Search Results (706)

Oligonucleotide therapeutics represent an expanding class of medicines that can regulate gene expression, RNA processing, protein translation, immune signaling, and biomolecular recognition through sequence-specific or structure-dependent mechanisms. Despite clinical progress, their application remains constrained by nuclease degradation, rapid clearance, inefficient tissue and cellular delivery, endosomal sequestration, off-target activity, immune recognition, and mechanism-specific requirements for target engagement. Chemical modification is central to oligonucleotide therapeutic development because it can mitigate some of these limitations while influencing target affinity, protein binding, pharmacokinetics, and intracellular activity. This review examines chemical modification strategies to improve the biological stability and functional performance of therapeutic oligonucleotides and is organized around major classes of chemical modification, including phosphate and backbone-linkage modifications, sugar and conformational modifications, backbone-replacement analogs, and conjugation-based approaches. Rather than presenting these chemistries as uniformly beneficial, this review emphasizes that the same modification can be enabling in one therapeutic mechanism and disruptive in another, so its value cannot be judged apart from the modality and molecular architecture in which it is placed. Clinically successful oligonucleotide designs are likely to rely on combinations of chemical features, including modified backbones, modified sugars, stereochemical control, terminal stabilization, and ligand- or formulation-based delivery strategies. Understanding how these features interact is essential to develop more predictable and mechanism-appropriate oligonucleotide therapeutics. Full article

Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins—BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms. Full article

Substance use disorders (SUDs) are increasingly associated with systemic inflammatory, neuroendocrine, and cardiometabolic dysregulation; however, the biological signatures underlying distinct substance-use patterns remain incompletely characterized. This study compared biomarker profiles among healthy controls and clinical groups comprising alcohol-associated polysubstance users (A + PS), non-alcohol substance users (PS-A), and alcohol-associated polysubstance users with comorbid post-traumatic stress disorder (PTSD+). Plasma levels of interleukin-6 (IL-6), C-reactive protein (CRP), cortisol, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were evaluated through comparative, multivariate, dose–response, and receiver operating characteristic (ROC) curve analyses. All clinical groups exhibited significantly increased IL-6, CRP, cortisol, and NT-proBNP levels compared with controls, indicating systemic physiological dysregulation associated with substance exposure. Among the evaluated biomarkers, IL-6 demonstrated the most robust and consistent performance across all analytical approaches. Multivariate regression identified alcohol consumption as an independent predictor of IL-6 elevation (p = 0.0003), while dose–response analysis revealed progressive increases in IL-6 according to alcohol consumption severity. ROC analysis further demonstrated that IL-6 exhibited the highest discriminatory performance (AUC = 0.844), outperforming CRP, cortisol, and NT-proBNP in distinguishing substance-using individuals from controls. Collectively, these findings were able to identify IL-6 as a central biomarker associated with substance-related systemic inflammatory dysregulation and support its translational potential as a sensitive indicator of physiological burden associated with chronic alcohol and substance exposure. Full article

During long-term service, asphalt pavements undergo environmental stress and ageing, which cause cracking, rutting, and other distresses and raise maintenance costs. Polyurethane (PU) has high mechanical strength, elastic recovery, and ageing resistance due to its unique molecular structure. As an asphalt modifier, PU has been reported to improve high-temperature stability, moisture resistance, and durability. However, PU and asphalt differ greatly in polarity, density, viscosity, and phase structure, and these differences often lead to segregation and phase separation. The prepolymer method can mitigate these compatibility limitations by adjusting molecular weight, terminal-group activity, and soft/hard segment ratio before dispersion, chain extension, crosslinking, and post-curing in asphalt, resulting in better compatibility and more controllable processing. This review discusses PU soft/hard segment structures, asphalt composition, prepolymer synthesis and curing, microstructural evolution, pavement performance, storage stability, and use in other systems to clarify modification mechanisms and potential applications. This critical review aims to clarify material–reaction–process–performance relationships within the prepolymer route, with scope limited to molecular design, preparation mechanisms, performance, storage stability, and representative engineering applications. Future work should consider real service conditions and build multiscale evaluation frameworks that jointly optimise prepolymer design, processing, storage stability, and pavement performance, helping translate laboratory findings into low-carbon, long-life road materials that can be produced at scale. Full article

