Efficient unsymmetric disulfide formation by molecular-scale tailoring of ortho-polyquinone-based polymer photocatalyst.

Disulfide bonds, especially unsymmetric disulfide bonds, have important applications in bioactivity and drug molecules, but the synthesis of unsymmetric disulfide bonds remains challenging due to efficiency and selectivity issues. Herein, this work utilizes anthraquinone (AQ) and cyclictriphosphonononitrile through a nucleophilic substitution reaction to synthesize an organic polymer (ANTH-AMI) that incorporates an ortho-polyquinone (o-polyquinone) redox center. The anthraquinone molecule functions as a redox center, capable of accepting photoinduced electrons and subsequently transferring them to initiate an electron-coupled hydrogenation reaction (AQ to AQH). Moreover, the proximity of the o-polyquinone redox sites facilitates the catalysis of unsymmetric disulfide bond formation. Consequently, the ANTH-AMI photocatalysts demonstrate exceptional yields (up to 82 %), substrate versatility, cycling stability, and scalable preparation in promoting unsymmetric coupling reactions of thiol. This work offers a solution for designing organic polymer photocatalysts with adjacent multiple redox centers for cross-coupling reactions.

A rhodamine-based fluorescent probe bearing 8-hydroxyquinoline group for the highly selective detection of Hg2+ and its practical application in cell imaging.

A highly selective and sensitive fluorescent probe, RHOQ, was designed for the detection of Hg2+ by incorporating an 8-hydroxyquinoline moiety onto a rhodamine molecular platform with a suitable linker. In MeOH-Tris (20 mM, pH = 7.4, 1 : 9, v/v) buffer solution, RHOQ exhibited 550-fold fluorescence enhancement at 594 nm upon addition of Hg2+, with a fast response and a low detection limit (9.67 × 10-8 M). The 1 : 1 binding mode of RHOQ with Hg2+ was established using Job's plot, UV-Vis, and fluorescence spectroscopic titration methods. Furthermore, RHOQ was successfully applied for the detection of Hg2+ in living cells with good membrane permeability.

Combination of melatonin-delivered endothelial progenitor cells with S-nitroso-N-acetyl-DL-penicillamine for improving critical limb ischemia in the rat.

BACKGROUND: This study tested whether combined shock wave (SW)-facilitated melatonin (Mel) delivered into endothelial progenitor cells (EPCs) (EPCSW-Mel) plus S-nitroso-N-acetyl-DL-penicillamine (SNAP) was superior to merely one modality alone for improving critical limb ischemia (CLI) in rats. METHODS: SD rats (n = 50) were equally categorized into group 1 (sham-control), group 2 (CLI), group 3 (CLI + SNAP), group 4 (CLI + EPCSW-Mel), and group 5 (CLI + EPCSW-Mel + SNAP), and ischemia-involved quadriceps were harvested by day 14. RESULTS: An in vitro study showed that at time points of 24/48/72 h, the cell viability/protein expression of endothelial nitric oxide synthase (eNOS)/and cellular expression of nitric oxide (NO) were highest in EPCs, lowest in EPCs + menadione, and much higher in EPCSW-Mel + Mena than in EPCs + Mena + Mel. Protein levels of oxidative-stress (NOX-1/NOX-2/oxidized protein)/early (AN-V+/PI-)/late (AN-V+/PI+) apoptosis and total intracellular/mitochondrial reactive oxygen species ROS exhibited an antithetical trend of cell viability among the groups (all P<0.0001). Matrigel assay of angiogenesis/positively-stained NO cells showed that they were much higher in EPCs + SNAP than in EPCs only (all P<0.0001). Ex vivo angiogenesis/arterial relaxation of carotid-artery rings were highest in left-common-carotid-artery (LCCA) + SNAP, lowest in LCCA + Mena, and notably higher in LCCA than in LCCA + Mena + SNAP (all P<0.0001). Laser Doppler showed ischemic to normal-blood-flow (INBF) ratio was highest in group 1, lowest in group 2, and it progressively increased from groups 3 to 5 (all P<0.0001). The protein levels of oxidative-stress (NOX-1/NOX-4/oxidized protein)/apoptotic [cleaved-caspase-3/cleaved apoptosis/mitochondrial-damage (cytosolic-cytochrome-C/p-DRP-1)]/fibrotic (Smad3/TGF-ß)/inflammatory (MMP-9/IL-1ß/TNF-α/NF-κB) biomarkers, exhibited an opposite trend, whereas the protein level of endothelial-cell surface markers (CD31/vWF/eNOS) and number of small vessels exhibited an identical pattern of INBF ratio among the groups (all P<0.0001). CONCLUSIONS: Combined EPCSW-Mel and SNAP therapy offered a synergic effect toward rescuing from CLI.

