Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in the OIM model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type I collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogenitor niche as is a strategy to treat OI.

External validation of different predictive scores for symptomatic intracranial hemorrhage after intravenous thrombolysis in Asian stroke patients.

OBJECTIVE: This study aimed to externally validate different predictive scores for symptomatic intracranial hemorrhage (SICH) after intravenous thrombolysis (IVT), with a particular focus on their predictive abilities in Asian stroke patients. METHODS: We retrospectively enrolled stroke patients who received a standard dose of alteplase within 4.5 hours from symptom onset at the First Affiliated Hospital of Dalian Medical University from July 2010 to August 2023. SICH was defined as the hemorrhagic transformation detected on the head CT scan completed within 48 h post-IVT, accompanied by a clinical deterioration of at least a 4-point increase in NIHSS score. Predictive abilities of the HAT, MSS, SEDAN, SPAN-100, and GRASPS scores were tested. Discrimination and calibration were performed using the area under the receiver operating characteristic curve (ROC-AUC), DeLong test, and Hosmer-Lemeshow (H-L) goodness-of-fit test. RESULTS: The study included 1007 stroke patients, of whom 31 (3.08 %) developed SICH. ROC-AUCs for predicting SICH were: 0.796 (95 %CI: 0.726-0.866) for the GRASPS score, 0.724 (95 %CI: 0.644-0.804) for the MSS score, 0.715 (95 %CI: 0.619-0.811) for the SEDAN score, 0.714 (95 %CI: 0.611-0.817) for the HAT score, and 0.605 (95 %CI: 0.491-0.720) for the SPAN-100 score (all P < 0.05). DeLong tests showed that the GRASPS score demonstrated significantly better discrimination than the MSS score (P = 0.010), the SEDAN score (P = 0.009), the HAT score (P = 0.049), and the SPAN-100 score (P = 0.000). H-L tests indicated good calibrations which were ranked HAT > SEDAN > MSS > SPAN-100 > GRASPS scores. CONCLUSION: The GRASPS score showed reasonable predictive ability for SICH, indicating its potential utility for Asian stroke patients receiving IVT.

Employing conductive porous hydrogen-bonded organic framework for ultrasensitive detection of peanut allergen Ara h1.

Peanut allergy has garnered worldwide attention due to its high incidence rate and severe symptoms, stimulating the demand for the ultrasensitive detection method of peanut allergen. Herein, we successfully developed a novel electrochemical aptasensor for ultrasensitive detection Ara h1, a major allergenic protein present in peanuts. A conductive nickel atoms Anchored Hydrogen-Bonded Organic Frameworks (PFC-73-Ni) were utilized as excellent electrocatalysts toward hydroquinone (HQ) oxidation to generate a readable current signal. The developed electrochemical aptasensor offers wide linear range (1-120 nM) and low detection limit (0.26 nM) for Ara h1. This method demonstrated a recovery rate ranging from 95.00% to 107.42% in standard addition detection of non-peanut food samples. Additionally, the developed electrochemical method was validated with actual samples and demonstrated good consistency with the results obtained from a commercial ELISA kit. This indicates that the established Ara h1 detection method is a promising tool for peanut allergy prevention.

Stereoselective benzylic C(sp3)-H alkenylation enabled by metallaphotoredox catalysis.

Selective activation of the benzylic C(sp3)-H bond is pivotal for the construction of complex organic frameworks. Achieving precise selectivity among C-H bonds with comparable energetic and steric profiles remains a profound synthetic challenge. Herein, we unveil a site- and stereoselective benzylic C(sp3)-H alkenylation utilizing metallaphotoredox catalysis. Various linear and cyclic (Z)-all-carbon tri- and tetrasubstituted olefins can be smoothly obtained. This strategy can be applied to complex substrates with multiple benzylic sites, previously deemed unsuitable due to the uncontrollable site-selectivity. In addition, sensitive functional groups such as terminal alkenyl and TMS groups are compatible under the mild conditions. The exceptional site-selectivity and broad substrate compatibility are attributed to the visible-light catalyzed relay electron transfer-proton transfer process. More importantly, we have extended this methodology to achieve enantioselective benzylic C(sp3)-H alkenylation, producing highly enantioenriched products. The applicability and scalability of our protocol are further validated through late-stage functionalization of complex structures and gram-scale operations, underscoring its practicality and robustness.

