Search Results (27,573)

Background: Drought tolerance in wheat is a complex trait controlled by multiple regulatory networks, among which calcium-dependent protein kinases (CDPKs) act as important components linking stress perception with downstream cellular responses. However, the functional contribution of individual CDPK members to drought adaptation in wheat remains largely unclear. This study aimed to identify and functionally characterize drought-responsive CDPK genes associated with differential drought responses in wheat. Methods: Two wheat lines derived from the same breeding background exhibiting contrasting drought adaption, 23B1 and 23B39, were subjected to PEG6000-induced osmotic stress. Growth traits, osmotic adjustment-related metabolites, membrane damage indicators, and antioxidant enzyme activity were evaluated. Transcriptomic analysis was performed at early drought-response stages, followed by differential expression analysis, functional enrichment, CDPK family screening, and qRT-PCR validation. The role of TaCDPK22-5A was further investigated using barley stripe mosaic virus (BSMV)-mediated virus-induced gene silencing (VIGS). Results: The drought-responsive line 23B1 maintained stronger growth, accumulated higher levels of proline and soluble sugars, exhibited enhanced peroxidase activity, and showed reduced membrane lipid peroxidation compared with 23B39. Transcriptome analysis revealed extensive transcriptional reprogramming under drought stress, with differentially expressed genes mainly associated with metabolic adjustment, transport regulation, secondary metabolism, and stress-responsive pathways. Among the identified CDPK members, TaCDPK22-5A showed a strong drought-responsive expression pattern in the line exhibiting stronger drought tolerance (23B1). Virus-induced gene silencing of TaCDPK22-5A significantly impaired drought tolerance, resulting in reduced growth, biomass accumulation, and chlorophyll retention under drought conditions. Conclusions: These findings demonstrate that TaCDPK22-5A contributes positively to drought adaptation in wheat and highlight CDPK-mediated calcium signaling as an important regulatory component of drought responses. The identified gene provides a potential target for improving drought resilience in wheat breeding. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer. Full article

Although tomato mosaic virus (ToMV) is an economically important tobamovirus, the physiological and molecular events occurring during the asymptomatic phase of infection remain poorly understood. In this study, we investigated the early responses of Nicotiana tabacum cv. Samsun to ToMV infection using an integrated physiological, biochemical, photosynthetic, and molecular approach. Viral accumulation was quantified via RT-PCR. Oxidative stress markers, antioxidant systems, photosynthetic performance, and gene expression were analyzed at 7 days post inoculation (DPI), before visible symptoms developed. Although infected plants remained symptomless, ToMV was detected in 80% of inoculated plants. Early infection induced oxidative stress, evidenced by increased malondialdehyde content, reduced free amino acid levels, and enhanced activities of superoxide dismutase and peroxidase. Total glutathione, phenolic compounds, and phenylpropanoids remained unchanged, whereas flavonoid content decreased significantly. ToMV infection also impaired the photosynthetic apparatus, resulting in reduced chlorophyll and carotenoid contents, decreased electron transport efficiency, and increased energy dissipation within photosystem II. Gene expression analysis revealed significant upregulation of defense- and stress-related genes (WRKY1, HSP70, GR, and DHAR), as well as chloroplast-associated genes (psaA and rbcL). Correlation analyses demonstrated coordinated relationships among viral accumulation, oxidative stress, antioxidant responses, and photosynthetic performance. These findings provide new insights into the asymptomatic phase of ToMV infection and identify potential early markers of host responses to viral infection. Full article

Bovine adenovirus (BAdV)-based vectors, particularly those derived from bovine adenovirus 3 (BAdV-3), are emerging non-human adenoviral platforms for veterinary vaccine development. Adenoviral vectors are attractive for vaccination because they mediate efficient transgene expression, remain largely episomal, and induce robust innate and adaptive immune responses. However, widely used human adenoviral vectors, especially human adenovirus 5 (HAdV-5), may be compromised by pre-existing anti-vector immunity, supporting the development of rare human serotypes and non-human adenoviral alternatives. BAdV-3 is the best-characterized BAdV for recombinant vector engineering and has been used to express heterologous antigens from bovine herpesvirus-1, bovine respiratory syncytial virus, influenza virus, and Mycobacterium tuberculosis. Available evidence indicates that BAdV-based vectors can induce humoral, cellular, and mucosal immune responses and support intranasal antigen delivery. Protective efficacy has been demonstrated in selected experimental models, including mice and ferrets for influenza and tuberculosis vaccine candidates, whereas cattle challenge evidence remains more limited and is primarily represented by BHV-1 gD-expressing BAdV-3 vectors. These features make BAdV vectors relevant to bovine respiratory disease control, livestock vaccination, and One Health-oriented vaccine preparedness. Nevertheless, the platform remains at an early developmental stage. Key gaps include limited target-species efficacy data, pre-existing BAdV immunity in cattle, vector shedding, recombination risk, genetic stability, producer cell optimization, manufacturing scalability, and regulatory feasibility. Full article

