Search Results (219)

Leaf-color mutants are crucial for elucidating chlorophyll metabolism mechanisms. Here, we identified yel, a stably inherited rice mutant with a dwarf and yellow-green leaf phenotype controlled by a single recessive nuclear gene. Using BSA-seq, we mapped the candidate causal gene to OsMPEC, encoding a magnesium protoporphyrin IX monomethyl ester cyclase with a G→T substitution. Multi-omics analysis revealed that the functional deficiency of OsMPEC protein—despite unchanged transcript levels—triggers global transcriptional repression of the chlorophyll metabolic network. This defect caused distinct metabolic consequences: impaired synthesis at the early stage (yel1) and toxic metabolite accumulation at the later stage (yel2). Furthermore, metabolic collapse induced systemic reprogramming of hormone signaling, shifting from pro-growth to stress and senescence modes. We propose that the yel phenotype is associated with a self-reinforcing inhibitory loop of “passive synthesis inhibition” and “active degradation acceleration.” This study clarifies OsMPEC’s role in chlorophyll homeostasis and demonstrates how a single genetic defect drives phenotype- through to network-level cascading effects. Full article

Endometriosis is a chronic, oestrogen-responsive inflammatory disease characterised by endometrial-like tissue outside the uterine cavity. Because retrograde menstruation is common, lesion establishment probably requires cellular competence and a permissive ectopic microenvironment. This hypothesis-driven narrative review evaluates fascin (FSCN1) as a candidate cytoskeletal effector and considers antecedent eutopic priming versus induction after ectopic adhesion. Functional evidence was integrated with a targeted public-data screen. Donor-level reanalysis of GSE179640 found no conclusive overall eutopic case–control difference and predominantly non-epithelial expression. Exploratory analysis of GSE203191 suggested higher FSCN1 expression within a HSPA6+ stromal subcluster in diagnosed cases, without a comparable epithelial signal or detectable increase in subcluster abundance. This small post hoc analysis remains hypothesis-generating. FSCN1 was absent from the published HECA stromal/macrophage differential-expression lists and was not prioritised by the 2023 endometriosis GWAS. The current evidence therefore argues against uniform epithelial or whole-eutopic overexpression but permits a lineage-restricted stromal state. Fascin participates in autophagy- and miR-145-sensitive invasion networks, although these pathways are pleiotropic. Validation requires cycle- and lineage-resolved tissue mapping, compositional controls, matched lesions, and direct FSCN1 perturbation. Fascin should currently be regarded as a candidate multi-marker component and preclinical target, not a validated biomarker or systemic therapeutic target. Full article

Reactive oxygen species (ROS) exert dual biological functions in plants. Though they form toxic byproducts of aerobic metabolism, ROS also serve as indispensable secondary messengers that orchestrate stress acclimation programs. For decades, plant physiologists operated under a pervasive assumption that constitutive and non-compartmentalized upregulation of antioxidant capacity would universally enhance abiotic stress tolerance. This long-standing dogma has now been thoroughly overturned. A growing body of evidence shows that sustained, global high antioxidant activity often impairs adaptation rather than helping it. In this review, we replace the simplistic “more antioxidants equal better tolerance” framework with a dynamic model of cellular redox homeostasis. We dissect three interconnected mechanisms though which unrestrained ROS scavenging generates deleterious phenotypic outcomes. First, indiscriminate clearance blunts transient ROS pulses and propagating ROS waves, the core signaling events acquired to trigger systemic acquired acclimation (SAA). Second, continuous antioxidant biosynthesis drains finite carbon skeletons, NADPH, and ATP pools, exacerbating evolutionary growth-defense resource trade-offs. Third, non-specific bulk ROS scavenging erases compartment-specific organellar retrograde signals, which rely on tightly controlled spatial and temporal ROS fluctuations. We concurrently define physiological boundary conditions where robust antioxidant activity remains vital for plant survival under extreme stress. Rather than advocating for the complete suppression of ROS detoxification, our analysis advocates context-dependent fine-tuning of redox signaling networks. We also summarize emerging precision redox monitoring and genetic engineering tools, and outline translational breeding pipelines to develop climate-resilient crops that balance stress survival and yield stability. This work delivers novel conceptual perspectives to advance fundamental plant redox biology. Full article