Counterion Distribution in the Stern Layer on Charged Surfaces.

Counterion adsorption at the solid-liquid interface affects numerous applications. However, the counterion adsorption density in the Stern layer has remained poorly evaluated. Here we report the direct determination of surface charge density at the shear plane between the Stern layer and the diffuse layer. By the Grahame equation extension and streaming current measurements for different solid surfaces in different aqueous electrolytes, we are able to obtain the counterion adsorption density in the Stern layer, which is mainly related to the surface charge density but is less affected by the bulk ion concentration. The charge inversion concentration is further found to be sensitive to the ion type and ion valence rather than to the charged surface, which is attributed to the ionic competitive adsorption and ion-ion correlations. Our findings offer a framework for understanding ion distribution in many physical and chemical processes where the Stern layer is ubiquitous.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Outcomes of Mitral Valve Repair for Posterior Leaflet Prolapse, Anterior Leaflet Prolapse, and Bileaflet Prolapse.

Background: Mitral valve repair (MVr) is an effective treatment for degenerative mitral regurgitation (DMR).And the outcomes and repair rates for posterior leaflet prolapse (PLP), anterior leaflet prolapse (ALP), and bileaflet prolapse (BLP) vary. This study aimed to compare the outcomes of mitral valve repair for patients with PLP, ALP, and BLP. Methods: From 2010 to 2019, 1192 patients with degenerative mitral valve regurgitation underwent surgery at our hospital. And 1069 patients were identified. The average age of all patients was (54.74 ± 12.17) years old for all patients. 273 patients (25.5%) had ALP, 148 patients (13.8%) had BLP, and 648 patients (60.6%) had PLP. All patients were followed up for an average duration of 5.1 years. We compared the outcomes of patients with ALP, PLP, and BLP. Results: Patients with ALP were the youngest of the 3 groups and had the highest prevalence of atrial fibrillation. Patients with PLP had the highest prevalence of hypertension, whereas patients with BLP and ALP had larger left ventricular end-diastolic and left ventricular end-systolic diameters. ALP and BLP repairs had a longer cardiopulmonary bypass and aortic cross-clamp time.10 patients dead in-hospital, 5 patients had PLP, 3 had ALP, and 2 had BLP. The 10-year survival cumulative incidences of reoperation among ALP, BLP, and PLP repairs were not significantly different. ALP repair still had higher cumulative incidences of recurrent mitral regurgitation (MR) compared to PLP. Conclusions: The rates of long-term survival and freedom from reoperation were not significantly different among patients with ALP, BLP, and PLP. ALP repair has higher cumulative incidences of recurrent MR compared to PLP.

Association of Helicobacter pylori infection with colorectal polyps/adenomas: A single-center cross-sectional study.