A New Bacterial Strain Producing Both of the Surfactin and Fengycin Lipopeptide Biosurfactant with Strong Emulsifications on Crude Oil.

A new lipopeptide-producing strain Cytobacillus sp. R3-1 was isolated from the production water of the Daqing oilfield in China and identified based on 16S rRNA gene sequence analyses. The strain R3-1 is capable of simultaneously producing both of the surfactin and fengycin, the two major families of the lipopeptide biosurfactant. The chemical structures of the surfactin and fengycin were confirmed by a combination of the ESI-MS, FT-IR, and amino acid analyses, and the impact of various temperatures, pH, and NaCl concentrations on the emulsifying activity (E24) was investigated. The lipopeptide biosurfactant produced by the strain R3-1 exhibited strong emulsifying activity with E24 value over 60% on crude oil and different hydrocarbons, including the cyclohexane, hexadecane, benzene, toluene, kerosene, diesel oil, and liquid paraffin. Meanwhile, it showed excellent emulsifying activity across a broad range of conditions of the temperature up to 60 °C, NaCl tolerance up to 100 g/L, and pH values between 5 and 9, which suggests that the strain R3-1 is a valuable microbial candidate for the simultaneous production of the surfactin and fengycin lipopeptide biosurfactant with strong emulsifying properties and stability under diverse environmental conditions and is a potential application in environmental bioremediation and enhanced oil recovery.

Influence of Fe Ions on Anode Performance and the Mechanism of Action during Copper Electrowinning Process.

The performance of the anode varies from the impurity ions in the copper electrowinning process. This work focused on the variation of the electrochemical behavior of the Pb-0.06%Ca-1.2%Sn anode as the Fe ions (Fe3+ and/or Fe2+) existed in the electrolyte by electrochemical characterization. Copper electrodeposition experiments were conducted under a current density of 300 A/m2, with the Fe ion concentration in the electrolyte controlled within the range of 0 to 20 g/L and the Cu ion concentration maintained at 45 g/L at a temperature of 45 °C. The variation in the corrosion resistance, catalytic activity, and structural composition of the anode film layer was analyzed in-depth according to the presence of Fe ions. The results show that the structure of PbO2 on the surface of the film was changed as Fe ions doped into the anode film, and the oxygen evolution activity of the anode was also improved. However, the corrosion resistance decreased with increasing Fe3+ concentration. Furthermore, the addition of 2 g/L Fe2+ in the electrolyte containing 2 g/L Fe3+ led to an elevation in the corrosion resistance of the anode to some extent and further increased the oxygen evolution activity.

Risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia.

