Search Results (117)

Effective drug delivery in oncology is challenged by a hierarchy of biological barriers—from abnormal vasculature and dense stroma to cellular immunosuppression and specialized interfaces like the blood–brain barrier. This review provides a contemporary analysis of smart nanoformulations through the lens of a rational, stage-gated design pipeline. We first deconstruct the solid tumor microenvironment as a multi-tiered obstacle (systemic, stromal, cellular), establishing a barrier-specific foundation for nanocarrier design. The core of the review articulates an architectural toolkit, detailing how intrinsic nanoparticle properties precondition in vivo identity via the protein corona, which in turn informs the selection of advanced ligands for cellular targeting and programmed intracellular trafficking. This integrated framework sets the stage for exploring sophisticated applications, including endogenous and externally triggered responsive systems, bio-orthogonal activation, immuno-nanoformulations, and combination strategies aimed at overcoming multidrug resistance. By synthesizing these components into a cohesive design philosophy, this review moves beyond a catalog of advances to offer a blueprint for engineering next-generation nanotherapeutics. We critically assess the translational landscape and contend that this hierarchical design approach is essential for developing more effective, personalized, and clinically viable cancer treatments. Full article

Non-long terminal repeat (Non-LTR) retrotransposons are mobile genetic elements that replicate through a “copy-and-paste” mechanism, enabling their expansion within the genome. Aberrant activation of these elements can induce genomic instability, elicit cellular stress responses, and activate inflammasome signaling, leading to tissue injury and disease. The central process of sterile inflammation involves the release and recognition of damage-associated molecular patterns (DAMPs), endogenous molecules that initiate inflammatory responses and form a common basis for many sterile inflammatory disorders. Recent studies have identified non-LTR retrotransposons as key endogenous triggers of DAMP-like signaling that drive sterile inflammation in both neuronal and non-neuronal tissues, contributing to the development of neurodegenerative and other chronic inflammatory diseases. In this review, we summarize recent advances in understanding how non-LTR retrotransposons, particularly LINE and SINE elements, influence sterile inflammation and disease pathogenesis. We highlight how their mobilization reshapes genomic architecture and gene regulation, and how the resulting signaling cascades promote chronic inflammation, immune dysregulation, and tissue injury. We also discuss emerging therapeutic strategies aimed at suppressing retrotransposon activity or interrupting downstream inflammatory signaling for treating sterile inflammation-related diseases. Full article

Produced from the parenchymatous tissue of the stem pith of Tetrapanax papyrifer, the material known as pith paper served as a distinctive support medium for Chinese export paintings during the 19th and early 20th centuries. Today, it is commonly found in collections worldwide. Due to its inherently fragile structure, conservation interventions are often necessary. However, the material’s chemical composition and deterioration mechanisms remain poorly understood, which not only complicates treatment decisions but also undermines preventive conservation efforts. This study presents a systematic investigation into the anatomical structure and ageing behaviour of pith paper using a multi-analytical approach. Optical and scanning electron microscopy revealed a preserved honeycomb-like cellular architecture composed of thin-walled, entirely of non-lignified parenchyma cells, which contributes to the material’s mechanical fragility. Artificial ageing experiments showed a significant loss of flexibility, increased yellowing, and a decline in pH with ageing time. Infrared spectroscopy identified molecular changes consistent with cellulose chain scission, with decreases in O–H and C–O–C absorptions revealing acid-hydrolysis-driven breakdown, while colourimetry pointed to the formation of chromophoric degradation products. These findings offer a foundational understanding of pith paper’s vulnerabilities and provide essential insights for the development of informed conservation and storage strategies. Full article

Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting adhesion, migration, angiogenesis, immune evasion, and metastasis. Their structural heterogeneity supports either subtype- or context-dependent functions. This review combines current studies of PGs in BC according to their classification into intracellular, cell-surface, pericellular, extracellular, and small leucine-rich PGs and a range of non-classical PGs. A literature-driven approach to focus on molecular mechanisms and clinical correlations will demonstrate how PGs respond with collagens, growth factors, cytokines, and proteolytic enzymes in order to modulate the ECM and affect therapy resistance. Indeed, PGs including syndecans, glypicans, perlecan, versican, biglycan and decorin showed the potential to be promoters or suppressors of cancer, with local effects on invasion, and have a significant modulating effect on BC subtypes or the prognosis and therapeutic response and may potentially serve as new biomarkers for stratification and liquid biopsy candidates. Furthermore, PGs appear to modulate the tumour immune landscape, are involved in the development of metastatic niches, and underlie signalling pathways like Wnt or TGFβ in a subtype-dependent manner, extending their translational prospects and therapeutic utility. PGs, taken together, seem to be major modulators of BC, with particular relevance for precision medicine. Full article