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, and Web of Science literature published between January 2010 and May 2026 was conducted, with seminal earlier studies retained where relevant. The review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes. Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD⁺ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies. Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety. The future of geroprotective medicine will depend not only on identifying additional pharmacological targets, but on demonstrating that their modulation produces durable and clinically meaningful benefits in humans. Full article

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43^G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43^G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43^G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43^G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPR^mt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPR^ER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43^G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models. Full article

Diabetic cardiomyopathy (DCM) is characterized by myocardial remodeling that may already be evident during prediabetes, yet the molecular alterations accompanying these early changes remain poorly understood. The present study examined mouse models of Nucleoside diphosphate kinase (NDPK-B)-deficient prediabetes and streptozotocin-induced diabetes using O-GlcNAc-associated proteomic profiling to define stage-specific molecular alterations during the progression from prediabetic to diabetic cardiomyopathy. Both models exhibited increased left ventricular extracellular matrix deposition and impaired diastolic function, together with activation of the hexosamine biosynthesis pathway. Profiling of O-GlcNAc-associated proteins uncovered extensive remodeling of the mitochondrial proteome already at the prediabetic stage, with respiratory complex I among the most prominently altered targets, alongside changes in substrate metabolism and inflammatory signaling. In overt DCM, the putative O-GlcNAc proteomic profile was associated with a shift toward wider lipid-dependent metabolic reprogramming and remodeling of mitochondrial proteins. These findings identify early remodeling of the mitochondrial O-GlcNAc-associated proteome as a molecular signature of prediabetic cardiomyopathy and highlight respiratory complex I proteins as candidate targets for future mechanistic investigations. Full article

Hyperspectral image classification relies heavily on the effective modeling of spatial–spectral representations. Recent deep learning architectures, including Transformers and state space models (SSMs), have shown promise for HSI classification. However, under few-shot scenarios, they may suffer from optimization instability in early-stage feature reduction, weakened local spatial–spectral correlations after direct sequence flattening, and attenuation of center-pixel spectral information caused by deep spatial aggregation. To mitigate these issues, we propose orthogonal projection spatial–spectral Mamba (O-Mamba), a lightweight architecture for few-shot HSI classification. First, we introduce a task-driven orthogonal projection module (TOPM) for learnable end-to-end spectral dimensionality reduction. In this module, orthogonal parameterization, supervised initialization, and an auxiliary loss jointly improve the stability of the projection process, reducing feature redundancy and mitigating representation collapse. Second, we design a 3D spatial–spectral Mamba encoder that employs 3D Convolutional Neural Networks (CNN) as local tokenizers to preserve local spatial–spectral structures and then uses Mamba to capture long-range sequence dependencies with linear complexity with respect to sequence length. Finally, to alleviate over-smoothing in the target-pixel representation, we propose a decoupled target–context fusion strategy. This mechanism separately preserves the original spectral signature of the center pixel and fuses it with high-level contextual features, which may improve the separability of spectrally similar classes. Extensive experiments on four benchmark datasets show that O-Mamba achieves competitive classification performance under the evaluated few-shot settings, while maintaining a relatively small model size and low computational cost compared with representative CNN, Transformer, and Mamba-based methods. Full article

This study investigates the atmospheric corrosion behavior of high-lead bronze alloys within a simulated aggressive environment characterized by high humidity, acidity, chlorides, oxygen, and CO₂. The evolution of surface morphology and corrosion products was systematically monitored using colorimetric analysis and micro-Raman spectroscopy. Results indicate that the initial patina primarily comprised cuprite (Cu₂O) and cassiterite (SnO₂), which are predominantly benign phases. During the early corrosion stage, lead oxidation and carbonation prevailed, generating abundant bright-white cerussite. Subsequently, as copper-driven corrosion became dominant, these white deposits diminished and were progressively replaced by characteristic green “bronze disease”, identified as atacamite (Cu₂(OH)₃Cl). The findings reveal that preferential lead corrosion is likely to induce localized pitting, thereby accelerating degradation of the copper substrate. Consequently, higher lead content may reduce the overall corrosion resistance of bronze artifacts under these specific conditions. These results offer experimental insights into atmospheric corrosion mechanisms and inform the development of evidence-based conservation strategies for bronze cultural heritage. Full article

