted trimeric protein containing a C-type lectin-like domain (CTLD). Located on chromosome 3p21.31. CLEC3B maintains organismal homeostasis through roles in immune regulation, angiogenesis, and musculoskeletal biology. Genetic studies demonstrate that CLEC3B deficiency impairs tissue repair, bone mineralization, and fibrinolytic balance. Altered CLEC3B expression is linked to cardiovascular disease progression, autoimmune susceptibility, and cancer prognosis. This review synthesizes CLEC3B’s biological functions and evaluates its translational potential: circulating CLEC3B as a prognostic and diagnostic biomarker; tissue-resident CLEC3B as a predictive marker for therapeutic response; and CLEC3B-related pathways as candidate therapeutic targets for potential amenable to replacement or inhibition strategies. We identify critical research gaps to guide future investigations, including limited structural data, ambiguous glycan specificity, incomplete proteolytic network mapping, and lack of validated disease models. Collectively, these gaps currently preclude definitive therapeutic claims. Full article

Background/Objectives: Stem cells with the ability to differentiate into other cell types and self-renewal afford a powerful apparatus for the healthcare system to replace and rejuvenate damaged tissues and organs in the treatment of various diseases. For the last few decades, stem cell therapy (SCT) has evolved from being an experimental approach to a recognized clinical treatment. SCT and regenerative medicine have garnered tremendous attention and become prominent tools, especially in treating chronic and acute disease and addressing organ failures, and in their repair and replacement, which are directly associated with human health, life, and longevity. Methods: In this review, after providing a brief history and need for the SCT, the employed delivery techniques utilizing various biomaterials, as well as recent developments in nanotechnological methods, are presented. It is focused on the current literature for the recent progress of stem cell therapy and tissue engineering for the application fields in neurological, ophthalmological, cardiovascular, orthopedic, and oncology, followed by the challenges associated with their applications. Results: In addition to safety concerns, challenges such as uncontrollable differentiations, genetic and epigenetic instability, limited cell survival and integration, immunological rejections, scaling and manufacturing drawbacks, as well as unpredictable behaviors and clinical limitations were reviewed. Conclusions: Future aspects with respect to regenerative medicine and tissue engineering, gene editing and personalized therapies, immunomodulation and anti-inflammatory applications, as well as neuroregeneration and treatment of neurodegenerative disorders are reflected. Full article

Against the backdrop of the advancing Transportation Power Strategy, long and large tunnels face critical challenges in ensuring the safety and efficiency of transportation scheduling due to their harsh environment, complex traffic network, and the need for coordination among multiple types of vehicles. Addressing the shortcomings of existing research—such as the disconnection between path planning and dynamic environments, insufficient coordination between timetables and paths, and incomplete conflict management—this paper constructs a comprehensive optimization model for the scheduling of construction vehicles in tunnel traffic networks. Firstly, integrating the improved social force model with the BPR function, an adaptive social force-BPR path planning model with a collision compensation mechanism is proposed, and the weights of sub-items are optimized using the improved AHP algorithm. Secondly, a constraint system covering paths, spatio-temporal logic, and three types of conflicts (crossing conflicts, head-on conflicts, and congestion conflicts) is established, and a bi-objective function of “minimum total scheduling time” and “minimum number of conflicts” is designed. Combined with the improved NSGA-II algorithm, the collaborative optimization of departure intervals and paths is realized. In particular, a conflict entropy repair operator is introduced to quantify the conflict chaos through node conflict entropy and vehicle conflict entropy, and the scheduling strategy is accurately adjusted based on the logic of “priority ranking-dynamic delay” to balance conflict resolution and efficiency loss. Finally, a case verification is carried out relying on a tunnel topological network with 30 nodes and 41 edges. The experimental results show that the optimal repulsion coefficient k_f of the social force model is 20, and the maximum departure interval of 8 min is the best configuration after introducing the repair operator. At this time, the total scheduling time is 136 min, and the total number of conflicts is only 2, completely avoiding high-risk head-on conflicts and congestion conflicts. The research outputs a vehicle scheduling scheme, enriches the theory of tunnel traffic scheduling, and provides scientific and feasible technical support for the coordinated scheduling of construction vehicles in long and large tunnels. Full article