Objective: To identify risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia and to construct a nomogram predictive model. Methods: This retrospective study included 292 patients who underwent gastrointestinal endoscopy under acupuncture anesthesia at the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from June 2020 to May 2023. Logistic regression analysis was used to identify risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia. A nomogram prediction model was constructed using the RMS package of R4.1.2 software based on the independent risk factors identified. The predictive performance of the model was assessed using consistency index (C-index), calibration curve, and receiver operating characteristic (ROC) curve. Results: Seventy-five patients (25.68%) had complications. Body mass index (BMI), history of cardiovascular diseases, fasting time, history of respiratory diseases, and Sedation-Agitation Scale (SAS) score were identified as risk factors for complications. Based on this risk, a nomogram predictive model was constructed. The C-index of the nomogram model was 0.927. Calibration curve showed a good consistency between actual observations and nomogram predictions. The ROC curve area under curve (AUC) was 0.927 (95% CI: 0.895-0.959), indicating a certain predictive value for the occurrence of complications. When the optimal cut-off value was selected, the sensitivity and specificity of the model were 77.0% and 92.0%, respectively, indicating that the predictive model was effective. Conclusions: BMI, history of cardiovascular disease, fasting time, history of respiratory disease, and SAS score are independent risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia. The constructed nomogram predictive model has a good performance in predicting the occurrence of complications in patients undergoing gastrointestinal endoscopy with under acupuncture anesthesia.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). METHODS: This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. RESULTS: Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). CONCLUSION: Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

A PLA-mediated transistor biosensor enables specific identification of tumor-derived exosomal PD-L1.

The expression of programmed death ligand 1 (PD-L1) on tumor-derived exosomes (tExos) forecasts the efficacy of immunotherapy and tumor diagnosis. Due to the heterogeneity of exosomes, current detection methods face challenges in distinguishing between tumor-derived and non-tumor-derived exosome PD-L1. To address this challenge, we introduce a novel field effect transistor (FET) biosensor based on proximity ligation assay (PLA) technology. This approach uses a single probe to simultaneously recognize two biomarkers on exosomes to identify tumor-derived exosome PD-L1 (tExo-PD-L1). This method, for the first time, integrates the PLA strategy with FET technology, allowing for tracking of exosomes that co-express multiple biomarkers. In clinical diagnostics, this strategy not only significantly improves the sensitivity and specificity, but also enhances the precision and accuracy, compared to conventional approaches that identify total Exo-PD-L1 or Exo-EpCAM using a single biomarker. This technology holds promise for enhancing the reliability of using exosomes as biomarkers in clinical diagnostics and further exploring the biological functions of exosomes more effectively.

Abnormal recognition-assisted and onset-offset aware network for pathological wearable ECG delineation.

Electrocardiogram (ECG) delineation is essential to the identification of abnormal cardiac status, especially when ECG signals are remotely monitored with wearable devices. The complexity and diversity of cardiac conditions generate numerous pathological ECG patterns, not only requiring the recognition of normal ECG but also addressing an extensive range of abnormal ECG patterns, posing a challenging task. Therefore, we propose an abnormal recognition-assisted network to integrate supplementary information on diverse ECG patterns. Simultaneously, we design an onset-offset aware loss to enhance precise waveform localization. Specifically, we establish a two-branch framework where ECG delineation serves as the target task, producing the final segmentation results. Additionally, the abnormal recognition-assisted network serves as an auxiliary task, extracting multi-label pathological information from ECGs. This joint learning approach establishes crucial correlations between ECG delineation and associated ECG abnormalities. The correlations enable the model to demonstrate sufficient generalization in the presence of diverse abnormal ECG patterns. Besides, onset-offset aware loss focuses intensively on wave onsets and offsets by applying biased weights to various waveform positions. This approach ensures a focus on precise localization, facilitating seamless integration into cross-entropy loss function. A large-scale wearable 12-lead dataset containing 4,913 signals is collected, offering an extensive range of ECG data for model training. Results demonstrate that our method achieves outstanding performance on two test datasets, attaining sensitivity of 94.97% and 94.27% and an error tolerance lower than 20 ms. Furthermore, our method is effective for various aberrant ECG signals, including ST-segment changes, atrial premature beats, and right and left bundle branch blocks.

Toripalimab in combination with HBM4003, an anti-CTLA-4 heavy chain-only antibody, in advanced melanoma and other solid tumors: an open-label phase I trial.

