Search Results (674)

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota–drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal–placental–infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course. Full article

Background: Acute limb ischemia (ALI) is a vascular emergency characterized by abrupt limb hypoperfusion, ischemia–reperfusion injury, and a high risk of thromboinflammatory and organ complications. Complement activation has been implicated in endothelial dysfunction, glycocalyx injury, and ischemia–reperfusion damage, but the clinical relevance of ongoing terminal complement blockade in patients presenting with ALI remains unclear, highlighting a gap between mechanistic understanding and real-world clinical outcomes. Methods: A retrospective cohort study was performed using the TriNetX federated research network. Adult patients with ALI were identified and stratified according to ongoing treatment with the C5 inhibitors eculizumab or ravulizumab. Outcomes included ischemic stroke, venous thrombosis, pulmonary embolism, arterial embolism, thrombotic disorders, acute kidney injury (AKI), and the composite outcome major adverse cardiovascular events (MACE) within 31 days. Propensity score matching was performed for demographic characteristics, cardiovascular comorbidities, complement-associated diseases and medications. Results: After propensity score matching, 112 patients remained in each cohort. Compared with matched controls, patients receiving C5 inhibition had a significantly higher risk of venous thrombosis (27.9% vs. 13.7%; p < 0.001), AKI (18.9% vs. 9.4%; p = 0.001), MACE (50.0% vs. 35.1%; p = 0.001), and thrombotic disorders (46.7% vs. 31.3%; p = 0.001). Time-to-event analyses confirmed significantly lower event-free survival for venous thrombosis (HR 2.3), AKI (HR 2.1), MACE (HR 1.6), and thrombotic disorders (HR 1.7). No significant differences were observed for ischemic stroke, pulmonary embolism, or arterial embolism. Conclusions: In patients with ALI, ongoing treatment with eculizumab or ravulizumab was not associated with an apparent reduction in short-term thromboinflammatory or cardiovascular complications. Instead, the observed outcome pattern suggests persistent vulnerability in this clinically uncommon but increasingly relevant high-risk population, although substantial residual confounding by indication and disease severity remains likely. These findings support further investigation of complement-targeted therapy, endothelial injury, and short-term vascular outcomes in ALI, and emphasize the translational relevance of linking mechanistic insights with clinical data to inform risk stratification and management strategies in this population. Full article

Plants are constantly exposed to a wide range of abiotic stresses that have significant negative impacts on growth and yield. Plant acclimation to these stresses is governed by integrated classical phytohormone and plant peptide hormone signalling networks that control the ability of a plant to survive and adapt to extreme environments. Classical phytohormones, including abscisic acid, auxins, gibberellins, cytokinins, jasmonates, salicylic acid, brassinosteroids, and the recently recognised phytomelatonin, act in concert with peptide-based plant hormones, among which C-terminally encoded peptides (CEPs) play prominent roles in coordinating stress perception, signal transduction, and adaptive responses throughout the plant. These integrated networks control stomatal behaviour, photosynthesis, osmolyte and antioxidant levels, root architecture, and energy metabolism, thereby helping plants maintain homeostasis and optimise survival while sustaining minimal growth under unfavourable conditions. Under stressful conditions, these networks do not operate in isolation but form highly dynamic, context-dependent regulatory circuits in which each physiological process is simultaneously regulated by multiple hormones acting through convergent and overlapping signalling pathways. Phytomelatonin has emerged as a particularly important integrative node within these networks, functioning both as a potent direct antioxidant through sequential ROS-scavenging catabolite cascades and as a bidirectional regulator of classical phytohormone signalling under diverse abiotic stresses. New technologies in the fields of transcriptomics, proteomics, phosphoproteomics, metabolomics, and systems biology have provided new information on the dynamic relationships between classical phytohormones and plant peptide hormones, revealing candidate regulatory nodes and transcription factor networks that mediate stress adaptation at molecular, biochemical, and physiological levels. However, it is important to distinguish between correlative associations identified through omics profiling and causal regulatory relationships validated through rigorous genetic and biochemical experimentation, as most omics-derived candidates remain to be functionally established. Empirical studies demonstrate how these networks can be used to improve crops by increasing stress tolerance through modulating classical phytohormone and plant peptide hormone signalling, including through exogenous phytomelatonin application, CRISPR-mediated hormone pathway editing, and CEP pathway manipulation, to produce resilient cultivars without reducing yields. Although these advances represent significant progress, challenges remain, including the inherent complexity and redundancy of the networks, context-dependence and severity-dependence of hormonal responses, the persistence of a significant translational gap between laboratory findings and field application, and incomplete mechanistic understanding of peptide hormone roles under combined stress conditions. Addressing these challenges will require integrative multi-omics approaches, higher-order computational modelling, and rigorous field-based functional validation alongside emerging tools such as synthetic biology and precision breeding. Full article

