Large-scale-adaptive fringe projection 3D measurement.

Fringe projection profilometry (FPP) faces significant challenges regarding calibration difficulty and stitching error accumulation when operating across scenes ranging from tens to hundreds of meters. This Letter presents a calibration-free 3D measurement method by integrating a binocular vision of a FPP scanner with a wide field-of-view (FoV) vision that constructs global benchmarks to unify local 3D scanning and global 3D stitching, which is adaptable to arbitrarily large-scale scenes. A posterior global optimization model is then established to determine the reconstruction parameters and stitching poses simultaneously at each scanning node with adaptively distributed benchmarks. Consequently, the integrated vision measurement system not only eliminates the large-scale pre-calibration and stitching error accumulation but also overcomes system structural instability during moving measurement. With the proposed method, we achieved 3D measurements with an accuracy of 0.25 mm and a density of 0.5 mm for over 50-m-long scenes.

Long Head of the Biceps Tendon Plays a Role in Stress Absorption and Humeral Head Restriction during the Late Cocking and Deceleration Phases of Overhead Throwing: A Finite Element Study.

BACKGROUND: Emerging evidence suggests that the long head of the biceps (LHBT) may play a role in stabilizing the glenohumeral joint, and this has led to controversy around the efficacy of biceps tenotomy for superior labral anterior and posterior (SLAP) lesions. Therefore, the aim of this finite element analysis (FEA) study was to determine the stress absorption and humeral head translation restriction effects of the LHBT within the glenohumeral joint during the late cocking and deceleration phases of overhead throwing with a view to resolving the controversy around tenotomy. METHODS: Eight FEA models were created using computed tomography and magnetic resonance imaging data from normal glenohumeral joints. The models represented four LHBT conditions: uninjured, subpectoral tenodesis, tenotomy, and type II SLAP lesions. The late cocking and deceleration phases of the overhead throwing were simulated for each model. The impacts of the four LHBT conditions on glenohumeral joint stress absorption and humeral head displacement restriction were studied based on 1) stress and related distributions on the cartilage, labrum, capsule, and LHBT and 2) humeral head translation variation. RESULTS: The FEA analysis showed that the magnitude of the contact stress on the articular cartilage, labrum, and capsule was the lowest in the uninjured models, followed by the subpectoral tenodesis, tenotomy, and type II SLAP lesion models. Humeral head translation was the most restricted in the subpectoral tenodesis models, followed by the tenotomy and type II SLAP lesion models. CONCLUSION: Finite element analysis demonstrated that the LHBT plays a significant role in stress absorption and displacement restriction in the late cocking and deceleration phases of overhead throwing. Subpectoral tenodesis of the LHBT exhibited lesser amount of stress and humeral head translation than those of tenotomy, thereby making it a better option for patients who engage in overhead throwing.

Advancements in the Transdermal Drug Delivery Systems Utilizing Microemulsion-based Gels.

Microemulsion gel, as a promising transdermal nanoparticle delivery system, addresses the limitations of microemulsions and enhances their performance in drug delivery and release. This article aims to discuss the advantages of microemulsion gel, including improved drug bioavailability, reduced drug irritation, enhanced drug penetration and skin adhesion, and increased antimicrobial properties. It explores the methods for selecting microemulsion formulations and the general processes of microemulsion preparation, as well as commonly used oil phases, surfactants, and co-surfactants. Additionally, the biomedical applications of microemulsion gel in treating conditions, such as acne and psoriasis, are also discussed. Overall, this article elucidates the significant potential of microemulsion gel in topical drug delivery, providing insights into future development and clinical applications.

Morin alleviates DSS-induced ulcerative colitis in mice via inhibition of inflammation and modulation of intestinal microbiota.

Ulcerative colitis (UC) is a chronic inflammatory condition with recurrent and challenging symptoms. Effective treatments are lacking, making UC management a critical research area. Morin (MO), a flavonoid from the Moraceae family, shows potential as an anti-UC agent, but its mechanisms are not fully understood. Using a dextran sulfate sodium (DSS)-induced UC mouse model, we employed network pharmacology to predict MO's therapeutic effects. Assessments included changes in body weight, disease activity index (DAI), and colon length. Immunofluorescence, hematoxylin and eosin (H&E), and PAS staining evaluated colon damage. ELISA and western blot analyzed inflammatory factors, tight junction (TJ)-associated proteins (Claudin-3, Occludin, ZO-1), and Mitogen-Activated Protein Kinase (MAPK)/ Nuclear Factor kappa B (NF-κB) pathways. 16S rRNA sequencing assessed gut microbiota diversity, confirmed by MO's modulation via Fecal Microbial Transplantation (FMT). Early MO intervention reduced UC severity by improving weight, DAI scores, and colon length, increasing goblet cells, enhancing barrier function, and inhibiting MAPK/NF-κB pathways. MO enriched gut microbiota, favoring beneficial bacteria like Muribaculaceae and Erysipelotrichaceae while reducing harmful Erysipelotrichaceae and Muribaculaceae. This study highlights MO's potential in UC management through inflammation control, mucosal integrity maintenance, and gut flora modulation.