The growing environmental impact of the construction sector is driving a shift toward sustainable design practices, in which digital technologies are integrated to enable designers to make informed decisions from the early design stages. In this study, a DSS is developed that combines BIM, VPL and TPL to identify the optimal wall stratigraphy for the building envelope. The process is structured into sequential phases, in which Autodesk Revit v2026.06.24.01, Dynamo v.3.6.1 and Python v3.9 are integrated within an end-to-end workflow. In the first phase, wall stratigraphies are modelled in BIM, and parametric variations in layers are allowed alongside customisation of the material database. In the second phase, an automated workflow calculates a set of indicators covering thermal performance, environmental assessments (LCA, MRc2 LEED and mandatory national requirements), and economic evaluations (LCC). In the third phase, indicators are imported into an automated Dynamo-based MCDM, where a hybrid AHP/PROMETHEE analysis is applied and results are directly integrated into BIM, thereby supporting sustainability-focused decisions. The tool is validated on different sustainable wall stratigraphies in warm-climate contexts. The hybrid solution is ranked first, followed by rammed earth, while platform frame and X-LAM are ranked lower. Full article

Although climate warming affects photosynthetic carbon sequestration in coastal wetland plants, the seasonality of this effect has not been assessed. We investigated the growth traits and photosynthetic properties of Phragmites australis by using open-top chambers (OTCs) to conduct a warming experiment in the coastal wetlands of the Yellow River Delta during a single growing season. The OTCs significantly elevated temperatures by ~1 °C across the growing season, and the effects of warming on stem diameter, net photosynthetic rate (P_n), and water use efficiency (WUE) were characterized by a significant month × warming interaction. Early-season carboxylation efficiency (φ) increased by 71%, but a significant late-season decline of P_n by 49% accompanied by a rise of intercellular CO₂ concentrations (C_i) and decline of stomatal limitation (L_s) led to a seasonal shift from stomatal to non-stomatal (biochemical) limitation of growth. A consistent increase in plant height and C_i across all months and concomitant decrease in L_s indicated that the additive effects of warming were independent of phenological stage. The results revealed that the phenological mediation of warming responses is trait specific. Carbon cycle models should therefore adopt trait-specific parameterizations to accurately project the impact of the wetland carbon sink under future warming. Full article

Background/Objectives: OrganoHIPEC is a phase-II, two-stage, open-label clinical trial that investigates if cytoreductive surgery (CRS) and patient-tailored HIPEC, based on a preclinical platform using patient-derived organoids, can improve disease control in peritoneal metastases from colorectal cancer (CRC-PM). Methods: Adults with limited CRC-PM and no distant metastases were included. CRC-PM were sampled for organoid development during diagnostic laparoscopy. These organoids were used in an in vitro HIPEC model to test various drugs suitable for intraperitoneal administration. After 3–6 months of systemic chemotherapy, patients without progression underwent CRS/HIPEC with personalized regimens based on organoid drug response. To detect an increase in 12-month peritoneal disease-free survival from 40% to 60%, 24 patients are needed. According to the two-stage design, if <7 of 10 patients in Stage-1 remain PM-free at 12 months, the trial is terminated. Results: Forty-seven patients were enrolled. Among 31 patients with available organoid data, the most active drugs were mitomycin-C (n = 14), cisplatin/mitomycin-C (n = 12), and low-dose (120 min) oxaliplatin (n = 4). No patient was sensitive to high-dose oxaliplatin (30 min) and cisplatin/doxorubicin. Ten patients had a potential follow-up >12 months. Peritoneal relapse occurred at 8 months in two patients, and one died of liver metastases at 7 months. Seven patients remained PM-free for >12 months (median 16.4, range 12.6–28.4). Conclusions: A comprehensive precision approach using patient-derived organoids to guide personalized HIPEC is feasible and shows promising early results. High-dose oxaliplatin is poorly active. As 7/10 patients achieved the endpoint of 12-month PM-free survival, Stage-1 was successfully completed. The trial is proceeding to Stage-2. Full article