Protein synthesis is a crucial biosynthetic process in all organisms, including plants. The integrity of the translational machinery, especially ribosomes, can be compromised during rapid cell division in ontogenesis or in response to environmental stress. In this study, Northern blotting was employed to analyze total RNA from various angiosperms, focusing on small 5′- and 3′-terminal 18S rRNA fragments. Stem-loop array RT-PCR was employed to map the cleavage sites within the target regions. Severe stress, such as extreme drought, induced the accumulation of three distinct 18S rRNA fragments across diverse angiosperm taxa, indicating that this phenomenon is likely universal. In rapidly dividing cells, such as those found in in vitro callus cultures and germinating wheat embryos, high levels of discrete 5′-terminal fragments were observed, while 3′-terminal fragments were absent. The stem-loop array RT-PCR mapping identified specific sites of 18S rRNA strand breaks. Structural annotation of the 3D model of the plant 40S subunit revealed spatial clustering of these sites in proximity to the RPS6 binding region. Notably, wheat cultivars that are tolerant to osmotic stress exhibited significantly higher levels of 18S rRNA fragmentation than sensitive cultivars. This suggests a regulatory mechanism rather than a mere byproduct of apoptotic-like regulated cell death. Additionally, fragmented ribosomes were gradually eliminated during embryo maturation, indicating a process of programmed functional ribophagy. Our findings suggest that a potential inability of plant tissues to selectively retain functional ribosomes might contribute to a decline in generative potential. Monitoring the integrity of the translational machinery could improve breeding efficiency and aid in preserving long-term stored germplasm. Full article

Deploying unmanned aerial vehicles (UAVs) cooperatively with legged robots for disaster response and inspection requires autonomous docking on miniature walking platforms. This study addresses the problem of landing a foldable quadrotor onto the back of a trotting wheel-legged robot ($300\times 180$ mm) and subsequently taking off while carrying it as a payload. Four tightly coupled challenges distinguish this task from conventional mobile-platform landing: (i) an extremely small landing surface, (ii) gait-induced periodic vibrations at $2.5$ Hz, (iii) continuous platform translation at $0.3$–$0.8$ m/s, and (iv) surface docking that requires simultaneous position and attitude matching rather than mere point tracking. The proposed framework comprises four components: (1) a novel single-servo crank-rocker folding mechanism that reduces the folded body footprint by 48.5% and the maximum linear dimension from 590 mm to 309 mm (↓47.6%) compared with the prior dual-servo design; (2) a staged Continuous Fast Nonsingular Terminal Sliding Mode (CFNTSM) controller combined with a Gait-Frequency-Aware Finite-time Extended Observer (GFA-FEO); (3) a Feature-wise Linear Modulation Soft Actor-Critic (FiLM-SAC) residual reinforcement-learning policy conditioned on physical states and mission phase, with an adaptive trust weight $\lambda \left(t\right)$; and (4) a payload-adaptive takeoff strategy with parameter hot-switching to handle the twofold mass increase. Extensive Monte Carlo simulations and ablation studies across three experiment groups demonstrate that the proposed hierarchical framework achieves sub-centimetre (<10 mm) position accuracy and <3° attitude matching on a walking platform. Quantitatively, the full method reduces docking RMSE by 42% relative to the model-based CFNTSM + GFA-FEO controller without residual RL (4.2 vs. 7.2 mm) and reduces post-lock takeoff RMSE by 63% through FEO hot-switching (16.2 vs. 44.2 mm). Full article