Transarterial Embolization Enhances Programmed Cell Death Ligand 1 Expression and Influences CD8+T Lymphocytes Cytotoxicity in an Orthotopic Hepatocellular Carcinoma Rat Model.

PURPOSE: To investigate the influence of transarterial embolization (TAE) on programmed cell death-ligand 1(PD-L1) expression and CD8+T tumour infiltrative lymphocyte cytotoxicity in the Sprague-Dawley (SD) rat model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: An orthotopic HCC model was established in twenty SD rats treated with TAE (lipiodol, n = 10) or sham (normal saline, n = 10) using homologous N1S1 hepatoma cells. Rats were euthanized 1 week after embolization. Flow cytometry was used to assess the proportion of CD4+T, CD8+T and programmed cell death-1+(PD-1+) CD8+T lymphocytes in the spleens and tumours. Distribution of CD8+T, granzyme-B+CD8+T lymphocytes and PD-L1+ cells was assessed by immunohistochemistry (IHC) or multiplex IHC. p value < 0.05 was considered statistically significant. RESULTS: The CD4/CD8 ratio and PD-1+CD8+ T lymphocytes exhibited higher values in TAE-treated tumours compared to sham-treated tumours (p = 0.021 and p = 0.071, respectively). Conversely, the number of CD8+T lymphocytes was decreased in TAE-treated tumours (p = 0.043), especially in the central region (p = 0.045). However, more CD8+T lymphocytes were found infiltrating the marginal region than central region in TAE-treated tumours (p = 0.046). The proportion of granzyme-B+CD8+T lymphocytes and the PD-L1 positive areas was elevated in tumours that treated with TAE (p all < 0.05). There was a negative correlation between PD-L1 expression and the number of infiltration of CD8+ T lymphocytes (p = 0.036). CONCLUSIONS: Immune cells are distributed unevenly in the tumours after TAE. The intrinsic induction state of the tumour after embolization may be insufficient to elicit a maximal response to PD-1/PD-L1 inhibitors.

The impact of dynamic caudal type homeobox 2 expression on the differentiation of human trophoblast lineage during implantation.

The trophoblast lineage differentiation represents a rate-limiting step in successful embryo implantation. Adhesion, invasion and migration processes within the trophoblast are governed by several transcription factors. Among them, CDX2 is a critical regulator shaping the destiny of the trophoblast. While its altered expression is a linchpin initiating embryo implantation in mice, the precise influence of CDX2 on the functionality and lineage differentiation of early human trophoblast remains unclear. In this study, we employed well-established human trophoblast stem cell (hTSC) lines with CDX2 overexpression coupled with a 3D in vitro culture system for early human embryos. We revealed that the downregulation of CDX2 is a prerequisite for syncytialization during human embryo implantation based on immunofluorescence, transcriptome analysis, CUT-tag sequencing and the construction of 3D human trophoblast organoids. While CDX2 overexpression inhibited syncytialization, it propelled hTSC proliferation and invasive migration. CDX2 exerted its influence by interacting with CGA, PTGS2, GCM1, LEF1 and CDH2, thereby hindering premature differentiation of the syncytiotrophoblast. CDX2 overexpression enhanced the epithelial-mesenchymal transition of human trophoblast organoids. In summary, our study provides insights into the molecular characteristics of trophoblast differentiation and development in humans, laying a theoretical foundation for advancing research in embryo implantation.

Transposition of the lingual thyroid gland to the submandibular region through a submandibular approach: A case report.

BACKGROUND: Ectopic thyroid at the base of the tongue is a rare congenital condition, and it is even rarer to have clinical symptoms and require surgical intervention. This disease is easily misdiagnosed preoperatively. This article reports the diagnosis, surgical treatment, and follow-up of a case of lingual thyroid. CASE SUMMARY: The patient was a 54-year-old woman who presented with laryngeal foreign body sensation and dysphagia for 20 d. The lingual thyroid was considered for general examination, and surgery was performed to transpose the lingual thyroid to the right submaxillary region. Pathological analysis confirmed thyroid tissue. The patient experienced complete remission after surgery, but developed hypothyroidism and required thyroid hormone replacement therapy, and her thyroid function gradually recovered over time. CONCLUSION: We report a rare case of lingual thyroid with marked laryngeal foreign body sensation and dysphagia. Symptoms were completely relieved by transposition surgery but postoperative hypothyroidism developed.