BACKGROUND: Helicobacter pylori (H. pylori) infection may be associated with colorectal polyps/adenomas, but the current evidence remains controversial. METHODS: We retrospectively screened the medical records of 655 participants who underwent both colonoscopy and H. pylori test from June 15, 2020 to April 30, 2023. The number, size, location, and pathological type of colorectal polyps/adenomas were compared between H. pylori positive and negative groups. Adjusting for age, gender, smoking, drinking, hypertension, diabetes, fatty liver, body mass index, and inflammatory and metabolic indicators, multivariate logistic regression analyses were performed to evaluate the association of H. pylori infection with the number, size, location, and pathological type of colorectal polyps/adenomas, where no polyp/adenoma was used as reference. RESULTS: Overall, 508 participants were included, of whom 154 and 354 were divided into H. pylori positive and negative groups, respectively. H. pylori positive group had significantly higher colorectal polyps/adenomas (74.7 % vs. 65.8 %, P=0.048), low-grade adenomas (55.7 % vs. 47.6 %, P=0.026), advanced adenomas (22.6 % vs. 13.3 %, P=0.008), and colorectal polyps/adenomas with sizes of ≥6 mm (61.7 % vs. 48.5 %, P=0.002) and ≥10 mm (25.2 % vs. 14.6 %, P=0.004) than H. pylori negative group. In multivariate logistic regression analyses, H. pylori infection was independently associated with low-grade adenomas (OR=2.677, 95 %CI=1.283-5.587, P=0.009), advanced adenomas (OR=3.017, 95 %CI=1.007-9.036, P=0.049), right-side colon polyps/adenomas (OR=5.553, 95 %CI=1.679-18.360, P=0.005), and colorectal polyps/adenomas with sizes of ≥10 mm (OR=4.436, 95 %CI=1.478-13.310, P=0.008), but not number of colorectal polyps/adenomas. CONCLUSION: H. pylori infection is associated with increased risk of colorectal polyps/adenomas, especially low-grade adenomas, advanced adenomas, right-side colon polyps/adenomas, and large colorectal polyps/adenomas.

Zinc finger protein 180 induces an apoptotic phenotype by activating METTL14 transcriptional activity in colorectal cancer.

Zinc finger protein 180 (ZNF180) is a multifunctional protein that interacts with nucleic acids and regulates various cellular processes; however, the function of ZNF180 in colorectal cancer (CRC) remains unclear. The present study investigated the role and function of ZNF180 in CRC, and aimed to reveal the underlying molecular mechanism. The results revealed that ZNF180 was downregulated in CRC tissues and was associated with a good prognosis in patients with CRC. Additionally, the expression of ZNF180 was downregulated by methylation in CRC. In vivo and in vitro experiments revealed that ZNF180 overexpression was functionally associated with the inhibition of cell proliferation and the induction of apoptosis. Mechanistically, chromatin immunoprecipitation­PCR and luciferase assays demonstrated that ZNF180 markedly regulated the transcriptional activity of methyltransferase 14, N6­adenosine­methyltransferase non­catalytic subunit (METTL14) by directly binding to and activating its promoter region. Simultaneous overexpression of ZNF180 and knockdown of METTL14 indicated that the reduction of METTL14 could suppress the effects of ZNF180 on the induction of apoptosis. Clinically, the present study observed a significant positive correlation between ZNF180 and METTL14 expression levels, and low expression of ZNF180 and METTL14 predicted a poor prognosis in CRC. Overall, these findings revealed a novel mechanism by which the ZNF180/METTL14 axis may modulate apoptosis and cell proliferation in CRC. This evidence suggests that this axis may serve as a prognostic biomarker and therapeutic target in patients with CRC.

AC-ModNet: Molecular Reverse Design Network Based on Attribute Classification.

Deep generative models are becoming a tool of choice for exploring the molecular space. One important application area of deep generative models is the reverse design of drug compounds for given attributes (solubility, ease of synthesis, etc.). Although there are many generative models, these models cannot generate specific intervals of attributes. This paper proposes a AC-ModNet model that effectively combines VAE with AC-GAN to generate molecular structures in specific attribute intervals. The AC-ModNet is trained and evaluated using the open 250K ZINC dataset. In comparison with related models, our method performs best in the FCD and Frag model evaluation indicators. Moreover, we prove the AC-ModNet created molecules have potential application value in drug design by comparing and analyzing them with medical records in the PubChem database. The results of this paper will provide a new method for machine learning drug reverse design.

Comparison of Mitral Valve Repair Versus Percutaneous Mitral Balloon Commissurotomy for Patients With Rheumatic Heart Disease: A Single-Centre Study.