Singlet oxygen (¹O₂), a highly reactive oxygen species generated in illuminated chloroplasts, is a major contributor to photooxidative damage in plants, particularly under high-light stress. This review summarizes the major sites of ¹O₂ production, its damage mechanisms, and the antioxidant defense and scavenging strategies that limit ¹O₂ accumulation. Particular emphasis is placed on recent advances in ¹O₂-mediated signal transduction. EX1 and β-carotene-derived oxidation products have been proposed to act as key components in ¹O₂ perception and signaling, mediating signal transmission from distinct subchloroplast locations and contributing to a spatially coordinated ¹O₂ signaling network. Plants counteract ¹O₂-induced damage through a multilayered defense–perception–signal transduction system. The functional partitioning of ¹O₂ signaling between grana margins and grana cores, together with the coordinated action of multiple signaling molecules, provides important insights into the mechanisms of plant photoprotection and offers potential strategies for improving crop tolerance to photooxidative stress. Full article

The liver ranks among the peripheral organs exhibiting the most robust circadian rhythmicity, with glucose homeostasis, lipid metabolism, and bile acid turnover governed by tightly phased diurnal oscillations. Mitochondria execute these programs, their output coordinated with the hepatocyte circadian state. The mitochondrial network undergoes dynamic remodeling across the 24 h cycle, encompassing oscillatory changes in bioenergetics, fusion–fission balance, and quality control. This interplay is bidirectional: core clock components drive rhythmic remodeling via cyclin-dependent kinase 1/mitogen-activated protein kinase (CDK1/MAPK)-dependent phosphorylation of dynamin-related protein 1 (DRP1) and the NAD⁺–SIRT1/SIRT3 axis, while retrograde signals modulate clock amplitude and entrainment. Circadian disruption is associated with mitochondrial dysfunction implicated in MASLD onset and progression to MASH and HCC, though this evidence remains largely correlative and derives predominantly from rodent models. This review integrates clock–mitochondria coupling with metabolic liver disease. Restoring this coupling has been proposed as a candidate chronotherapeutic strategy, supported by preliminary rhythmicity data in primary human hepatocytes and a hepatocellular carcinoma cell line, though causal validation in healthy human liver is lacking. Time-restricted feeding, NAD⁺ precursors, PPAR agonists, and ACC inhibitors converge on clock-regulated pathways and may benefit from circadian-informed timing, though this remains unverified. Full article

Wallerian degeneration (WD), which occurs distal to peripheral nerve injury, is a tightly regulated process. Axonal degeneration during the onset of WD represents a self-destructive process that begins with an early phase and progresses to an execution phase characterized by fragmentation of axons and myelin sheaths. Efficient clearance of axonal and myelin debris, together with the reprogramming of Schwann cells and macrophages into a repair phenotype, constitutes a critical extrinsic prerequisite for successful axonal regeneration. In parallel, signaling molecules produced during WD trigger intrinsic responses in injured neurons that are essential for neuronal survival and the initiation of the regenerative program. This review provides an overview of the key events involved in WD, which are often studied separately, with the aim of elucidating their interrelationships and their impact on nerve regeneration. Such an integrated overview may aid in identifying molecular targets for the development of novel therapeutic strategies to enhance axonal regeneration. Full article