BACKGROUND: HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma. METHODS: The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored. RESULTS: A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy. CONCLUSIONS: HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma. TRIAL REGISTRATION NUMBER: NCT04727164.

Phloridzin prevents diabetic cardiomyopathy by reducing inflammation and oxidative stress.

Oxidative stress and inflammation significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Persistent inflammatory stimuli drive the progression of myocardial fibrosis and impaired cardiac function. Phloridzin (Phl), a natural compound, demonstrates both anti-inflammatory and antioxidant properties. Nevertheless, its therapeutic potential and underlying mechanisms in DCM remain unclear. This study aimed to elucidate the mechanisms through which Phl inhibited myocardial fibrosis and exerted its antioxidative effects. The impact of Phl on DCM was evaluated using a high-fat/high-sugar diet combined with streptozotocin to induce an animal model and an in vitro H9C2 cell model stimulated by high glucose (HG). Untargeted metabolomics identified potential mechanisms underlying myocardial fibrosis. Phl treatment significantly enhanced left ventricular ejection fraction (EF%) and shortening fraction (FS%), while reducing myocardial injury markers, such as lactate dehydrogenase and creatine phosphokinase-MB, and suppressing myocardial collagen fiber accumulation. Simultaneously, Phl attenuated myocardial inflammation via inhibition of MyD88/NF-κB signaling, modulated the Nrf2/GPX4 axis to counter oxidative stress, and mitigated ferroptosis. In vitro, Phl inhibited high glucose-induced myocardial hypertrophy and fibrosis in H9C2 cells, while also repressing NF-κB activation in cardiomyocytes. Metabolomic profiling revealed that Phl ameliorated DCM through modulation of glycerophospholipid metabolic pathways, linking these metabolic shifts to enhanced antioxidant capacity, thereby reflecting its ability to reduce oxidative stress in the myocardium. Collectively, Phl provides cardioprotective effects by alleviating inflammation and oxidative damage.

Structural Reassignment of Covalent Organic Framework-Supported Palladium Species: Heterogenized Palladacycles as Efficient Catalysts for Sustainable C-H Activation.

Recent decades have witnessed remarkable progress in ligand-promoted C-H activation with palladium catalysts. While a number of transformations have been achieved with a fairly broad substrate scope, the general requirements for high palladium loadings and enormous challenges in catalyst recycling severely limit the practical applications of C-H activation methodologies in organic synthesis. Herein, we incorporate N,C-ligand-chelated palladacycles into rigid, porous, and crystalline covalent organic frameworks for the C-H arylation of indole and pyrrole derivatives. These heterogeneous palladium catalysts exhibit superior stability and recyclability compared to their homogeneous counterparts. We not only produce several highly reactive palladacycles embedded on new framework supports to facilitate C-H activation/C-C bond-forming reactions but also reassign heterogenized palladium species on frameworks containing a benzaldehyde-derived imine moiety as imine-based palladacycles via comprehensive characterization. Our findings provide guidance for the rational design of framework-supported metallacycles in the development of heterogeneous transition-metal catalysis.

Thalamic functional dysconnectivity in patients with left-hemisphere chronic capsular and pontine stroke.

Background: Through its extensive connection with the cortex, the thalamus constitutes the hub of cortico-subcortical circuits and participants in multi-dimensional functions. However, the differential involvements of thalamic functional connectivity in chronic capsular and pontine stroke are still unknown. Methods: The research recruited 66 left-lesion chronic stroke patients, including 46 capsular strokes (CS) and 20 pontine stroke (PS) patients, and 67 normal controls (NC). The thalamic subfields functional connectivities were compared between groups using a two-way repeated analysis of variance (ANOVA), corrected for confounders including age, gender, education and scanners. Spearman partial correlation was used to explore the potential association between altered thalamic FC and clinical variables. Results: The ipsilesional thalamus of CS patients had abnormally decreased FC with widespread cognitive-related areas while increased FC with visual- and somatic-motor areas. In contrast, the ipsilesional thalamus of PS patients mainly demonstrated increased FC in these sensorimotor areas. Even in the contralesional thalamus, we observed similar (with the ipsilesional) but less extensive functional dysconnectivity patterns in both the CS and PS patients (P < 0.05, corrected using family-wise error [FWE] at the voxel level). Finally, we found significant group x subfields interactions on thalamic functional connectivity, where capsular vs. pontine stroke demonstrate varied functional dysconnectivity with specific thalamic subfields. Finally, a weak correlation was found between FC of both ipsilesional/contralesional thalamic subfields and motor, working and verbal memory. Conclusions: The thalamic functional dysconnectivity after chronic stroke are lesion-location and subfields dependent. Moreover, functional dysconnectivity were shown in both the ipsilesional and contralesional thalamus with similar patterns.