Rapid detection of lung cancer based on serum Raman spectroscopy and a support vector machine: a case-control study.

BACKGROUND: Early screening and detection of lung cancer is essential for the diagnosis and prognosis of the disease. In this paper, we investigated the feasibility of serum Raman spectroscopy for rapid lung cancer screening. METHODS: Raman spectra were collected from 45 patients with lung cancer, 45 with benign lung lesions, and 45 healthy volunteers. And then the support vector machine (SVM) algorithm was applied to build a diagnostic model for lung cancer. Furthermore, 15 independent individuals were sampled for external validation, including 5 lung cancer patients, 5 benign lung lesion patients, and 5 healthy controls. RESULTS: The diagnostic sensitivity, specificity, and accuracy were 91.67%, 92.22%, 90.56% (lung cancer vs. healthy control), 92.22%,95.56%,93.33% (benign lung lesion vs. healthy) and 80.00%, 83.33%, 80.83% (lung cancer vs. benign lung lesion), repectively. In the independent validation cohort, our model showed that all the samples were classified correctly. CONCLUSION: Therefore, this study demonstrates that the serum Raman spectroscopy analysis technique combined with the SVM algorithm has great potential for the noninvasive detection of lung cancer.

Sensitive detection of H2S based on Ce doped ZnCo2O4 hollow microspheres at low working temperature.

In order to develop a highly efficient H2S gas sensor at low working temperature, in this work, a kind of novel Ce-doped ZnCo2O4 hollow microspheres (Ce/ZnCo2O4 HMSs) were successfully synthesized using a template-free one-pot method, showing a sensitive response toward H2S. The microstructure and morphology of the material were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The gas-sensing performance of the composite was investigated, showing that the ZnCo2O4 doped with 6 mol% Ce had the highest response to 20 ppm H2S at a low operating temperature of 160 °C with a response value of 67.42, which was about 2 times higher than that of original ZnCo2O4. The prepared Ce/ZnCo2O4 HMS sensor in response to H2S exhibited a linear range of 0.1-200 ppm with a low detection limit of 0.1 ppm under the conditions of ambient humidity of 45% and ambient temperature of 20 °C. Meanwhile, it also possessed good selectivity, repeatability and reproducibility. The response value of the sensor decreased by 5.32% after 7 months of continuous monitoring of H2S in an atmospheric environment of a pig farm, indicating that the sensor had a long-term stability and continuous service life with important application prospects.

Cooperative Catalysis-Enabled (4 + 3) Cycloaddition of 2-Indolylmethanols with In Situ-Generated ortho-Naphthoquinone Methides.

A cooperative catalysis-enabled (4 + 3) cycloaddition of 2-indolylmethanols with ortho-naphthoquinone methides (o-NQMs), which were in situ-generated from enynones, has been established in the presence of silver/Brønsted acid cocatalysts. In the reaction pathway, the key o-NQM intermediates were formed through Ag(I)-catalyzed cyclization of enynones, while the indole-based carbocation intermediates were generated via Brønsted acid-catalyzed dehydration of 2-indolylmethanols. By this approach, a wide range of seven-membered cyclohepta[b]indoles were synthesized in good yields with high efficiency under mild reaction conditions, which serves as a useful strategy toward constructing indole-fused seven-membered rings. Moreover, the catalytic asymmetric version of this (4 + 3) cycloaddition has been realized under the cooperative catalysis of Ag(I) with chiral phosphoric acid, which offered chiral cyclohepta[b]indole with a good enantioselectivity (75% ee). This work not only represents the first cooperative catalysis-enabled (4 + 3) cycloaddition of 2-indolylmethanols but also provides a good example for o-NQM-involved cycloadditions, which will contribute to the chemistry of 2-indolylmethanols and enrich the research contents of cooperative catalysis.

Individual-based morphological brain network changes in children with Rolandic epilepsy.