VISA/MAVS is a central signaling hub that links viral RNA sensing to type I interferon production and inflammatory responses. Because of its potent signal-amplifying capacity, VISA activity must be precisely controlled: insufficient activation compromises antiviral defense, whereas excessive or spontaneous activation can drive chronic inflammation and autoimmune disease. Recent studies have revealed a complex regulatory network governing VISA signaling, involving post-translational modifications, dynamic protein interactions, selective degradation pathways, metabolic cues, and intrinsic inhibitory mechanisms that collectively determine its activation threshold, signaling duration, and downstream output. In this review, we discuss the molecular mechanisms that regulate VISA activation, signal propagation, signal termination, and quiescence maintenance under resting conditions. We propose that immune homeostasis is achieved not through a simple on–off switch, but through continuous regulation of the VISA signalosome life cycle. This framework provides an integrated view of VISA and offers new insights into the molecular mechanisms underlying immune homeostasis. Full article

Background and Objectives: The method of femoral canal opening during intramedullary fixation may influence the biological response to surgery. The aim of this study was to compare the early biological responses associated with mechanical canal opening and manual canal opening during Proximal Femoral Nail Antirotation (PFNA) fixation in patients with pertrochanteric femoral fractures, with a particular focus on inflammation, coagulation, organ dysfunction, and bone metabolism. Materials and Methods: This single-centre prospective randomised study consisted of 60 participants (50 women) with a mean age of 80.33 ± 11.13 years, who were randomly assigned to either manual femoral canal opening (n = 30) or mechanical canal opening (n = 30). Outcomes were assessed preoperatively and postoperatively during a 72 h follow-up period. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov ID NCT07648719; registration date: 15 June 2026; study start: 1 March 2025). Results: Across all participants, surgery was associated with a significant decrease in haemoglobin levels, calcium, and estimated glomerular filtration rate, while fibrinogen, urea, creatinine, CRP (C-reactive protein), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) significantly increased postoperatively. Patients in the mechanical canal opening group demonstrated significantly higher postoperative levels of leukocytes (p = 0.002), CRP (p = 0.001), NT-proBNP (p = 0.002), fibrinogen (p = 0.026), activated partial thromboplastin time (p = 0.035), urea (p = 0.001), and creatinine (p = 0.018), as well as greater reductions in haemoglobin (p < 0.001), compared with the manual canal opening group. Bone turnover markers also differed between groups: postoperative bone-specific alkaline phosphatase levels were significantly higher in the mechanical canal opening group (p = 0.001), whereas the increase in total procollagen type 1 N-terminal propeptide was more pronounced in the manual canal opening group (p = 0.045). Conclusions: The method of femoral canal opening during PFNA fixation significantly influences early postoperative systemic inflammation, coagulability, organ stress, and bone turnover dynamics. Manual opening of the femoral canal was associated with lower early systemic and bone stress biomarker responses compared with mechanical canal opening. Whether these differences translate into improved clinical outcomes, particularly in elderly patients with limited physiological reserve, remains to be determined. Full article