Background: Cholangiocarcinoma (CCA) is a rare and aggressive malignancy of the biliary tree. Renal metastasis represents an exceptionally rare event, reported in fewer than 0.5% of cases. Its clinical and imaging presentation may closely mimic benign renal conditions, particularly renal infarction, posing a significant diagnostic challenge. Case Presentation: We report the case of a 72-year-old man who initially presented with intense right-sided flank pain without urinary symptoms. Combined imaging findings, including absent Doppler signal on ultrasound and absent contrast uptake on contrast-enhanced ultrasound (CEUS) in two-thirds of the right renal parenchyma, led to an initial diagnosis of right renal infarction. Seven months later, re-evaluation prompted by macroscopic haematuria, significant weight loss, cholestatic syndrome, and markedly elevated CA 19-9 revealed an invasive renal tumour mass associated with biliary ductal dilatation. Renal biopsy with immunohistochemical analysis (CK7+, PAX8−, c-kit weakly positive) confirmed renal metastasis from extrahepatic cholangiocarcinoma. The patient’s clinical course was complicated by acute cholangitis, Clostridioides difficile enterocolitis, and upper gastrointestinal haemorrhage, requiring endoscopic retrograde cholangiopancreatography (ERCP) with biliary stenting, endoscopic ultrasound (EUS)-guided hepaticogastrostomy, and endoscopic haemostasis. Conclusions: A systematic review of the published literature identified only two previous dedicated case reports of renal metastasis from CCA, making this, to our knowledge, the third such case and the first involving an extrahepatic primary tumour presenting through its renal metastasis. This case highlights the diagnostic pitfall of mistaking hypovascular renal metastasis for renal infarction, the indispensable role of immunohistochemistry, and the importance of early percutaneous biopsy in avascular renal lesions without a confirmed thromboembolic aetiology. Full article

Coronary heart disease (CHD) is a global cardiovascular disease with high morbidity and mortality, and its complex pathological mechanism poses great challenges to clinical prevention and treatment. Paeoniflorin (PA), a monoterpene glycoside active ingredient from Ranunculaceae plants, has shown potential in cardiovascular protection, but its specific anti-CHD molecular targets and systematic regulatory networks remain unclear. In this study, a mouse model of CHD was established, and a multi-omics strategy combining label-free quantitative proteomics and metabolomics was adopted to explore the mechanism of PA in treating CHD. The results showed that PA significantly improved cardiac function, alleviated myocardial pathological injury and fibrosis, and regulated lipid metabolism in CHD model mice, with the high-dose group showing the optimal effect. Proteomic analysis identified 51 key differentially expressed proteins (DEPs) reversed by PA, which were mainly enriched in complement and coagulation cascades, and neutrophil extracellular trap formation pathways, with the C3-Cfd-C3aR signaling axis as the core hub. Further verification confirmed that PA could downregulate the expression of C3, Cfd, C3aR, and their downstream molecule BTK, thereby inhibiting myocardial inflammatory response and cardiomyocyte apoptosis. In addition, PA downregulated the expression of platelet activation markers ITGA2B/ITGB3. Metabolomic analysis revealed that PA reversed 57 abnormal metabolites in CHD mice, which were enriched in GABAergic synapse, retrograde endocannabinoid signaling and other pathways. Molecular docking confirmed that PA could stably bind to C3, Cfd, C3aR, BTK, and ITGA2B/ITGB3 with strong binding activity. In conclusion, PA exerts anti-CHD effects through a multi-target and multi-pathway synergism, mainly by targeting the C3-Cfd-C3aR axis to inhibit inflammation, apoptosis and platelet activation, and regulating metabolic disorders. This study provides experimental evidence and theoretical support for the clinical application of PA as a multi-target therapeutic drug for CHD. Full article