Background/Objectives: Protein kinase C-δ (PKC-δ) is a pivotal regulator of cellular signalling, and its dysregulation contributes to oncogenesis. While certain isolated PKC-δ domains have been crystallised, the full-length architecture and interdomain interactions remain largely unresolved, limiting mechanistic insight and the design of selective modulators. We aimed to define the full-length, inactive conformation of PKC-δ and identify accessible, functionally relevant binding sites for ligand discovery. Methods: We generated a consensus structural model of full-length inactive PKC-δ using multi-template comparative modelling guided by established inactivity markers. Molecular docking was used to predict ligands targeting the C2 domain, which were subsequently validated in breast cancer cell models, including wild-type and C2 domain-overexpressing lines. Results: Analysis of the model revealed the architecture of the C2/V5 interdomain space, providing a structural rationale for regulation of the nuclear localisation signal (NLS). Docking identified two ligand classes: ligand 1 engaged a C2 domain surface oriented toward the C2/V5 pocket, while ligand 2 targeted the C2 domain phosphotyrosine-binding domain (PTD). Experimental validation in breast cancer cell models demonstrated that both ligands reduced cell viability; ligand 1 showed enhanced effects in C2-overexpressing cells, consistent with predicted accessibility, whereas ligand 2 partially counteracted the C2 domain-induced viability phenotype, likely via interference with PTD-mediated interactions. Conclusions: Full-length structural context is essential for identifying accessible, functionally relevant binding sites and understanding context-dependent kinase regulation. Integrating computational modelling with phenotypic validation establishes a framework for selective PKC-δ modulation, offering insights to guide ligand discovery, improve isoform selectivity, and inform strategies to mitigate kinase inhibitor resistance in precision oncology. Full article

Seasonal human coronaviruses (HCoVs), including HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, circulate globally in an epidemic pattern and account for a substantial proportion of common cold cases, particularly in infants, the elderly, and immunocompromised individuals. Although clinical manifestations are typically mild, these HCoVs exhibit ongoing antigenic drift and have demonstrated the potential to cause severe diseases in certain populations, underscoring the importance of developing targeted and broad-spectrum vaccines. This review systematically examines the pathogenesis, epidemiology, genomic architecture, and major antigenic determinants of seasonal HCoVs, highlighting key differences in receptor usage and the roles of structural proteins in modulating viral tropism and host immunity. We summarize recent advances across various vaccine platforms, including inactivated, DNA, mRNA, subunit, viral-vectored, and virus-like particle (VLP) approaches, in the development of seasonal HCoV vaccines. We specifically summarize preclinical and clinical findings demonstrating variable cross-reactivity between SARS-CoV-2 and seasonal HCoV vaccines. Evidence indicates that cross-reactive humoral and cellular immune responses following SARS-CoV-2 infection or vaccination predominantly target conserved epitopes of structural proteins, supporting strategies that incorporate conserved regions to achieve broad-spectrum protection. Finally, we discuss current challenges in pathogenesis research and vaccine development for seasonal HCoVs. We propose future directions for the development of innovative pan-coronavirus vaccines that integrate both humoral and cellular antigens, aiming to protect vulnerable populations and mitigate future zoonotic spillover threats. Full article

Three-dimensional (3D) bioprinting is increasingly explored as a strategy for myocardial repair and regenerative medicine. Conventional 3D casting often yields heterogeneous cellularization, slow electromechanical maturation, and inadequate vascularization; by contrast, bioprinting places cells and biomaterials in predefined architectures to program alignment, stiffness, vascular pathways, and electrical coupling that better recapitulate native myocardium. This review focuses on cardiac-specific advances in 3D bioprinting. We compare major platforms (jetting, light-based, extrusion, and volumetric) and their trade-offs for cardiac applications; distill bioink design principles trending toward natural–synthetic hybrids, including conductive and shape-morphing components; and outline practical characterization readouts spanning rheology, print fidelity, swelling/degradation, and cardiac function. We also summarize cell sources and co-culture strategies. Applications surveyed include cardiac patches, engineered tissues, chambered constructs, and organoids. Finally, we discuss current limitations and potential future directions for 3D bioprinting cardiac tissues. Collectively, recent advances position 3D bioprinting to accelerate the realization of in vivo-like engineered heart tissues. Full article

