Aberrant pre-mRNA splicing is a pervasive feature of cancer and an emerging therapeutic vulnerability. Recurrent mutations in core spliceosomal components, including SF3B1, SRSF2, U2AF1, and ZRSR2, are common in myeloid malignancies, while dysregulated splicing regulators and cis-acting splice-site alterations shape cancer-relevant isoform programs across solid tumors. Together with high transcriptional output, rapid proliferation, and oncogene-driven RNA-processing demand, these alterations can reduce the capacity of cancer cells to tolerate additional splicing perturbation, creating a therapeutic window for pharmacological splicing modulation. Multiple strategies are under investigation, including SF3B complex modulators, splicing kinase inhibitors, RBM39-directed molecular glues, PRMT/arginine-methylation-directed approaches, and selected splice-switching strategies. Early clinical experience indicates that pharmacodynamic modulation of splicing is achievable in patients, yet objective clinical benefit has been inconsistent. This reflects narrow therapeutic windows, incomplete concordance between peripheral-blood pharmacodynamic markers and tumor-tissue splicing perturbation, and the limited predictive value of mutation status alone. Rational combinations with apoptosis-targeted agents, oncogene-directed therapies, DNA-damaging agents, PARP inhibitors, and immunotherapies may offer a more effective route to clinical translation than maximal single-agent splicing inhibition. Continued progress will require more selective splicing-directed modalities, pharmacodynamic biomarkers that measure splicing perturbation in the relevant tumor or blood compartment, longitudinal mapping of genetic and tumor cell-state plasticity-driven resistance, and biomarker-defined combination trials to support expansion from hematologic malignancies into solid tumors.

Deep-ultraviolet (DUV) optical materials with wide bandgaps and non-centrosymmetric structures are critical for advanced optoelectronic applications such as DUV lithography, high-resolution spectroscopy and nonlinear optics. In this work, we report the discovery of a noncentrosymmetric phase of KNaSiF6 (space group Pna21), synthesized via a hydrothermal cation-exchange method. Single crystals with dimensions up to 4.45 mm × 1 mm × 1 mm were grown. The crystal exhibits an absorption edge below 200 nm, corresponding to a bandgap greater than 6.2 eV. Vibrational spectroscopy (IR and Raman) confirms the integrity of the [SiF6]2- anionic groups, and energy-dispersive X-ray spectroscopy verifies the expected stoichiometry. First-principles calculations on the Pna21 phase yield a small second-harmonic generation (SHG) coefficient of ∼0.00227 pm V-1, consistent with the weak SHG response observed experimentally. The combination of a DUV transparency window, a wide bandgap and a noncentrosymmetric structure renders Pna21-KNaSiF6 a promising candidate for next-generation DUV optical windows and nonlinear optical crystals.

Films of linear and cyclic dipeptides as well as alanine amino acid, deposited on ZnSe windows, have been irradiated with a 12C4+ beam of 0.98 MeV u-1 at 10, 80 and 300 K. The effects of irradiation have been studied by measuring in situ the IR absorption spectrum before, during and after the irradiation. The main effect observed is film degradation due to ion-induced fragmentation and sputtering; notably the cyclic species exhibiting higher radioresistance than the linear ones. The measurements at low temperature also provide evidence of the formation of new species of lower masses. Moreover, the similarity between the IR spectra of irradiated alanine and pristine linear alanine-alanine films, suggests ion-induced peptide polymerization and supports the idea that cyclic dipeptides may have survived the harsh conditions of the early universe, contributing to possible radiation-induced pathways leading to larger organic species of potentially prebiotic significance.