Background: Myocardial fibrosis (MF) is a dynamic remodeling process characterized by excessive extracellular matrix (ECM) deposition, fibroblast activation, and dysregulated matrix turnover. Although initially reparative, persistent fibrotic remodeling promotes myocardial stiffening, electrical instability, and progressive cardiac dysfunction across diverse cardiovascular diseases. Circulating biomarkers reflecting collagen synthesis, degradation, proteolytic regulation, and inflammatory activation have emerged as potential tools for assessing fibrotic activity and risk stratification. Methods: This targeted narrative review was based on manually guided searches of PubMed and Scopus, supplemented by citation chaining and inclusion of landmark mechanistic and translational studies. Publications addressing myocardial extracellular matrix remodeling, circulating fibrosis-related biomarkers and imaging-derived fibrosis phenotypes were selected for qualitative synthesis. Results: Myocardial fibrosis reflects interconnected inflammatory, neurohormonal, oxidative, and extracellular matrix remodeling pathways. Among circulating biomarkers, C-terminal propeptide of procollagen type I (PICP) showed the most consistent association with myocardial collagen burden and adverse outcomes, whereas carboxy-terminal telopeptide of type I collagen (CITP), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), galectin-3, osteopontin, soluble suppression of tumorigenicity 2 (sST2), and natriuretic peptides provided more context-dependent signals. Standalone interpretation remains limited by restricted cardiac specificity, renal dysfunction, systemic inflammation, assay heterogeneity, and lack of standardized thresholds. Integration with cardiac magnetic resonance (CMR)-derived late gadolinium enhancement (LGE), T1 mapping, and extracellular volume (ECV) may improve biological and structural phenotyping. Conclusions: Circulating biomarkers capture complementary dimensions of myocardial remodeling but cannot replace structural imaging. We propose an updated, hypothesis-generating biomarker–imaging framework integrating inflammatory activation, collagen turnover, matrix quality, hemodynamic stress, and structural imaging to support phenotypic stratification and future validation of antifibrotic strategies. Full article

Introduction: Heat shock proteins (HSPs) are stress-responsive molecular chaperones that are frequently dysregulated in cancer and contribute to tumorigenesis, invasion, metastasis, immune interactions, and resistance to therapy. Distinct HSP families, including HSP27, HSP60, HSP70, HSP90, and HSP110, promote malignant progression through complementary effects on apoptosis regulation, mitochondrial function, proteostasis, and stabilization of oncogenic signaling pathways. This makes HSPs attractive therapeutic targets. Their coordinated roles within stress-adaptive chaperone networks further garner interest in targeting multiple HSP families in cancer therapy. Discussion: Preclinical and clinical studies have established multiple HSP families as promising anticancer targets; however, clinical translation of HSP-directed therapies has been challenged by toxicity, compensatory heat shock responses, and resistance mechanisms. Many N-terminal HSP90 inhibitors have shown clinical utility but have also highlighted the need for alternative approaches, including C-terminal inhibition, HSP70-directed therapies, and rational combination strategies targeting compensatory survival pathways. Emerging inhibitors targeting HSP27, HSP60, and HSP110, as well as HSP-based vaccines, further expand therapeutic opportunities across cancer subtypes. Collectively, these approaches highlight the growing therapeutic relevance of disrupting interconnected HSP networks rather than targeting individual chaperones in isolation. Conclusions: Future development of heat shock protein-targeted therapies will require a deeper understanding of HSP-mediated chemoresistance. Clinical trial and drug development approaches may benefit from combination or multi-targeted strategies that simultaneously disrupt multiple components of the heat shock protein network to achieve more durable anticancer responses. Full article

Cadmium (Cd) is a typical heavy metal pollutant in aquatic environments. It enters fish through the gills, digestive tract, and body surface, and accumulates mainly in the liver and kidneys, with species- and tissue-specific distribution. Cadmium triggers apoptosis by inducing oxidative stress, calcium imbalance, and DNA damage. These signals are integrated and amplified by the mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/AKT, and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, ultimately activating three downstream apoptotic execution pathways: the death receptor, mitochondrial, and endoplasmic reticulum stress pathways. These three pathways form an interactive network through molecular nodes such as BH3 interacting domain death agonist (Bid), Ca²⁺, c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP), synergistically amplifying the apoptotic effect, with the mitochondrial pathway playing a central role. Cadmium-induced apoptosis is dose-dependent: low concentrations activate protective responses, whereas high concentrations strongly promote apoptosis. Current research gaps remain regarding dynamic pathway crosstalk, chronic low-dose effects, species differences, and fish-specific apoptotic molecules (e.g., caspase-12 homologs). Future studies should focus on constructing multidimensional response maps, clarifying pathway activation thresholds and interaction contributions, and developing composite protective strategies based on Nrf2 activators, metal chelators, and antioxidants, thereby promoting translation into ecological risk assessment and aquaculture pollution control. Full article