BACKGROUND: Percutaneous mitral balloon commissurotomy (PMBC) is the standard treatment option for patients with rheumatic mitral stenosis (MS), according to current guidelines. This study aimed to compare the outcomes of rheumatic mitral valve repair (rMVR) and PMBC in this patient population. METHODS: Baseline, clinical, and follow-up data from 703 patients with rheumatic heart disease who underwent PMBC or rMVR at the current centre were collected and analysed. A 1:1 propensity score (PS) matching method was used to balance the differences in baseline characteristics between the two groups. The primary outcome was mitral valve reoperation, and the secondary outcome was all-cause mortality. RESULTS: Propensity score matching generated 101 patient pairs for comparison. In the matched population, there were no significant differences in the early clinical outcomes between the groups. The median follow-up time was 40.9 months. Overall, patients in the rMVR group had a statistically significantly lower risk of mitral valve reoperation than those in the PMBC group (HR 0.186; 95% CI 0.041-0.835; p=0.028). Regarding all-cause mortality, no statistically significant differences were observed between the rMVR and PMBC groups (HR 4.065; 95% CI 0.454-36.374; p=0.210). CONCLUSIONS: Compared with PMBC, rMVR has more advantages for the correction of valve lesions; therefore, it may offer a better prognosis than PMBC in select patients with rheumatic MS. However, this finding needs to be verified in future studies with larger sample sizes and longer follow-up periods.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Enantioselective Aminosilylation of Alkenes by Palladium/Ming-Phos-Catalyzed Tandem Narasaka-Heck/Silylation Reaction.

A Pd-catalyzed enantioselective aminosilylation of alkenes via tandem Aza-Heck/silylation reaction under Pd/Sadphos catalysis is disclosed. A wide array of oxime esters and silicon reagents are tolerated, furnishing the chiral pyrrolines bearing one quaternary or two contiguous stereocenters in good yield with high enantioselectivity. Not only terminal alkenes but also tri-substituented internal alkenes successfully participate in the reaction, delivering vicinal stereocenters in complete diastereoselectivity and high enantioselectivity. DFT study is conducted to probe the reaction pathway and the origin of the enantioselectivity, which revealed that the stereoinduction arises from the weak interaction between the aromatic ring of the substrate fragment and naphthyl group in the ligand.

3D Porous Fibers with Spatial Traps and Excellent Zn2+ Transport Kinetics Enable Stable Zn-Based Aqueous Battery.

Adverse side reactions and uncontrolled Zn dendrites growth are the dominant factors that have restricted the application of Zn ion batteries. Herein, a 3D self-supporting porous carbon fibers (denoted as PCFs) host is developed with "trap" effect to adjust the Zn deposition. The unique open structural design of N-doped carbon can act as the zincophilic sites to induce uniform deposition and inhibit adverse side reactions. More importantly, the porous hollow PCFs host with "trap" effect can induce Zn deposition in the fiber by adjusting the local electric field and current density, thereby increasing the specific energy density of the battery and inhibiting dendrite growth. In addition, the 3D open frameworks can regulate Zn2+ flux to enable outstanding cycling performance at ultra-high current densities. As expected, the PCFs framework guarantees the uniform Zn plating and stripping with an outstanding stability over 6000 cycles at the current density of 40 mA cm-2. And the Zn@PCFs||MnO2 full battery shows an excellent lifespan over 1300 cycles at 2000 mA g-1.

GWO+RuleFit: rule-based explainable machine-learning combined with heuristics to predict mid-treatment FDG PET response to chemoradiation for locally advanced non-small cell lung cancer.