Distant Retrograde Orbits (DROs) and Near-Rectilinear Halo Orbits (NRHOs), as categories of Lagrange orbits, have been selected for the construction of future deep-space navigation constellations in the Earth-Moon space due to their unique orbital trajectories and dynamical characteristics. To obtain high-precision orbit and clock solutions, the orbit determination (OD) and time synchronization (TS) performance of DRO and NRHO based on Beidou Navigation Satellite System (BDS) L-band and Ka-band signals were analyzed. Considering the constraints of onboard resources and cost, it may be infeasible to establish Ka-band links with all BDS satellites. Therefore, multiple experiments with different link configuration schemes were designed. The results show that an orbit determination accuracy of about 500 m and the time synchronization accuracy of 50 ns can be achieved using only L-band observations. In contrast, much higher accuracy can be obtained with full Ka-band links, with orbit and clock accuracy reaching 80 m and 7 ns, respectively. Moreover, higher orbit and clock accuracies can be obtained with more Ka-band links based on L-band observations. Furthermore, with the addition of the DRO-NRHO links, the orbit determination and time synchronization performance of each scheme was further improved by 15%. And the orbit determination accuracy can be better than 65 m, while the time synchronization accuracy can be better than 5 ns. Although the analysis is based on BDS signals, the proposed framework is general in nature and can be extended to other GNSS-based or future space navigation systems, providing a reference for the design of high-precision cislunar navigation and timing architectures. Full article

Aberrant RNA splicing and metabolic reprogramming are defining hallmarks of cancer that were historically studied as parallel processes. Increasing evidence now reveals extensive crosstalk between these pathways, whereby RNA splicing reshapes metabolic circuits, and metabolic states reciprocally influence splice-site selection and spliceosome activity. In this review, we synthesize recent mechanistic insights into how splicing programs regulate metabolic adaptation across diverse cancer contexts. We discuss recurrent oncogenic mutations in spliceosomal components and dysregulation of RNA-binding proteins (RBPs) that drive alternative splicing events in key metabolic regulators, which promote metabolic plasticity required for tumor growth. We further examine how metabolites and nutrient-sensing pathways directly modulate splicing factor activity, spliceosome dynamics, and RNA processing. We also summarize a new mechanism of mitochondrial quality control mediated by retrograde signals from mitochondria to the spliceosome to enhance mitophagy of dysfunctional mitochondria. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Background/Objectives: Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis (PEP) is a clinically significant complication of ERCP, occurring in approximately 2–10% of general cases and at higher rates in high-risk patients. Early prediction of PEP risk may support timely intervention and improved patient management. This retrospective single-center study comparatively evaluated tabular clinical data, endoscopic image data, and multimodal fusion approaches for PEP prediction. Methods: Retrospective data collected from the Sindh Institute of Advanced Endoscopy and Gastroenterology were analyzed using machine learning and deep learning techniques. XGBoost(version 3.2.0) was applied to tabular clinical data, while EfficientNet-B0, ResNet50, and DenseNet201 were used for endoscopic image analysis. A multimodal contrastive learning (MMCL)-based framework combining ResNet50 image features with multilayer perceptron (MLP)-based tabular features was additionally implemented for binary PEP prediction. Class imbalance mitigation techniques, including data augmentation and balancing strategies, were applied during training. Model performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, F1-score, and precision. SHAP analysis was performed to identify important predictive features. Results: The tabular XGBoost model achieved the best predictive performance with an AUC of 0.95 and a sensitivity of 0.50, while five-fold cross-validation yielded an AUC of 0.79 and a sensitivity of 0.48. Among image-based models, ResNet50 achieved the highest performance, with an AUC of 0.76 and a sensitivity of 0.40. The multimodal model achieved an AUC of 0.57 and a sensitivity of 0.20. SHAP analysis identified cannulation time, ampulla type, and age as prominent features associated with PEP prediction. Conclusions: This exploratory study suggests that structured clinical data currently provide stronger predictive signals for PEP prediction than the available image and multimodal data within this limited cohort. The relatively low occurrence of PEP contributed to class imbalance despite mitigation strategies. Future multicenter studies with larger datasets, improved image availability, synthetic data generation, and advanced multimodal fusion techniques may improve predictive performance and clinical applicability. Full article