Tenecteplase (TNK) is a modified variant of alteplase (TPA) that offers advantages such as a long plasma half-life and high fibrin specificity. Previous studies have demonstrated the noninferiority of TNK to TPA in patients with acute ischemic stroke (AIS). Although very elderly patients (aged ≥ 80 years) represent a significant proportion of AIS cases, research on the safety and efficacy of TNK in this population remains limited. Therefore, this study aimed to evaluate the comparative efficacy and safety of TNK versus TPA in treating AIS in very elderly patients. We conducted a meta-analysis of randomized controlled trials (RCTs) from Embase, PubMed, and the Cochrane Library up to May 20th, 2026. The outcomes included modified Rankin Scale (mRS) scores of 0-1 and 0-2 at 90 days, symptomatic intracranial hemorrhage (SICH), all-cause mortality, and parenchymal hematoma. We also performed subgroup analysis to assess the effects of patient race. We utilized mainly Review Manager 5.4 software to conduct the data synthesis and statistical analysis. Five RCTs (EXTEND-IA TNK, AcT, ATTEST-2, TRACE-2, and ORIGINAL) involving 1307 very elderly patients were included. Pooled analysis showed that TNK was associated with higher odds of excellent and good functional outcomes at 90 days compared with TPA (excellent: odds ratio (OR) 1.85, 95% confidence interval (CI) 1.06-3.23, p = 0.03, I2 = 75%; good: OR 1.35, 95% CI: 1.06-1.71, p = 0.01, I2 = 3%). Leave-one-out sensitivity analysis showed that the association between TNK and excellent functional outcomes was no longer statistically significant after exclusion of the ORIGINAL trial (OR 1.38, 95% CI 0.91-2.08, p = 0.13, I2 = 52%). No statistically significant differences were observed between TNK and TPA in SICH (OR 1.00, 95% CI 0.54-1.89, I2 = 0%), 90-day mortality (OR 0.84, 95% CI 0.63-1.11, I2 = 0%), or parenchymal hematoma (OR 0.73, 95% CI 0.30-1.74, I2 = 5%). In this pooled analysis of noninferiority-designed RCTs, TNK was associated with a trend toward improved functional outcomes compared with TPA in very elderly patients with AIS. However, the statistical significance of the excellent functional outcome was dependent on the inclusion of the ORIGINAL trial, and the association was no longer significant after its exclusion. This finding, combined with the high heterogeneity and small sample sizes, and the high risk of bias related to deviations from intended interventions in most included trials, suggests that the results should be regarded as hypothesis-generating. As all included trials were designed as noninferiority studies, adequately powered superiority trials are warranted to confirm the potential benefit of TNK over TPA in this population.Affiliation [1] has been split into two different affiliations. Please check if action taken is appropriate and amend if necessary.Thank you for checking. The splitting of Affiliation [1] into two separate affiliations is not appropriate. Although its institutional components are separated by semicolons, they collectively constitute one complete affiliation and should remain under a single affiliation number. The official English name has recently been updated. Please replace Affiliation [1] in its entirety with the following: "Neurology Department, Beijing Hospital, National Center for Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China" Please also remove all Chinese text currently displayed in Affiliation [1]. We are unable to correct it directly because the editing window closes unexpectedly whenever we click on Affiliation [1] in the online proofing system. We confirm that the wording above is the correct and complete form of Affiliation [1]. Please retain it as a single affiliation and do not split it.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.We have checked the authors and their respective affiliations. Please note the following corrections: The former Affiliation [3], which has been marked for deletion in the proof, should be removed completely.Keying Zhang's previous affiliation did not include the name of her department. We have now added the department name to make her affiliation complete. Please retain the revised affiliation, including the newly added department information.After the deletion of the former Affiliation [3], the former Affiliation [4], which corresponds to Keying Zhang, should be renumbered as Affiliation [3]. Accordingly, Keying Zhang's affiliation number should also be changed from [4] to [3].We are unable to make this renumbering in the online proofing system. Please make the necessary corrections during production. The final affiliation list should contain only Affiliations [1], [2], and [3], with no Affiliation [4].

Water quality assessment in agriculturally dominated basins requires approaches that capture seasonal pressure pathways rather than isolated optical signals. The Meriç-Ergene Basin in Türkiye was selected because cropland covered 70.49% of the basin in 2025 and because limited surface water extent, seasonal hydroclimatic variability, and land use pressure create suitable conditions for pressure-based water quality assessment. This study developed a monthly Google Earth Engine-Python-ArcMap framework to model organic pressure, inorganic-sediment pressure, and total water quality pressure during 2019-2025 using Sentinel-2, Sentinel-1, CHIRPS, ERA5-Land, land use/land cover (LULC), terrain, drainage, and long-term surface water indicators. Unlike concentration retrieval studies, the framework produced relative pressure scores based on satellite and environmental proxies. Organic pressure showed the strongest seasonal contrast, with a seasonal mean range of 0.181, and was highest during spring-summer conditions. Inorganic-sediment pressure exhibited a distinct seasonal pattern, with higher values during autumn-winter and the largest spatial range among the pressure components (0.410). Total water quality pressure was more compressed seasonally, with a seasonal mean range of 0.062. High sediment pressure conditions were episodic: high inorganic-sediment pressure score (ISPS) records accounted for only 0.49% of valid monthly observations, and maximum hotspot persistence reached 0.036. Interannual fitted changes were small for all pressure scores, indicating limited basin-scale directional change during 2019-2025. The framework provides a reproducible screening tool for identifying seasonal pressure windows and prioritizing field monitoring in data-limited basins.