OBJECTIVE: To investigate the local cortical morphology and individual-based morphological brain networks (MBNs) changes in children with Rolandic epilepsy (RE). METHODS: Based on the structural MRI data of 56 children with RE and 56 healthy controls (HC), we constructed four types of individual-based MBNs using morphological indices (cortical thickness [CT], fractal dimension [FD], gyrification index [GI], and sulcal depth [SD]). The global and nodal properties of the brain networks were analyzed using graph theory. The between-group difference in local morphology and network topology was estimated, and partial correlation analysis was further analyzed. RESULTS: Compared with the HC, children with RE showed regional GI increases in the right posterior cingulate gyrus and SD increases in the right anterior cingulate gyrus and medial prefrontal cortex. Regarding the network level, RE exhibited increased characteristic path length in CT-based and FD-based networks, while decreased FD-based network node efficiency in the right inferior frontal gyrus. No significant correlation between altered morphological features and clinical variables was found in RE. CONCLUSIONS: These findings indicated that children with RE have disrupted morphological brain network organization beyond local morphology changes. SIGNIFICANCE: The present study could provide more theoretical basis for exploring the neuropathological mechanisms in RE.

The Safety and Efficacy of ZelanteDVT™ Catheter Rheolytic Thrombectomy in the Treatment of Patients with Iliac Vein Stent Thrombosis.

BACKGROUND: To examine the safety and efficacy of ZelanteDVT™ catheter rheolytic thrombectomy in the treatment of patients with iliac vein stent thrombosis. METHODS: A retrospective analysis method was conducted by means of collecting the data of 32 patients who had completed the treatment of iliac vein stent thrombosis with ZelanteDVT catheter rheolytic thrombectomy from March 2019 to March 2023. Data on clinical characteristics, technical success, clinical success, complications, and early follow-up were analyzed. RESULTS: The technical success rates were 100%, intraoperatively, in which 22 cases were improved to thrombus clearance Grade II (50-90%), 10 were Grade III (>90%). There were 21 cases treated with subsequent catheter-directed thrombolysis, and the average urokinase administration of (120.90 ± 29.63)∗10ˆ4 units. The clinical success rates were 100% and the swelling of the affected limbs were significantly improved, a significant difference in the pre/postoperative between-thigh circumference difference [(5.16 ± 1.08) vs. (1.75 ± 0.84), P < 0.000]. The pre/postoperative Venous Clinical Severity Score was [(12.94 ± 1.70) vs. (7.44 ± 1.31), P < 0.000]. No serious complications occurred during the perioperative period. The postoperative and 12-month stent patency rate was 100.00% (32/32) and 71.88% (23/32), respectively. CONCLUSIONS: The ZelanteDVT catheter rheolytic thrombectomy seems to have a promising application prospect for the treatment of patients with iliac vein stent thrombosis.

Role of 8-hydroxyguanine DNA glycosidase 1 deficiency in exacerbating diabetic cardiomyopathy through the regulation of insulin resistance.

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance.

Thermosensitive curcumin/silver/montmorillonite-F127 hydrogels with synergistic photodynamic/photothermal/silver ions antibacterial activity.

Bacterial infections and the emergence of super-resistant bacteria pose a significant risk to human health. Effective sterilization to prevent the development of bacterial drug resistance remains a challenge. Herein, curcumin/silver/montmorillonite (Cur/Ag/Mt) was prepared through a green chemical reduction method with montmorillonite as the carrier, curcumin as the reducing agent and the capping agent, and citric acid as the structure guide agent. Then, a novel dual light-responsive and thermosensitive Pluronic F127-based hydrogel (CAM-F) was prepared by encapsulating Cur/Ag/Mt within the F127 hydrogel. The Cur/Ag/Mt showed strong absorption in the near-infrared region that efficiently converts light into heat for photothermal therapy when the molar ratio of curcumin to silver nitrate was 2 : 1. Specifically, triangular silver nanoparticles reduced by curcumin were immobilized on the Mt layers, which could enhance photodynamic therapy by the metal-enhanced singlet oxygen and metal-enhanced fluorescence mechanisms. Upon combining 405 nm and 808 nm laser irradiation, the CAM-F hydrogel could simultaneously generate reactive oxygen species, increase the local temperature, and sustain the release of Ag+, thus displaying excellent bactericidal performance against Gram-negative and Gram-positive bacteria. The antibacterial rates of CAM-F hydrogels were 99.26 ± 0.95% and 99.95 ± 0.98% for Escherichia coli and Staphylococcus aureus, respectively. The findings suggest the potential of the CAM-F hydrogel as a stable, biologically safe, and broad-spectrum antimicrobial material. The thermosensitive CAM-F hydrogels for synergetic phototherapy may provide a promising strategy for solving clinical problems caused by pathogenic infections.

Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.

Room temperature synthesis of nanocomposite thin films with embedded Cs2AgIn0.9Bi0.1Cl6 lead-free double perovskite nanocrystals with long-term water stability, wide range pH tolerance, and high quantum yield.