A novel esterase regulates Klebsiella pneumoniae hypermucoviscosity and virulence.

Klebsiella pneumoniae, an emerging multidrug-resistant pathogen, exhibits hypermucoviscosity (HMV) as a critical virulence trait mediated by its capsular polysaccharide (CPS). Recent discoveries have determined acetylation as a significant modification for CPS, although its impact on HMV and virulence was previously unknown. This study elucidates the roles of two enzymes: Klebsiella pneumoniae Acetylated CPS Esterase (KpACE), an esterase that removes acetyl groups from CPS, and WcsU, an acetyltransferase that adds acetyl groups to CPS. KpACE is highly upregulated in an ompR-deficient mutant lacking HMV, and its overexpression consistently reduces HMV and diminishes virulence in a mouse model of pneumonia. The esterase domain-containing KpACE effectively deacetylates model sugar substrates and CPS-K2. Site-directed mutagenesis of the conserved catalytic histidine residue at position 370 significantly reduces its enzymatic activity. This reduction correlates with decreased HMV, affecting key virulence traits including biofilm formation and serum resistance. Similarly, a deficiency in the wcsU gene abolishes CPS acetylation, and reduces HMV and virulence. These results highlight the importance of the delicate balance between CPS acetylation by WcsU and deacetylation by KpACE in regulating the pathogenicity of K. pneumoniae. Understanding this balance provides new insights into the modulation of virulence traits and potential therapeutic targets for combating K. pneumoniae infections.

The efficacy of an intracoronary cocktail administration in preventing no-reflow during excimer laser coronary angioplasty in patients with in-stent restenosis: A pilot study. (ELCA- cocktail study).

BACKGROUND: The no-reflow phenomenon is a significant complication during excimer laser coronary angioplasty (ELCA) procedures, which can lead to adverse outcomes. This study explores the efficacy of intracoronary administration of a cocktail solution comprising nitroglycerin, heparin, and verapamil on preventing no-reflow during ELCA in patients with in-stent restenosis (ISR). METHODS: This study included patients undergoing ELCA with contrast infusion for ISR. Based on whether receiving the intracoronary cocktail solution during ELCA, participants were divided into two groups: the cocktail (+) group and the cocktail (-) group. The primary endpoint was the incidence of no-reflow, which was defined as the cessation of blood flow into the distal coronary artery in the absence of a clear angiographic explanation for impairment of flow. RESULTS: A total of 54 lesions in 51 patients were included. The mean age of the study population was 61.8 ± 9.7 years, with 84.3 % male. Baseline clinical characteristics were well-balanced. The incidence of no-reflow was significantly lower in the cocktail (+) group compared to the cocktail (-) group (0 % vs. 17.9 %, P = 0.024). No cases of hypotension, major bleeding or coronary perforation in either group. Major adverse cardiac events (MACE) within 6-month were no significant difference between the groups (4.0 % vs. 3.8 %, P = 0.977). CONCLUSIONS: The pilot study suggests that intracoronary administration of a cocktail comprising heparin, nitroglycerin, and verapamil may reduce the incidence of no-reflow during ELCA in patients with ISR. However, given the limited sample size and the non-randomized design, these findings should be considered hypothesis-generating. Future validation needs to be confirmed through multicenter studies with larger sample sizes.