Objective.Vital rules learned from fluorodeoxyglucose positron emission tomography (FDG-PET) radiomics of tumor subregional response can provide clinical decision support for precise treatment adaptation. We combined a rule-based machine learning (ML) model (RuleFit) with a heuristic algorithm (gray wolf optimizer, GWO) for mid-chemoradiation FDG-PET response prediction in patients with locally advanced non-small cell lung cancer.Approach.Tumors subregions were identified using K-means clustering. GWO+RuleFit consists of three main parts: (i) a random forest is constructed based on conventional features or radiomic features extracted from tumor regions or subregions in FDG-PET images, from which the initial rules are generated; (ii) GWO is used for iterative rule selection; (iii) the selected rules are fit to a linear model to make predictions about the target variable. Two target variables were considered: a binary response measure (ΔSUVmean ⩾ 20% decline) for classification and a continuous response measure (ΔSUVmean) for regression. GWO+RuleFit was benchmarked against common ML algorithms and RuleFit, with leave-one-out cross-validated performance evaluated by the area under the receiver operating characteristic curve (AUC) in classification and root-mean-square error (RMSE) in regression.Main results.GWO+RuleFit selected 15 rules from the radiomic feature dataset of 23 patients. For treatment response classification, GWO+RuleFit attained numerically better cross-validated performance than RuleFit across tumor regions and sets of features (AUC: 0.58-0.86 vs. 0.52-0.78,p= 0.170-0.925). GWO+Rulefit also had the best or second-best performance numerically compared to all other algorithms for all conditions. For treatment response regression prediction, GWO+RuleFit (RMSE: 0.162-0.192) performed better numerically for low-dimensional models (p= 0.097-0.614) and significantly better for high-dimensional models across all tumor regions except one (RMSE: 0.189-0.219,p< 0.004).Significance. The GWO+RuleFit selected rules were interpretable, highlighting distinct radiomic phenotypes that modulated treatment response. GWO+Rulefit achieved parsimonious models while maintaining utility for treatment response prediction, which can aid clinical decisions for patient risk stratification, treatment selection, and biologically driven adaptation. Clinical trial: NCT02773238.

De Novo Urological Malignancies After Renal Transplantation: An Asian 30-Year Experience.

BACKGROUND: As the incidence of urological malignancies after renal transplantation (RT) is observed to be greater than in the general population, a better understanding of them is important. We present our experience with urological tumors in RT recipients at our transplant center, and analyze their incidence, management and outcomes. MATERIALS AND METHODS: A retrospective analysis of 2177 RT recipients on follow-up at our center between 1990 and 2022 was conducted for de novo genitourinary malignancy. Patients diagnosed with malignancy before transplantation were excluded. Clinicopathological data at diagnosis and follow-up were collected and analyzed. Kaplan-Meier estimates were used to evaluate overall survival (OS) and cancer-specific survival (CSS). Statistical analysis was performed using IBM SPSS v.24 (IBM Corp., Armonk, NY, USA). RESULTS: The overall incidence of Urological malignancies was 3.9%, with 89 cancers diagnosed in 85 patients. Renal cell carcinoma was most common (n = 61, 68.5%), followed by prostate cancer (n = 10, 11.2%), urothelial carcinoma (n = 10, 11.2%), squamous cell carcinoma of the penis/scrotum (n = 7, 7.9%), and testicular cancer (n = 1, 1.1%). Mean duration between transplantation and diagnosis of malignancy was 9.9 (0.4-20.7) years. At a median follow-up of 4.6 (018.2) years, 27 deaths were seen; 7(25.9%) were due to urological malignancy. CSS rates were 86% and 78% at five and ten years, respectively, after diagnosis. CONCLUSION: We present one of the largest series of de novo urological malignancies observed over an extended 30-year follow-up of RT recipients, demonstrating an elevated risk in line with other studies. Regular surveillance for malignancies is advised, in order to ensure early diagnosis and management.

Chiral Supramolecular Self-Assembly Catalysts with Enhanced Metal Ion Interaction for Higher Enantioselectivity.