The synthesis of Cs2AgIn0.9Bi0.1Cl6 nanocrystals was achieved at room temperature under ambient conditions using the ligand-assisted reprecipitation (LARP) method. The synthesized NCs exhibit bright orange emission when excited at 375 nm and have broad photoluminescence (PL) emission spectra with a maximum of 630 nm. A photoluminescence quantum yield (PLQY) of 36% was observed in these NCs without any polymer coatings. Polystyrene (PS), and poly (methyl methacrylate) (PMMA) were used to enhance the water stability and PLQY values up to 64%. Nanocomposite thin films with these polymer encapsulations exhibit good thermal stability up to at least 353 K and high quantum yields. PMMA-coated NCs showed long-term water stability for at least 4 months. The composites remain photostable when in contact with water for at least 120 min under continuous 365 nm UV illumination at 1 mW cm-2. Due to their excellent optical properties, aqueous stability, and wide range pH tolerance, these nanocomposite thin films could be employed for a variety of biological applications.

Stability assessment of surrounding rock in downward mining route supported by slab-wall backfill structure.

Characteristic of ground pressure in surrounding rock is generally considered as the theoretical basis of parameter optimization for stope structure and technology. To explore the feasibility of efficient method for the second-step downward route backfill stopes in Shanjin gold mine, various numerical simulation methods were used to investigate the effect of slab-wall backfill structure on stability of surrounding rock in downward route mining system. The maximum principal stress, artificial false roof stress, and displacement were analyzed to evaluate the level of ground pressure in different mining areas. These results indicate the optimized structural parameters for backfill stopes, which may also provide a low-cost way to achieve a high safety for downward route mining system.

Preparation and efficacy of antibacterial methacrylate monomer-based polymethyl methacrylate bone cement containing N-halamine compounds.

Introduction: Our objective in this study was to prepare a novel type of polymethyl methacrylate (PMMA) bone cement, analyze its material properties, and evaluate its safety and antibacterial efficacy. Methods: A halamine compound methacrylate antibacterial PMMA bone cement containing an N-Cl bond structure was formulated, and its material characterization was determined with Fourier transform infrared spectroscopy (FT-IR) and 1H-NMR. The antibacterial properties of the material were studied using contact bacteriostasis and releasing-type bacteriostasis experiments. Finally, in vitro and in vivo biocompatibility experiments were performed to analyze the toxic effects of the material on mice and embryonic osteoblast precursor cells (MC3T3-E1). Results: Incorporation of the antibacterial methacrylate monomer with the N-halamine compound in the new antibacterial PMMA bone cement significantly increased its contact and releasing-type bacteriostatic performance against Staphylococcus aureus. Notably, at 20% and 25% additions of N-halamine compound, the contact and releasing-type bacteriostasis rates of bone cement samples reached 100% (p < 0.001). Furthermore, the new antibacterial bone cement containing 5%, 10%, and 15% N-halamine compounds showed good biocompatibility in vitro and in vivo. Conclusion: In this study, we found that the novel antibacterial PMMA bone cement with N-halamine compound methacrylate demonstrated good contact and releasing-type bacteriostatic properties against S. aureus. In particular, bone cement containing a 15% N-halamine monomer exhibited strong antibacterial properties and good in vitro and in vivo biocompatibility.

Characterization of a LanC-free pathway for the formation of an ll-MeLan residue and an alloAviMeCys residue in the newly identified class V lanthipeptide triantimycins.

The thioether-connected bis-amino acid lanthionine (Lan) residues are class-defining residues of lanthipeptides. Typically, the cyclization step of lanthionine formation, which relies on the addition of a cysteine to an unsaturated dehydroamino acid, is directed either by a standalone cyclase LanC (class I) or by a cyclase domain (class II-IV). However, the pathways of characterized class V members often lack a known cyclase (domain), raising a question on the mechanism by which their multi-macrocycle systems are formed. Herein, we report a new RiPP gene cluster in Streptomyces TN 58, where it encodes the biosynthesis of 3 distinct class V lanthipeptides-termed triantimycins (TAMs). TAM A1∼A3 share an N-terminal ll-MeLan residue, and only TAM A1 contains an additional internal ll-Lan residue. TAM A1 also has a C-terminal (2S, 3R)-S-((Z)-2-aminovinyl)-3-methyl-d-cysteine (alloAviMeCys) residue, which is distinct from the previously reported (2S, 3S)-AviMeCys residue in other RiPPs. Gene deletion, heterologous coexpression, and structural elucidation demonstrated that the cyclization for an ll-MeLan formation occurs spontaneously and is independent of any known lanthionine cyclase. This study provides a new paradigm for lanthionine formation and facilitates genome mining and engineering efforts on RiPPs containing (Me)Lan and (allo)Avi(Me)Cys residues.

Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer.

BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.