Ascoviruses (AVs) are obligate intracellular pathogens that target the larval and pupal stages of lepidopteran insects, specifically moth caterpillars. AVs are unique among viruses in their (i) transmission mode, (ii) gross pathology, (iii) virion ultrastructure, (iv) genomic architecture featuring a remarkable combination of genes, and (v) ability to reprogram host cell death and lipid biosynthetic pathways to generate virion-containing vesicles (VCVs). The metabolically active acellular VCVs are repurposed to complete virogenesis and to facilitate dissemination by endoparasitoid wasps. Since their discovery in the late 20th century, research has focused on these distinctive traits and, to a lesser extent, their potential for biological control. Among AV proteins are the large DNA-binding P64 family, inhibitor of apoptosis-like proteins (IAPs), executioner caspase and caspase-like proteins, and lipid-modifying enzymes, which together drive their novel cytopathology. This review synthesizes current knowledge of AV biology and proposes a framework for understanding VCV formation by integrating predicted viral protein functions with host cellular pathways, including the ceramide–sphingosine-1-phosphate rheostat and apoptosis. Full article

Phyllodes tumors, also known as cystosarcoma phyllodes, represent a rare and complex category of fibroepithelial neoplasms that primarily affect the breast. These tumors are characterized by their unique histological architecture, which resembles leaf-like structures, as suggested by the etymology of the term “phyllodes,” derived from the Greek word “phyllodes,” meaning “leaf-like”. The World Health Organization (WHO) has classified these tumors into three distinct categories—benign, borderline, and malignant—based on various histopathological criteria, including cellular atypia, mitotic activity, and stromal overgrowth. With a peak incidence occurring between the ages of 40 and 52, these tumors primarily affect women and constitute 0.3% to 1% of all breast tumors. Imaging modalities currently employed (mammography, ultrasound, and MRI) play a crucial role in the initial assessment of breast masses. Histopathological characteristics, such as stromal cellularity and mitotic activity, and immunohistochemical markers, like Ki-67 and p53, are important in the diagnosis, categorization, treatment plans, and prognosis of breast phyllodes tumors. Surgical intervention, with the goal of achieving complete excision of the tumor along with adequate margins, is the primary treatment option. Adjuvant therapies, such as radiotherapy, may be considered but are still debatable. Understanding the nuances of these tumors is crucial for healthcare professionals, as they present unique challenges in both diagnosis and treatment. Full article

Transposable elements (TEs), once regarded as genomic “junk,” are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions—especially retrotransposons such as LINE-1, Alu, and SVA—on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration. Full article

The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial–Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including WNT, Notch, Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF). Specifically, we discuss how these regulatory networks control the precise locations and functions of crypt cell types that are necessary to achieve cellular organization and homeostasis in the normal colon crypt. In addition, we detail how the crypt’s hierarchical structure is profoundly perturbed in colorectal cancer (CRC) development. Tumorigenesis appears to be driven by LGR5+ cancer stem cells (CSCs) and the hyperproliferation of TA cells as colonocytes undergo metabolic reprogramming. Goblet cells lose their secretory phenotype, while REG4+ Paneth-like cells foster SC niches. Tumor microenvironment is also disrupted by upregulation of M cells and by tumor-immune crosstalk that is promoted by tuft cell expansion. Moreover, the presence of enteroendocrine cells in CRC has been implicated in treatment resistance due to its contribution to tumor heterogeneity. These cellular changes are caused by the disruption of homeostasis signaling whereby: overactivation of WNT/β-catenin promotes stemness, dysregulation of Notch inhibits differentiation, suppression of BMP promotes hyperproliferation, and imbalance of FGF/WNT/BMP/NOTCH enhances cellular plasticity and invasion. Further discussion of emerging therapies targeting epithelial markers and regulatory factors, emphasizing current development in novel, precision-based approaches in CRC treatment is also included. Full article

N, as plants’ most essential nutrient, profoundly shapes root system architecture (RSA), with LRs being preferentially regulated. This review synthesizes the intricate molecular mechanisms underpinning N sensing, signaling, and its integration into developmental pathways governing LR initiation, primordium formation, emergence, and elongation. We delve deeply into the roles of specific transporters (NRT1.1, nitrate transporter 2.1 (NRT2.1)), transcription factors (Arabidopsis nitrate regulated 1 (ANR1), NLP7, TGACG motif-binding factor (TGA), squamosa promoter-binding protein-like 9 (SPL9)) and intricate hormone signaling networks (auxin, abscisic acid, cytokinins, ethylene) modulated by varying N availability (deficiency, sufficiency, excess) and chemical forms (NO₃⁻, NH₄⁺, organic N). Emphasis is placed on the systemic signaling pathways, including peptide-mediated long-distance communication (CEP—C-terminally encoded peptide receptor 1 (CEPR1)) and the critical role of the shoot in modulating root responses. Furthermore, we explore the emerging significance of carbon–nitrogen (C/N) balance, post-translational modifications (ubiquitination, phosphorylation), epigenetic regulation, and the complex interplay with other nutrients (phosphorus (P), sulfur (S)) and environmental factors in shaping N-dependent LR plasticity. Recent advances utilizing single-cell transcriptomics and advanced imaging reveal unprecedented cellular heterogeneity in LR responses to N. Understanding this sophisticated regulatory network is paramount for developing strategies to enhance nitrogen use efficiency (NUE) in crops. This synthesis underscores how N acts as a master regulator, dynamically rewiring developmental programs through molecular hubs that synchronize nutrient sensing with root morphogenesis—a key adaptive strategy for resource acquisition in heterogeneous soils. Full article