The grain refinement of high-stacking-fault-energy metals during high-pressure torsion (HPT) is governed by dislocation activity and boundary evolution. However, how local misorientation evolves during different stages of grain refinement remains insufficiently clarified. In this study, AA1050 aluminium was processed by HPT to selected equivalent strains of 0, 0.90, 2.69, 10.76 and 53.78, and electron backscatter diffraction (EBSD) was used to analyse grain morphology, boundary fractions and EBSD-derived misorientation parameters. The results reveal strongly stage-dependent grain refinement during HPT. The average grain size decreases rapidly from 12.63 μm in the initial state to 3.29 μm at ε = 0.90 and 2.19 μm at ε = 2.69, remains nearly unchanged at ε = 10.76, and finally decreases to 0.58 μm at ε = 53.78. The fraction of low-angle grain boundaries increases markedly at ε = 0.90, indicating intensive formation of dislocation substructures, whereas high-angle grain boundaries become dominant at high strain. Grain orientation spread (GOS) and grain reference orientation deviation (GROD) exhibit non-monotonic evolution, whereas the geometrically necessary dislocation (GND) density increases markedly at the early deformation stage and subsequently decreases with further deformation. These results indicate that the stage-dependent grain refinement of AA1050 during HPT is closely associated with dislocation-mediated grain subdivision involving alternating grain elongation and fragmentation. Full article

Background: Seed dormancy is crucial for plant survival and agricultural productivity, yet its molecular mechanisms, particularly the role of maternal effects, remain poorly understood. Methods: In this study, we applied a SWATH-based, label-free, quantitative shotgun proteomic mass spectrometry approach to investigate the temporal dynamics of dormancy establishment in Xanthium strumarium, a wild plant with two seeds in one burr that, despite sharing the same genetic and environmental conditions, exhibit distinct dormancy states. Results: Our data show that dormant seeds undergo coordinated metabolic suppression, marked by a decrease in energy metabolism, cell cycle arrest, and auxin signaling, explaining their smaller size. Simultaneously, dormant seeds exhibit metabolic re-prioritization towards fatty acid desaturation, cell wall modification, and an active epigenetic program stabilized by dormancy-promoting factors alongside a transcriptionally quiescent state in early–mid development. However, in the late developmental stage, molecular signaling pathways showed a recalibration distinguished by changes in seed metabolism (such as carbon–nitrogen reallocation, sulfur assimilation, and GABA production), hormonal fluctuations, and epigenetic regulation. Notably, previously reported high DOG1 transcript abundance, together with the absence of detectable DOG1 protein in the proteomic dataset, suggests that post-transcriptional mechanisms may contribute to DOG1 regulation. Conclusions: Based on these findings and the available literature, we propose a framework whereby dormancy establishment occurs in two phases: an early DOG1-mediated priming phase followed by a temperature-sensitive plasticity phase during seed maturation. Full article

Nucleic acids are critical biomarkers that provide essential information throughout disease progression, making their detection critical to early diagnosis of both infectious and non-infectious diseases. However, existing detection methods, including classical analytical techniques and even most reported biosensors, are often constrained by complex procedures, high costs, and limited sensitivity, with the majority operating at the femtomolar level and failing to achieve single-molecule detection needed for early-stage diagnosis. Here, we report an electrochemical biosensor based on silver nanoflowers (AgNFs) integrated with stem-loop probes (SPs) for universal nucleic acid detection, using Norovirus RNA as a model target to validate the platform. The SPs serve as critical elements in a signal amplification system, converting target binding into a biotin–streptavidin recognition event, which leads to the accumulation of AgNFs-SP complexes on laser-induced graphene (LIG) electrodes and generates a strong electrochemical signal. Under optimized conditions with a 50 min hybridization incubation (total assay time ~60 min), the sensor exhibits a linear response to Norovirus RNA concentrations from 1 aM to 10 fM, with a measured detection limit of 1 aM, achieving single-molecule-level detection capability. For applications requiring faster turnaround, a 20 min hybridization incubation (~30 min total assay time) shifts the linear range to 0.1 fM–1 pM with a measured detection limit of 0.1 fM, offering more rapid quantification when the maximum sensitivity is not required. The proposed biosensor is cost-effective, amenable to miniaturization, and designed as a versatile platform adaptable to other nucleic acid targets by simply modifying the probe sequence, showing broad potential for early diagnosis of various diseases. Full article