Ring finger protein 126 (RNF126) is a RING-type E3 ubiquitin ligase that has recently emerged as a multifaceted regulator of cellular homeostasis, stress adaptation, and disease progression. Through its structurally distinct zinc-finger and catalytic RING domains, RNF126 orchestrates substrate recognition and ubiquitin transfer, generating diverse ubiquitin linkages with both proteolytic and nonproteolytic functions. Initially characterized as a component of the protein quality control (PQC) machinery, RNF126 cooperates with chaperones such as BAG6 and UBQLN1 to eliminate mislocalized and misfolded proteins, thereby maintaining proteostasis. Beyond PQC, RNF126 plays pivotal roles in DNA damage response pathways by regulating homologous recombination, non-homologous end joining, checkpoint signaling, and genome stability through substrates, including MRE11, Ku80, RNF168, and 14-3-3σ. Genetic studies have further demonstrated its importance in embryogenesis and male fertility, and accumulating evidence has identified RNF126 as a critical driver of malignancy in multiple cancers. RNF126 promotes tumor progression by degrading or modulating key regulators, such as p21, PTEN, p53, PDKs, and LKB1, thereby enhancing proliferation, metabolic reprogramming, anoikis resistance, metastasis, and chemo/radioresistance. Intriguingly, RNF126 exhibits context-dependent functions, acting as an oncogene or tumor suppressor depending on the tissue type and substrate selection. In addition to cancer, RNF126 has been implicated in neurodegeneration, cardiac pathology, antiviral immunity and adaptive immune regulation. This review summarizes the current knowledge of RNF126 structure, ubiquitin signaling mechanisms, physiological functions, and pathological roles, while discussing emerging therapeutic strategies and future challenges for targeting RNF126 in precision medicine. Full article

When an individual A is accused of having committed a morally impermissible action X, it is generally accepted that they may invoke three types of defenses to mitigate, or even eliminate, their moral responsibility (or at least the fittingness of blame): justifications, excuses, and exemptions. However, another consideration—one that does not prima facie fall under any of these three types of defenses—also appears capable of influencing moral responsibility: the passage of time. A might argue that, although they did indeed commit the morally impermissible action X, the fact that it occurred twenty years ago partially absolves them from responsibility. This idea, which underlies several legal principles—such as statutes of limitations, rehabilitation, and sentence reduction—raises underexplored philosophical issues. In this paper, we argue that the passage of time does not constitute an autonomous moral defense. Rather, it is morally relevant only insofar as it makes possible certain transformations—including psychological reform, repentance, and processes of moral repair—capable of modifying the normative conditions under which it is appropriate to hold an agent to account. Accordingly, the attenuation of diachronic responsibility is best understood not as a direct consequence of temporal distance itself, but as a consequence of changes in those normative conditions. Full article

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

Jellyfish stings are the most common type of marine life injuries. However, at present, the treatment measures against jellyfish stings are mostly empirical and supportive, with uncertain therapeutic outcomes, and there is a lack of specific antidotes based on the toxic mechanism of jellyfish venom in clinical practice. In our previous study, polyphenol epigallocatechin-3-gallate (EGCG) was found to neutralize the toxicity of jellyfish Nemopilema nomurai venom (NnV) in vivo and in vitro. Herein we further demonstrated that EGCG exerted its antagonistic effect against NnV through inhibiting the oxidative stress, pro-apoptotic proteins, and systemic inflammatory responses. Subsequently, we constructed a polyethylene glycol (PEG)-EGCG/tetracycline hydrochloride (HTC) co-loaded micellar nanocomplex in order to enhance the stability and bioavailability of EGCG in vivo, which successfully integrated the membrane-repair function of PEG, the enzyme inhibitory effect of HTC and the antioxidant properties of EGCG. Notably, this micellar nanocomplex demonstrated significant protective effects against both functional damage and pathological alterations in a non-lethal NnV-envenomed mouse model. When administered 1 h after NnV envenomation, EGCG (40 mg/kg), HTC and PEG-EGCG (containing 40 mg/kg EGCG) only partially improved abnormal blood biochemical indicators and moderately alleviated histopathologic damage, and PEG-EGCG/HTC containing merely 8 mg/kg EGCG completely mitigated the toxic reactions in envenomed mice. In the preventive regimen, the administration of EGCG, HTC or PEG-EGCG 30 min before exposure showed no significant improvement in abnormal blood biochemical indicators and histopathologic damage, while PEG-EGCG/HTC could still significantly improve the functional impairments and histopathologic damage of the heart and liver in NnV-envenomed mice. These findings suggest the clinical translational potential of PEG-EGCG/HTC against jellyfish envenomation. Full article

Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), advanced pT stage (p = 0.0003) and L1 status (p = 0.0019) in testicular seminoma, high grade (p < 0.05), advanced pT (p < 0.0001), and high UICC stage (p = 0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p = 0.0396), and nodal metastases in papillary thyroid cancer (p = 0.0332). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored. Full article

Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed “regenerative inflammation,” in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF–IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions. Full article

Pancreatic ductal adenocarcinoma (PDAC) is molecularly characterized by near-universal KRAS mutations and recurrent alterations in TP53, CDKN2A, and SMAD4. Gene fusions are exceptionally rare and have not been established as canonical drivers of PDAC. We report a case of metastatic PDAC harboring an EIF3E::RSPO2 gene fusion in the absence of detectable KRAS or other common driver mutations. A 48-year-old female was diagnosed with stage IV PDAC via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Comprehensive molecular profiling using the Oncomine Precision Assay GX5 revealed no pathogenic single-nucleotide variants, indels, or copy number variations. However, an EIF3E::RSPO2 fusion, predicted to be a gain-of-function alteration, was identified as the sole genomic alteration. Immunohistochemistry showed retained mismatch repair protein expression and preserved SMAD4. Although RSPO2 fusions have been described in preclinical colorectal cancer models and are well-established activators of the Wnt signaling pathway in this setting, their clinical occurrence in PDAC remains poorly documented. This finding indicates a KRAS wild-type tumor with a potential KRAS-independent oncogenic mechanism that may involve aberrant Wnt/β-catenin signaling and raises the possibility of a rare, biologically distinct PDAC subset. Comprehensive genomic profiling in advanced PDAC may uncover actionable non-canonical drivers with therapeutic implications. Full article

Following spinal cord injury (SCI), a complex lesion scar forms at the injury site that matures and remodels over weeks, profoundly influencing neural repair and functional recovery. This lesion consists of a fibrotic scar at its core surrounded by an astrocytic scar (or border). While the astrocytic scar has been extensively studied for decades, the fibrotic scar has only recently emerged as a critical player in post-injury pathophysiology. Fibrotic scarring plays a dual role: it contributes to tissue stabilization and limits secondary damage, yet its persistence can pose a barrier that inhibits axonal regeneration and hinders recovery. Despite growing interest, key aspects of fibrotic scar formation and function remain poorly understood. This review synthesizes the current knowledge of fibrotic scarring after SCI, including its temporal progression, cellular composition, molecular mechanisms, and interactions with other cell types at the injury site, and we discuss emerging therapeutic strategies targeting fibrosis. We further highlight critical knowledge gaps and outline future directions to define how fibrotic scarring shapes the injury microenvironment and influences neural repair. Full article

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

Background/Objectives: Chronic wounds remain a formidable clinical challenge due to the suboptimal efficacy of conventional delivery systems and therapeutics. Textilinin-1, a venom-derived Kunitz-type serine protease inhibitor, has previously established its profile as a potent hemostatic agent. However, its potential as a multifunctional biopharmaceutical for wound management remains largely untapped. This study evaluates the pharmacological effects of Textilinin-1 in preclinical models of cutaneous wound repair. Methods: We employed an integrated platform comprising bioinformatics, in vitro cellular assays, and in vivo murine excisional wounds and a pilot porcine proof-of-concept model to assess the wound healing-promoting effects of Textilinin-1 and explore associated cellular responses associated with key stages of the wound healing cascade. Results: Textilinin-1 was associated with multiple cellular responses relevant to tissue repair. It attenuated M1-like inflammatory activation and showed preliminary growth-inhibitory activity against Staphylococcus aureus under the tested conditions. Concurrently, it enhanced the proliferative and migratory capacity of fibroblasts, endothelial cells, and keratinocytes, which are key cellular targets for wound closure. In pre-clinical pilot porcine and rodent models, Textilinin-1 treatment was associated with accelerated wound contraction and improved structural tissue quality. Conclusions: Our findings provide preclinical evidence that Textilinin-1 may promote cutaneous wound repair and modulate cellular responses relevant to key stages of the wound healing cascade. These results support further investigation of Textilinin-1 as a candidate for wound repair applications. Future studies are required to define its precise molecular mechanisms, evaluate its efficacy in chronic or otherwise compromised wound models, and optimize its topical formulation or hydrogel-based delivery. Full article