This study examines the prevalence, characteristics, and behavioral responses associated with firearm thefts from vehicles in the United States. Data are from a national survey of firearm owners conducted by YouGov in February-March 2026 (n = 1,976). Overall, 2.7% of respondents reported having experienced a firearm theft from a vehicle. Multivariable Firth logistic regression analyses indicated that older age was associated with lower odds of experiencing a theft, while non-Hispanic Black and Hispanic respondents had significantly higher odds compared to non-Hispanic White respondents. Among those reporting a theft (n = 53), most incidents involved a single event and primarily included handguns. Thefts most commonly occurred from pickup trucks, sedans, and sport utility vehicles, often in residential settings such as driveways or nearby streets, and frequently during late-night hours. Methods of entry included forced access, breaking windows, or exploiting unlocked vehicles. Firearms were typically stored in accessible locations such as glove compartments, center consoles, or under seats. Respondents reported limited use of dedicated locking devices. Following a theft, 85% of respondents reported the incident to law enforcement and provided identifying information about the firearm (i.e., make/model; serial number); however, most stolen firearms were not recovered. Following the theft incident, most respondents reported behavioral modifications such as removing firearms from unattended vehicles (72.9%) or improving vehicle security with technology (29%). Replication is needed with larger samples and research on the efficacy of firearm theft prevention from vehicles through education, secure in-vehicle storage, and related policies should be tested.

Acute kidney injury (AKI) is a serious clinical condition with high morbidity and mortality, yet early detection and effective treatment remain challenging. Herein, we developed ultrasmall quantum dots (QDs) for dual-modal imaging-guided early detection and antioxidant therapy of AKI. Benefiting from the ultrasmall hydrodynamic size, the as‑prepared Ag₂Se@Mn QDs exhibit favorable renal clearance and prolonged retention in injured kidneys. The QDs possess concentration-dependent T1-weighted magnetic resonance imaging (MRI) contrast and near-infrared fluorescence properties, enabling real-time, non-invasive visualization of cisplatin-induced AKI progression. Especially, MRI revealed renal dysfunction up to 66 h earlier than conventional clinical indicators, providing a critical window for early intervention. Furthermore, the inherent ROS-scavenging activity of Mn²⁺ endows QDs with potent antioxidant capacity by efficiently eliminating hydroxyl radicals (·OH) and superoxide anions (O₂•-), and thus comprehensively alleviate renal damage and recover renal functions without obvious side-effects. This "all-in-one" theranostic strategy offers an alternative approach for precision management of AKI.

Combined cold and salt stress antagonizes jasmonate signaling via MYC2 suppression, reallocating resources to flavonoid-based defense and revealing a strategic target for crop multi-stress resilience. Plants are frequently exposed to a combination of abiotic stresses, but the mechanisms governing their non-additive interactions remain largely unclear. In this study, we integrated phenomic, transcriptomic, and metabolomic analyses to elucidate the interplay between cold and salt stress in pepper (Capsicum annuum L.). Unlike individual stresses, which led to progressive damage, the combined stress elicited a pronounced antagonistic effect during a critical 6 ~ 9 h window, characterized by reduced electrolyte leakage (< 40%), a higher relative water content (25 ~ 30%), and attenuated oxidative injury. Transcriptomic profiling revealed that salt stress up-regulated FERL and the master regulator MYC2, involved in the jasmonate (JA) signaling pathway, by 40- and 20-fold, respectively, but these responses were significantly suppressed under combined stress. Further, targeted metabolomics revealed that pelargonidin-3-O-glucoside accumulated by a twofold increase to 1.2 μg g⁻1 under combined stress compared to salt stress alone. Functional validation using virus-induced gene silencing of CaMYC2 (78% efficiency) confirmed that MYC2 is essential for this antagonistic protection. Silenced plants exhibited exacerbated wilting, doubled hydrogen peroxide content, and reduced antioxidant enzyme activities. Collectively, these findings demonstrate that combined cold-salt stress reconfigures defense prioritization by antagonizing JA signaling through MYC2 suppression, thereby reallocating metabolic resources toward flavonoid-based protection. This study provides a mechanistic framework for understanding non-additive stress interactions and identifies strategic targets for enhancing crop multi-stress resilience.