Understanding the interaction between metal ions as catalytic centers and supramolecular scaffolds as chiral substrates plays an important role in developing chiral supramolecular catalysts with high enantioselectivity. Herein, we found that compared with l-norleucine chiral amphiphile (l-NorC16), l-methionine chiral amphiphile (l-MetC16) with the only heteroatom of S site difference in the hydrophilic group can form a similar supramolecular chiral nanoribbon (NR) with the bilayer structure through the self-assembly approach; yet, the interaction between the Cu(II) ion catalytic centers and supramolecular scaffolds is reinforced, favoring the chirality transfer and therefore enhancing their catalytic enantioselectivity of Diels-Alder reaction from 23% [l-NorC16-NR-Cu(II)] to 78% [l-MetC16-NR-Cu(II)]. Our work demonstrates a new strategy from the perspective of strengthening the metal ion-supramolecular scaffold interaction for the preparation of chiral supramolecular catalysts with good catalytic enantioselectivity.

Stable detection of diazinon residues in vegetables by an electrochemiluminescent aptasensor based on the in-situ production of H2O2 from dual-catalytic glucose.

Stable detection of diazinon (DZN) residues in vegetables is important for food safety. In this work, an electrochemiluminescence (ECL) aptasensor with dual-catalytic glucose in-situ production of H2O2 was constructed for the stable detection of DZN in vegetables. Firstly, MWCNTs@MB was prepared using π-π stacking interactions between methylene blue (MB) and multi-walled carbon nanotubes (MWCNTs) to enhance the loading of MB on an electrode and thus catalyze the generation of H2O2 from glucose. Secondly, Cu2O@AuNPs was formed by loading AuNPs on the surface of Cu2O through spontaneous reduction reaction, which improved the interfacial charge transfer, Cu2O nano-enzyme had glucose oxidase mimicking activity and could further catalyze the production of more H2O2 from glucose. MWCNTs@MB and Cu2O@AuNPs played a key role in the in-situ generation of co-reacting reagent H2O2, which solved the problem of unstable detection caused by the easy decomposition of the H2O2 solution added to the luminescence system. In addition, the aptamer was immobilized on the electrode surface by forming Au-S bonds with Cu2O@AuNPs. As a result, the ECL aptasensor performed good linearity in 1.00 pg mL-1-1.00 µg mL-1 and a low limit of detection (LOD) to 0.39 pg mL-1 (S/N = 3). This work provided an effective method for the accurate and stable detection of DZN residues in vegetables, which was of great significance in ensuring food safety and assessing the environmental risk of DZN.

Visualization of Acrolein Upregulation during Ferroptosis by a Ratiometric Fluorescent Probe.

Ferroptosis is a pattern of cell death caused by iron-dependent accumulation of lipid peroxides and is closely associated with the occurrence and development of multiple diseases. Acrolein (ACR), one of the final metabolites of lipid peroxidation, is a reactive carbonyl species with strong biotoxicity. Effective detection of ACR is important for understanding its role in the progression of ferroptosis and studying the specific mechanisms of ferroptosis-mediated diseases. However, visualization detection of ACR during ferroptosis has not yet been reported. In this work, the first ratiometric fluorescent probe (HBT-SH) based on 2-(2'-hydroxyphenyl) benzothiazole (HBT) was designed for tracing endogenous ACR with an unprecedented regiospecific ACR-induced intramolecular cyclization strategy, which employs 2-aminoethanethiol as an ACR-selective recognition receptor. The experimental results showed that HBT-SH has excellent selectivity, high sensitivity (LOD = 0.26 µM) and good biocompatibility. More importantly, the upregulation of ACR levels was observed during ferroptosis in HeLa cells and zebrafish, indicating that ACR may be a specific active molecule that plays an essential biological role during ferroptosis or may serve as a potential marker of ferroptosis, which has great significance for studying the pathological process and treatment options of ferroptosis-related diseases.

Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex.

Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297-HerA, demonstrating that DUF4297-HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.