Energy Reserve Allocation in the Trade-Off between Migration and Reproduction in Fall Armyworm.

Striking a trade-off between migration and reproduction becomes imperative during long-range migration to ensure proper energy allocation. However, the mechanisms involved in this trade-off remain poorly understood. Here, we used a takeoff assay to distinguish migratory from non-migratory individuals in the fall armyworm, which is a major migratory insect worldwide. Migratory females displayed delayed ovarian development and flew further and faster than non-migratory females during tethered flight. Transcriptome analyses demonstrated an enrichment of fatty acid genes across successive levels of ovarian development and different migratory behaviors. Additionally, genes with roles in phototransduction and carbohydrate digestion along with absorption function were enriched in migratory females. Consistent with this, we identified increased abdominal lipids in migratory females that were mobilized to supply energy to the flight muscles in the thorax. Our study reveals that the fall armyworm faces a trade-off in allocating abdominal triglycerides between migration and reproduction during flight. The findings provide valuable insights for future research on this trade-off and highlight the key energy components involved in this strategic balance.

Osmotic signaling releases PP2C-mediated inhibition of Arabidopsis SnRK2s via the receptor-like cytoplasmic kinase BIK1.

Osmotic stress and abscisic acid (ABA) signaling are important for plant growth and abiotic stress resistance. Activation of osmotic and ABA signaling downstream of the PYL-type ABA receptors requires the release of SnRK2 protein kinases from the inhibition imposed by PP2Cs. PP2Cs are core negative regulators that constantly interact with and inhibit SnRK2s, but how osmotic signaling breaks the PP2C inhibition of SnRK2s remains unclear. Here, we report that an Arabidopsis receptor-like cytoplasmic kinase, BIK1, releases PP2C-mediated inhibition of SnRK2.6 via phosphorylation regulation. The dominant abi1-1 ABA-signaling mutation (G180D) disrupts PYL-PP2C interactions and disables PYL-initiated release of SnRK2s; in contrast, BIK1 releases abi1-1-mediated inhibition of SnRK2.6. BIK1 interacts with and phosphorylates SnRK2.6 at two tyrosine residues, which are critical for SnRK2.6 activation and function. Phosphorylation of the two tyrosine residues may affect the docking of the tryptophan "lock" of PP2C into SnRK2.6. Moreover, the bik1 mutant is defective in SnRK2 activation, stress-responsive gene expression, ABA accumulation, growth maintenance, and water loss under osmotic stress. Our findings uncover the critical role of BIK1 in releasing PP2C-mediated inhibition of SnRK2s under osmotic stress.

Phase 2 dose-ranging study to evaluate the efficacy and safety of liposomal irinotecan (LY01610) as a second-line treatment for patients with relapsed small cell lung cancer.

Background: This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). Methods: This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60 mg/m2, 80 mg/m2, and 100 mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Findings: From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval <90 days. In all 66 patients, the ORR was 32% (21/66, 95% confidence interval [CI], 21-44), with a median DoR of 5.2 months (95% CI, 3.0-8.3). Median PFS and OS were 4.0 (95% CI, 2.9-5.5) and 9.7 (95% CI, 7.2-12.3) months, respectively. The ORR of 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 33% (2/6), 33% (10/30), and 30% (9/30), respectively. The median DoR of 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 4.2 (95% CI, 2.8-not reached), 6.9 (95% CI, 2.5-9.9), and 4.0 (95% CI, 2.7-6.8) months, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) in the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 33% (2/6), 47% (14/30), and 50% (15/30), respectively. The most common ≥ grade 3 TRAEs of all 66 patients were neutropenia (27%), leukopenia (24%) and anemia (15%). Interpretation: LY01610 exhibited promising clinical efficacy and manageable safety profiles in patients with relapsed SCLC, the 80 mg/m2 dose group had the best benefit-risk ratio. Funding: This study was supported by Luye Pharma Group Ltd.