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design. Full article

Background/Objectives: Ventilator weaning imposes profound hemodynamic stress, unmasking cardiopulmonary vulnerability. Since conventional predictors of post-tracheostomy weaning failure remain elusive, biomarker-driven risk stratification offers a translational approach. We evaluated the prognostic utility of admission N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an early triaging tool for weaning failure and explored its therapeutic implications alongside optimal tracheostomy timing. Methods: In this large-scale retrospective cohort study, we analyzed 707 critically ill patients who underwent tracheostomy in a medical intensive care unit. We investigated the association between baseline NT-proBNP levels—measured as a molecular surrogate of cardiovascular stress at ICU admission; echocardiographic parameters; and weaning outcomes. Multivariable logistic regression analysis was utilized to identify independent pathophysiological predictors associated with weaning failure. Results: Patients experiencing weaning failure exhibited significantly elevated admission NT-proBNP levels compared to those successfully weaned (3077.0 vs. 1410.0 pg/mL, p < 0.001). High admission NT-proBNP (>3271 pg/mL) was independently associated with an increased risk of weaning failure (adjusted odds ratio [aOR] 2.86, 95% confidence interval [CI] 1.81–4.53, p < 0.001). Conversely, an early clinical intervention—tracheostomy performed within 10 days of mechanical ventilation initiation—was associated with a significantly lower risk of weaning failure (aOR 0.55, 95% CI 0.35–0.87, p = 0.010). Furthermore, elevated biomarker levels strongly correlated with prolonged intensive care unit stays and higher 90-day mortality. Conclusions: Admission NT-proBNP serves as a powerful biomarker associated with cardiopulmonary vulnerability from the earliest stages of critical illness. Integrating this diagnostic biomarker with interventional strategies like optimal tracheostomy timing has significant prognostic implications. This biomarker-guided approach facilitates personalized risk stratification from ICU admission, potentially optimizing weaning pathways for mechanically ventilated patients. Full article

The increasing application of industrial robots in modern production systems contrasts with a persistently high programming complexity that requires specialized know-how and creates substantial entry barriers. This work addresses this problem by introducing a systematic approach to robot programming based on Large Language Models (LLMs) that automatically translates natural language task descriptions into executable robot programs. The solution follows a two-stage pipeline: in Stage 1, the LLM structures the input into coherent process steps, and in Stage 2 these process steps are transformed into C++ code using a high-level function library. The performance is evaluated in simulation for the automated electrical cabinet assembly use case with terminal blocks, which is a significant element of various production processes. The architecture, based on the Robot Operating System 2 (ROS2) and MoveIt2, further integrates a standardized AutomationML-based configuration management for dynamic parameter handling and persistent state storage. A graphical user interface visualizes intermediate results, enables manual interventions and enables a simple operation for potential users without programming experience. The evaluation of the presented approach shows a success rate of up to 95% for interpreting natural language instructions and generating code in the application scenario focused. The system reliably recognizes object attributes and correctly executes complex assembly instructions. In general, this work demonstrates how modern LLMs can bridge the semantic gap between human intent and robotic code for industrial applications. The developed high-level abstraction makes the system usable for non-programmers, highlights the potential for intuitive robot programming, and simultaneously identifies concrete technical challenges. Full article

Two-dimensional (2D) MXene membranes have emerged as a focal platform for ionic separations owing to their exceptional mechanical flexibility, intrinsic hydrophilicity, abundant surface terminations, and high electrical conductivity. This review summarizes recent advances in MXene-based membranes, with an emphasis on structural engineering strategies and their translation to ion-separation applications. We first outline representative fabrication routes for MXene membranes. We then discuss how separation mechanisms can be understood and deliberately tuned across four key scenarios: monovalent/monovalent ion separations, monovalent/multivalent ion separations, anion/cation separations, and heavy-metal ion separations. Finally, we highlight outstanding challenges and future opportunities, aiming to provide actionable guidance for the rational design and scalable manufacturing of high-performance MXene membranes for ionic separations. Full article