Myxoma virus (MYXV) is a leporipoxvirus that causes lethal disease in Leporids. Hares and rabbits belong to the Leporidae family and are believed to have had a common ancestor 12 million years ago. After seventy years of contact with European hares without causing mortalities or disease manifestation, a recombinant MYXV infected Iberian hares (Lepus granatensis) causing high mortalities. Like all poxviruses, MYXV encodes a wealth of immune modulators required for successful virulence that also mediate host species jumping, for example, into hares. Here, we summarize the data of known MYXV immune modulators, their cellular functions, and their effects on European rabbits. Additionally, we suggest that the critical restrictions MYXV would encounter in colonizing a potentially new host species stem from their interactions with the host’s innate immune environment. Lastly, we synthesize our understanding of some poxvirus genome architectural features that might have facilitated the host species jump of MYXV into hares from rabbits. Full article

Sleep is a vital biological function governed by neuronal networks in the brainstem, hypothalamus, and thalamus. Disruptions in these circuits contribute to the sleep disturbances observed in neurodegenerative disorders, including Parkinson’s disease, epilepsy, Huntington’s disease, and Alzheimer’s disease. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and abnormal protein accumulation adversely affect sleep architecture in these conditions. The interaction among these pathological processes is believed to modify sleep-regulating circuits, consequently worsening clinical symptoms. This review examines the cellular and molecular mechanisms that impair sleep regulation in experimental models of these four disorders, emphasizing how oxidative stress, neuroinflammation and synaptic dysfunction contribute to sleep fragmentation and alterations in rapid eye movement (REM) sleep and slow-wave sleep (SWS) phases. In Parkinson’s disease models (6-OHDA and MPTP), dopaminergic degeneration and damage to sleep-regulating nuclei result in daytime somnolence and disrupted sleep patterns. Epilepsy models (kainate, pentylenetetrazole, and kindling) provoke hyperexcitability and oxidative damage, compromising both REM and SWS. Huntington’s disease models (R6/2 and 3-NP) demonstrate reduced sleep duration, circadian irregularities, and oxidative damage in the hypothalamus and suprachiasmatic nucleus. In Alzheimer’s disease (AD) models (APP/PS1, 3xTg-AD, and Tg2576), early sleep problems include diminished SWS and REM sleep, increased awakenings, and circadian rhythm disruption. These changes correlate with β-amyloid and tau deposition, glial activation, chronic inflammation, and mitochondrial damage in the hypothalamus, hippocampus, and prefrontal cortex. Sleep disturbances across these neurodegenerative disease models share common underlying mechanisms like oxidative stress, neuroinflammation, and mitochondrial dysfunction. Understanding these pathways may reveal therapeutic targets to improve both motor symptoms and sleep quality in neurodegenerative disorders. Full article

The fusion of keel petals is a defining trait of Papilionoideae flowers, contributing to floral architecture and promoting self-pollination but hindering hybridization in crops like soybean. Here, we investigated the cellular and molecular basis of keel petal fusion in Glycine max (L.) Merr. cv. Jack using anatomical and transcriptomic approaches. Microscopy revealed that keel petal fusion involves marginal cell reshaping and postgenital adhesion with defective cuticle continuity, consistent with fusion modes in other Papilionoideae species. Comparative transcriptome analysis between fused and unfused petal stages identified 23,328 differentially expressed genes, with lipid and cuticle metabolism genes showing coordinated downregulation during fusion. A set of 384 keel-enriched genes was identified, among which a previously uncharacterized gene, KPEG1 (Keel Preferential Expression Gene 1), was preferentially expressed in fused keel petals. Protein interaction network analysis revealed that KPEG1 co-expresses with epigenetics-related genes, suggesting a regulatory role in fusion through chromatin-mediated mechanisms. These findings uncover the cellular dynamics and transcriptional reprogramming underlying keel petal fusion in soybean and provide a candidate regulator for further functional studies. Full article