Background/Objectives: Geranylgeraniol (GGOH), an isoprenoid intermediate of the mevalonate pathway, regulates bone cell viability and function, particularly by mitigating cellular toxicity induced by nitrogen-containing bisphosphonates (N-BPs). Despite this, its role in osteoporosis remains underexplored. This scoping review synthesises evidence on the effects of GGOH in in vitro and in vivo models of osteoporosis. Methods: PubMed, Scopus, and Ovid were searched using GGOH- and osteoporosis-related terms. Primary studies evaluating GGOH exposure in cellular or animal osteoporosis models were eligible. Twenty-nine studies met the inclusion criteria. Results: In vitro findings demonstrate that GGOH reverses N-BP-induced depletion of geranylgeranyl pyrophosphate, restoring protein prenylation which is essential for osteoclast and osteoblast survival, cytoskeletal organisation, and differentiation. GGOH reduced osteoclast apoptosis, restored nuclear factor of activated T-cells 1 and carbonic anhydrase II expression, and prevented N-BP-associated suppression of bone resorption. In osteoblasts and mesenchymal stem cells, GGOH improved viability, upregulated osteogenic markers including runt-related transcription factor 2, alkaline phosphatase, collagen type I, and bone morphogenetic proteins, and rescued mineralisation impaired by alendronate or zoledronate. Independent of N-BPs, GGOH exerted divergent effects on osteoclasts, by inhibiting osteoclastogenesis or promoting retinoic acid receptor-mediated bone resorption and attenuating zoledronate protection in vascular calcification settings in a model-specific manner. In vivo, dietary GGOH supplementation improved trabecular and cortical bone parameters and reduced serum C-terminal telopeptide of type I collagen in obese mice, indicating suppression of bone resorption. Conclusions: Overall, although GGOH shows osteoprotective potential, its capacity to antagonise N-BP efficacy limits systemic co-administration. Current evidence suggests that local delivery may warrant future investigation as a strategy to mitigate N-BP-induced skeletal toxicity. However, studies evaluating bone tissue exposure, pharmacokinetics, and clinically achievable concentrations are required before this approach can be translated. Full article

Members of the Picornaviridae family of viruses have single-stranded positive-sense RNA genomes, and are conventionally considered to contain a single open reading frame (ORF) preceded by a long 5′ untranslated region (UTR). The 5′UTR contains an internal ribosomal entry site (IRES) that mediates end-independent initiation of translation of ORF1, resulting in synthesis of a polyprotein that is proteolytically processed to yield the individual structural and nonstructural proteins. However, recent studies indicate that the dogma that picornavirus genomes contain a single ORF (ORF1) is an oversimplification, and that members of many picornavirus genera contain an additional ORF that is translated to yield an accessory protein that may influence pathogenicity and tissue specificity. This review summarizes the structural organization of picornavirus genomes that contain a second ORF. Most commonly, these ORFs overlap the 5′-end of ORF1, but they may also be wholly distinct from ORF1 or located entirely within it in a different reading frame. Ribosomal access to these alternate ORFs has been shown or is hypothesized to depend on a remarkable variety of non-canonical translation mechanisms, including ribosomal recruitment by a second IRES, leaky scanning after IRES-mediated internal ribosomal entry, cap-independent initiation, frame-shifting and termination–reinitiation. Full article

Understanding gene expression requires integrating multiple regulatory layers, because transcript abundance does not necessarily correspond to translational activity or protein abundance. Ribosome profiling and proteomics help distinguish increased translation from ribosome stacking or translational buffering, but no de facto standard framework exists for unsupervised integration of transcriptome, translatome, and proteome profiles. Here, we propose a four-dimensional tensor decomposition-based unsupervised feature extraction approach for tri-omics integration. We applied higher-order singular value decomposition to transcriptome, Ribo-seq, and proteome profiles measured under branched-chain amino acid starvation. The resulting singular value vectors captured relationships among the three omics layers, including a component consistent with ribosome stacking, where transcriptome and translatome signals increased while proteome signals decreased, and another consistent with translational buffering, where proteome variation was suppressed despite transcriptome and translatome changes. Gene selection identified 1781 genes associated with ribosome stacking and 227 genes associated with translational buffering. Enrichment analyses linked the former to translation, post-translational protein modification, RNA polymerase II transcription, cell cycle regulation, endoplasmic reticulum protein processing, ubiquitin-mediated proteolysis, and stress-related pathways, and the latter to ribosome, translation elongation and termination, spliceosome, immune- and stress-related pathways, and ribosomopathy-associated diseases. Robustness analyses indicated that the results were not substantially affected by the duplicated proteome replicate or missing-value handling. Under the tested settings, comparison with MOFA+ and mixOmics suggested that our approach more directly extracted components interpretable as ribosome stacking and translational buffering. These results demonstrate that tensor decomposition-based unsupervised feature extraction is useful for identifying functionally relevant gene clusters from tri-omics data. Full article