We previously demonstrated that botulinum neurotoxin A (BoNT-A) exerts bilateral antinociceptive effects, involving trans-synaptic transport at the level of the lumbar spinal cord. However, the potential distribution of the toxin to supraspinal sites has not yet been investigated. In the present study, we examined the distribution of cleaved SNAP-25 (cl-SNAP-25), a marker of BoNT-A activity, in the rat brain following peripheral unilateral BoNT-A administration. Brain tissues from rats treated with BoNT-A (7 U/kg, into the hind paw) were analyzed using immunofluorescent tyramide signal amplification to detect cl-SNAP-25. To assess the contribution of trans-synaptic transport, a BoNT-A-neutralizing antitoxin (2 IU) was administered intrathecally 24 h after BoNT-A injection. Signal intensity was evaluated using a semi-quantitative immunohistochemical scoring method based on cl-SNAP-25-positive nerve fibers. Bilateral cl-SNAP-25 immunoreactivity was observed in multiple supraspinal regions, most prominently within the trigeminal complex and the facial and gracile nuclei. Signal intensity was significantly reduced by intrathecal antitoxin, indicating that trans-synaptic transport contributes to central BoNT-A distribution. Peripherally administered BoNT-A reaches distant supraspinal regions, possibly via neuronal retrograde and trans-synaptic transport. Further studies are warranted to clarify exact pathways and alternative distribution routes, determine the functional relevance of central BoNT-A presence, and assess its clinical implications. Full article

Metabolic state strongly shapes social and reproductive behaviors, yet the neural circuits that convert internal energy signals into behavioral responses remain poorly defined. The ventral premammillary nucleus (PMv) of the hypothalamus has been implicated in this process, particularly through leptin receptor-expressing (LepRb) neurons, but its brain-wide circuit organization is still unclear. Here, we used Cre-dependent retrograde (RV) and anterograde (HSV) viral tracing techniques in LepRb-Cre mice to construct a comprehensive, single-cell-resolution input–output map of PMv^LepRb neurons. 3D reconstruction showed that these neurons receive dense convergent inputs, mainly from hypothalamic and forebrain regions involved in energy balance, motivation, and limbic processing. In contrast, their outputs extend not only back to several input regions but also prominently to midbrain and pontine autonomic centers, including the periaqueductal gray (PAG) and parabrachial nucleus (PB). Quantitative analysis revealed that forebrain regions were more likely to participate in reciprocal connectivity, whereas brainstem regions were dominated by outgoing projections. This organization suggests that PMv^LepRb neurons are positioned to integrate metabolic and motivational signals and relay them to downstream systems controlling instinctive behavioral and autonomic responses. These findings provide a structural basis for understanding how energy state can influence decisions related to social competition and reproduction. Full article

Although human mammary glands were traditionally considered sterile, accumulating evidence has established the presence of distinct microbial communities that may have colonized breast tissue primarily via retrograde nipple flow or via hematogenous or lymphatic translocation from other body sites. Comparative studies reveal differences in the microbiota of healthy and diseased breast tissues, with variations in microbial signatures across breast cancer subtypes and in comparison with adjacent normal tissues. This review synthesizes current evidence on the composition of the breast microbiome, the factors shaping its development, and alterations it undergoes in inflammatory and malignant breast diseases. Furthermore, the article discusses mechanistic insights, methodological challenges, and future therapeutic perspectives based on published studies employing culture-independent approaches, such as 16S rRNA gene sequencing and metagenomic analyses. Key host-related factors influencing breast-associated microbial communities, including hormonal regulation, environmental exposure, diet, and therapeutic interventions, are explored. The existing literature is assessed to identify key associations between the breast microbiome and host signaling pathways, as well as the significant challenges that remain unresolved, including low biomass contamination, inter-study variability, limited longitudinal data, and an incomplete understanding of causality. Addressing these limitations is critical for advancing microbiome-based diagnostic and therapeutic strategies for breast disease. Full article