Efficient intracellular delivery of biomacromolecules and nanomaterials requires transient membrane permeabilization while preserving high cell viability, cell recovery, and processing throughput. However, conventional carrier-mediated delivery, electroporation, and passive mechanical extrusion approaches are often constrained by cargo-size limitations, cytotoxicity, limited processing throughput, or channel clogging. Here, we report a piezoelectric ultrasound-assisted microjetting platform for high-throughput, carrier-free intracellular delivery. The platform integrates a high-frequency piezoelectric actuator with a tapered micropore, enabling active ejection of cell suspensions through the nozzle. During microjetting, cells experience localized mechanical perturbation while passing through the micropore and undergo secondary deformation within the ejected droplets, which may promote transient membrane permeabilization. In addition, intra-droplet vortical flow may facilitate local cargo transport toward the cell membrane during the transient membrane-resealing window. Using this platform, we achieved efficient delivery of dextrans with different molecular weights (4-200 kDa), large plasmid DNA (9.3 kbp), polymer nanoparticles (100 nm), and quantum dots across multiple cell types while maintaining high cell viability and recovery. Under optimized conditions, the platform achieved delivery efficiencies of up to 86% and a processing throughput of up to 5 × 107 cells per min. These results suggest that piezoelectric ultrasound-assisted microjetting offers a clogging-resistant strategy with potential for future scale-up in carrier-free intracellular delivery of biomacromolecules and nanomaterials.

This study aimed to determine the anesthetic therapeutic window of Thymus vulgaris L. essential oil (TVEO) in juvenile Colossoma macropomum (tambaqui), through the integrated analysis of behavioral parameters, electrocardiographic recordings, opercular activity during the induction, and recovery periods of anesthesia, as well as the measurement of blood glucose levels in the animals after the anesthetic procedure. The fish were divided into the control, vehicle, and TVEO-treated groups at concentrations of 18.6 mg. L⁻1, 27.9 mg. L⁻1, 37.2 mg. L⁻1, and 46.5 mg. L⁻1, administered by immersion baths. Anesthetic efficacy was evaluated by means of induction time, loss of righting response, and recovery time. Electrocardiographic recordings were used to monitor heart rate and rhythm, allowing the analysis of possible pharmacological effects on cardiac electrical conduction. A concentration of 18.6 mg. L⁻1 promoted mild anesthesia without loss of postural response or relevant cardiovascular changes. Concentrations of 27.9 mg. L⁻1 and 37.2 mg. L⁻1 induced effective anesthesia, with rapid induction, adequate recovery, and electrocardiographic stability, characterizing the main therapeutic window. The concentration of 46.5 mg. L⁻1 resulted in transient cardiovascular depression, evidenced by a reduction in heart rate, suggesting autonomic modulation and possible interaction with cardiac ion channels. Thymus vulgaris essential oil exhibits concentration-dependent anesthetic action in C. macropomum, with concentrations of 27.9, 37.2, and 46.5 mg. L⁻1 representing the window for anesthesia in moderate to deep planes. The findings indicate the involvement of central and cardiovascular pharmacological mechanisms, reinforcing the potential of TVEO as a natural alternative to synthetic anesthetics in fish.

Fanhuncao (Jacobaea cannabifolia and J. litvinovii) is a traditional Chinese herb with reported antitumor potential. Retrorsine, a pyrrolizidine alkaloid from Fanhuncao, requires CYP3A4‑mediated metabolic activation, but its dual outcomes (anti‑liver cancer efficacy vs. organ‑specific toxicity) remain unclear. To elucidate how CYP3A4-dependent activation of retrorsine drives both anti-liver cancer activity and organ-specific toxicity, and to identify differential cell death pathways in target organs. UPLC-HRMS profiled pyrrolizidine alkaloids in Fanhuncao. Cytotoxicity screening, molecular docking, and molecular dynamics identified retrorsine as the lead compound. Network pharmacology/toxicology predicted targets of dehydro-retrorsine. In vitro assays and Western blotting were performed on hepatoma cells. In vivo efficacy and toxicity were evaluated in H22 tumor-bearing mice. Retrorsine achieved significant tumor growth inhibition at high dose. Mechanistically, it simultaneously inhibited EGFR/PI3K/AKT/mTOR and NF-κB pathways while activating intrinsic mitochondrial apoptosis (altered Bax/Bcl-2, cytochrome c release, Caspase-9/3 activation). Retrorsine upregulated CYP3A4 in tumor cells, suggesting a potential self‑amplifying metabolic loop that requires further validation. However, this efficacy was accompanied by dose-dependent hepatorenal toxicity with organ-specific mechanisms: liver injury via oxidative stress and mitochondrial apoptosis; kidney injury via Caspase-3/GSDME-dependent pyroptosis. Retrorsine is a potent multi-target anti-liver cancer natural product, but its therapeutic window is narrowed by inseparable organ-specific toxicities (hepatic apoptosis vs. renal pyroptosis) arising from CYP3A4-dependent metabolic activation. Future decoupling strategies should focus on targeted delivery, structural modification, or combination therapies.