S-adenosyl-L-homocysteine hydrolase (SAHH) is an evolutionarily conserved enzyme present in eukaryotes, bacteria, and archaea. As the rate-limiting enzyme in the methionine cycle, it catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine (SAH) to adenosine and homocysteine, thereby modulating the S-adenosylmethionine/SAH ratio and cellular methylation potential. Dysregulation of SAHH activity is causally linked to cancer, cardiovascular disorders, and neurodegenerative conditions. This review systematically examines the biological distribution, catalytic mechanisms, structural architecture, and regulation of SAHH across diverse species. We highlight lineage-specific adaptations—including C-terminal truncation, a 40-residue substrate-binding-domain insertion, and a His-Phe molecular gate—that fine-tune substrate preference, cofactor affinity, and thermostability, with metal ions and NAD⁺ serving as key modulators of activity and conformational dynamics. These variations exemplify an evolutionary trade-off between catalytic efficiency and structural rigidity, particularly pronounced in archaeal and thermophilic orthologs. Collectively, these insights underpin the enzyme’s multifaceted translational value: SAHH serves as a therapeutic target for diverse diseases (e.g., cancer, viral infections, tuberculosis), a source of diagnostic/prognostic biomarkers (e.g., plasma homocysteine and SAH/SAM ratio), and a versatile biocatalyst for synthesizing pharmaceutical-grade adenosine and its derivatives. By integrating mechanistic, structural, and evolutionary perspectives, this review establishes a unified framework that explains these functional adaptations and their translational implications. This framework guides the rational development of SAHH-targeted inhibitors, diagnostic tools, and engineered biocatalysts, with broad applications in precision medicine and biotechnology. Full article

Insect antimicrobial peptides (AMPs) are classically viewed as terminal effectors of innate immunity, but emerging evidence suggests that some can also shape defined neural states. In this Review, we argue that insect systems provide a powerful framework for resolving immune–brain communication at the level of individual peptide effectors, because genetically tractable innate-immune pathways allow pathway activation to be distinguished from peptide-specific effector function. Rather than surveying AMP families exhaustively, we focus on representative cases in which peptide identity, source, and timing can be linked to sleep, memory-related plasticity, and responses to acute injury. These studies show that the neural consequences of AMP induction cannot be inferred from pathway activation alone, but require peptide-level analysis of effector identity, cellular context, and exposure logic. This perspective also raises the question of translational potential. At present, direct biomedical development of endogenous insect AMPs in neural contexts remains limited, whereas more tangible applied interest has centered on insect venom peptides that share AMP-like physicochemical features. We therefore discuss insect venoms separately from endogenous AMP physiology. Venom peptides are not physiological equivalents of endogenous insect AMPs, but represent evolutionarily diversified AMP-like templates for scaffold discovery, mechanistic probing, and therapeutic engineering. Together, this review develops a peptide-level perspective on insect neuroimmune biology while highlighting insect venoms as a valuable, but highly constrained, source of templates for biomedical discovery. Full article

Skeletal muscle dysfunction (SMD) is a critical extrapulmonary comorbidity in chronic obstructive pulmonary disease (COPD), contributing to exercise intolerance, poor quality of life, and increased mortality. Building upon and extending the disuse model, this review synthesizes evidence establishing COPD-induced SMD as a distinct myopathy with intrinsic disease drivers. Its pathophysiology is driven by a self-reinforcing network: mitochondrial energetic crisis featuring bioenergetic failure and dysregulated dynamics, chronic oxidative stress and inflammation fueling catabolic drive via ubiquitin–proteasome system activation, and epigenetic dysregulation through alterations in key histone deacetylases (HDACs) and microRNA expression, which collectively orchestrate a pro-atrophic phenotype. We further explore how these molecular insights are translating into novel diagnostic tools, including circulating biomarkers like myomiRs and C-terminal agrin fragment, and imaging techniques such as shear wave elastography. Although exercise training remains the cornerstone of management, its limited efficacy underscores the need for adjunctive and targeted therapies. We discuss promising strategies from pharmacological and nutritional support to emerging agents targeting specific pathways, including the IL-36 receptor, lipoprotein-associated phospholipase A2, aryl hydrocarbon receptor, and mitsugumin 53. Effective management of COPD-related SMD will hinge on a precision medicine framework, leveraging biomarker-guided stratification to deploy personalized combinatorial interventions aimed at preserving muscle mass and function. Full article