Accurate inverse kinematics for rehabilitation robotic arms remains challenging because of strong nonlinearity, multiple feasible joint configurations, and strict joint-limit constraints. Inspired by the cooperative construction, adaptive exploration, and collective information-sharing behaviors of beavers, this study develops an improved biomimetic beaver behavior optimizer (IBBO) for optimization-based inverse kinematics solving. In the proposed framework, biologically inspired cooperative search is translated into an engineering-oriented numerical strategy through four complementary mechanisms: a strict elitist replacement with rollback to preserve population fitness consistency, a momentum-inspired information transfer scheme to accumulate effective search directions, a lightweight memetic coordinate-wise local search to strengthen late-stage exploitation, and an adaptive builder–disturbance schedule to progressively shift the search from exploration to refinement. The optimization capability of IBBO is first evaluated on the CEC2017 benchmark suite, where it demonstrates competitive accuracy and robustness. It is then applied to inverse kinematics solving for representative rehabilitation robotic arms by minimizing pose errors under joint constraints. The experimental results show that IBBO can consistently generate feasible joint solutions with improved terminal pose accuracy and stable convergence compared with baseline metaheuristics. Beyond numerical improvement, this study provides a biomimetic optimization framework that transfers beaver-inspired cooperative behaviors into rehabilitation robotics, offering an effective computational approach for constrained inverse kinematics problems. Full article

Tomato (Solanum lycopersicum L.) is a globally important vegetable crop and a key model species for studying reproductive development in other Solanaceae members with edible fleshy fruits, such as eggplant, sweet and hot peppers, and Physalis spp. The morphogenesis and patterning of tomato floral organs fundamentally determine fruit yield and quality. Recent advances in high-throughput sequencing and gene editing have significantly deepened our understanding of the molecular network regulating tomato reproductive development. This process, from the transition of vegetative shoot apical meristem to the inflorescence meristem, forming floral meristems with primordia of sepals, petals, stamens, carpels, and fruits, is precisely coordinated by a genetic network involving homeobox and other types of transcription factors, along with signaling pathways. This review systematically outlines the core regulatory network, with an emphasis on the MADS-domain transcription factor family and its associated ABCDE model. Integrating insights from hormone signaling and mutant phenotypes, we summarize the maintenance of inflorescence meristem identity, the specification of floral meristems, and the morphogenetic patterns and core gene regulatory mechanisms for each floral whorl in tomato. We further extend this framework to the flower–fruit continuum, examining how carpel development, floral meristem termination, and ovule differentiation influence fruit morphology, locule number, pericarp structure, and metabolic traits. Finally, we discuss the integration of floral organ development with molecular design breeding and formulate a forward-looking research agenda that translates floral regulatory mechanisms to breeding strategies for yield, uniformity, and fruit quality. This synthesis provides a theoretical foundation and genetic resources for the genetic improvement of tomato flower architecture and its underlying regulatory mechanisms. Full article

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) possesses dual enzymatic functions, i.e., kinase and E3 ubiquitin ligase activities, orchestrating proliferation, survival, apoptosis, DNA damage response, and immune modulation. Recent genomic and mechanistic studies have revealed MAP3K1’s paradoxical, context-dependent roles as both an oncogene and a tumor suppressor. We discuss MAP3K1’s multidomain architecture, featuring an N-terminal RING and PHD domain (E3 ligase activity), a TOG domain (microtubule dynamics), and a C-terminal kinase domain, enabling the integration of c-jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) signaling pathways. MAP3K1 functions as a molecular switch balancing survival and apoptosis, with caspase-3 cleavage at Asp878 activating pro-apoptotic JNK/p38 signaling. Genomic analyses across >35 cancer types reveal MAP3K1 alterations at frequencies of <1–14%, highest in breast and endometrial cancers. These alterations show tissue specificity: loss-of-function mutations predominate in hormone receptor-positive breast cancer with a favorable prognosis, whereas gain-of-function mutations in melanoma activate oncogenic ERK signaling. MAP3K1 mutations predict response to mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors, with mutant cancers showing higher MEK inhibitor response than wild-type tumors. Despite substantial progress, critical gaps remain regarding MAP3K1’s E3 ligase substrates, context-dependent activity determinants, and therapeutic strategies. Addressing these through inhibitor development, biomarker validation, and mechanistic studies will accelerate potential clinical translation of MAP3K1 biology. Full article