MXenes, a rapidly expanding family of two-dimensional transition-metal carbides and nitrides, are increasingly viewed as strong candidates for defense-oriented multifunctional systems because they combine metallic conductivity, surface tunability, mechanical flexibility, and solution processability within a lightweight platform. Unlike conventional metals, ceramics, and semiconductors, which usually optimize one or two parameters at the expense of density, brittleness, or integration compatibility, MXenes offer a rare opportunity to coordinate electromagnetic, mechanical, thermal, and sensing functions within one material family. Different from existing reviews that focus on laboratory-level record performance or single-function optimization, this review presents an innovative deployment-oriented perspective and fills the research gap of systematic military-oriented evaluation for MXenes. In this review, we examine MXenes from a deployment-oriented perspective rather than through isolated record values. We first summarize their formation chemistry and major synthesis routes, including HF and in-situ HF etching, bifluoride and alkaline methods, molten-salt strategies, electrochemical approaches, and precursor-free chemical vapor deposition. We then discuss the principal levers of property regulation, focusing on composition design, surface-termination control, and heterostructure engineering, and show how these strategies shape the performance envelopes relevant to shielding, stealth, impact response, energy storage, and sensing. This review constructs a full-chain analytical framework from synthesis, property regulation to military application and deployment challenges for the first time. Finally, we identify the main barriers to translation, especially manufacturing inconsistency, termination heterogeneity, oxidation and interfacial degradation, and limited application-level validation, and outline the most realistic paths toward deployable defense technologies. Full article

Clinical genomics has traditionally focused on protein-coding variation, yet many pathogenic mechanisms arise through alterations in RNA processing, stability, localisation, translation, and surveillance. Prior reviews have addressed individual RNA layers, splicing, non-coding RNAs, RNA therapeutics, or RNA diagnostics in isolation. This review presents an integrated, mechanism-matched framework linking RNA-level disease mechanisms to diagnostic reasoning and therapeutic selection across all major RNA layers, offering a practical resource for clinical geneticists and translational researchers. I examine how splicing defects, pseudoexon inclusion, polyadenylation disruption, RNA editing loss, untranslated-region variants, premature termination codons, stop-loss variants, RNA-binding protein dysfunction, non-coding RNA dysregulation, altered codon usage, ribosome stalling, and surveillance pathway failure, including nonsense-mediated decay, nonstop decay, and no-go decay, each create distinct and mechanistically addressable disease states. A central argument of this review is that treatment selection must be mechanism-matched rather than gene- or variant-class-based: splice defects may require antisense oligonucleotide (ASO)-mediated correction or small-molecule splice modulation; toxic transcripts may require ASO- or siRNA-mediated silencing; haploinsufficiency may require mRNA replacement or transcript rescue; premature termination codons are candidates for readthrough only when transcript and protein context are favourable. I further argue that RNA sequencing, long-read transcriptomics, allele-specific expression analysis, and functional assays are essential for both diagnosis and therapeutic stratification. The framework described here moves clinical variant interpretation beyond descriptive classification toward mechanism-based, RNA-centric precision medicine. Full article

Interferon (IFN)-resistant cell clones 3Cl8 and 3γR8, isolated from wild-type Friend erythroleukemia cells 745A were characterized to identify the resistance defect. The 3Cl8 cell clone is resistant to type I IFNs and sensitive to type II IFN, whereas 3γR8, derived from 3Cl8, is resistant to both type I and II IFNs. Here, we report that no activation of the JAK-STAT pathway is detected after IFN treatment of resistant cells. Interestingly, the absence of major transcripts of the IFNAR2 receptor chain has been observed in type I IFN-resistant cells, and a point mutation relative to the IFNGR2 receptor chain (β chain) has been identified in type II IFN-resistant cells, inducing a frameshift leading to premature termination of translation. In addition, we have identified a new polymorphism of the murine IFNAR1 chain and possibly the presence of a murine IFNAR2b transmembrane, non-transducing chain in 745A cells, similar to that observed in humans and differing from previous reports on other murine systems. Full article