The white lupin trehalase gene LaTRE1 regulates cluster root formation and function under phosphorus deficiency.

Under phosphorus (P) deficiency, white lupin (Lupinus albus L.) forms specialized root structure, called cluster root (CR), to improve soil exploration and nutrient acquisition. Sugar signaling is thought to play a vital role in the development of CR. Trehalose and its associated metabolites are the essential sugar signal molecules that link growth and development to carbon metabolism in plants, however, their roles in the control of CR are still unclear. Here, we investigated the function of the trehalose metabolism pathway by pharmacological and genetic manipulation of the activity of trehalase in white lupin, the only enzyme that degrades trehalose into glucose. Under P deficiency, validamycin A treatment, which inhibits trehalase, led to the accumulation of trehalose and promoted the formation of CR with enhanced organic acid production, whereas overexpression of the white lupin TREHALASE1 (LaTRE1) led to decreased trehalose levels, lateral rootlet density, and organic acid production. Transcriptomic and virus-induced gene silencing (VIGS) results revealed that LaTRE1 negatively regulates the formation of CRs, at least partially, by the suppression of LaLBD16, whose putative ortholog in Arabidopsis (Arabidopsis thaliana) acts downstream of ARF7- and ARF19-dependent auxin signaling in lateral root formation. Overall, our findings provide an association between the trehalose metabolism gene LaTRE1 and CR formation and function with respect to organic acid production in white lupin under P deficiency.

Detecting early-warning biomarkers associated with heart-exosome genetic-signature for acute myocardial infarction: A source-tracking study of exosome.

The genetic information of plasma total-exosomes originating from tissues have already proven useful to assess the severity of coronary artery diseases (CAD). However, plasma total-exosomes include multiple sub-populations secreted by various tissues. Only analysing the genetic information of plasma total-exosomes is perturbed by exosomes derived from other organs except the heart. We aim to detect early-warning biomarkers associated with heart-exosome genetic-signatures for acute myocardial infarction (AMI) by a source-tracking analysis of plasma exosome. The source-tracking of AMI plasma total-exosomes was implemented by deconvolution algorithm. The final early-warning biomarkers associated with heart-exosome genetic-signatures for AMI was identified by integration with single-cell sequencing, weighted gene correction network and machine learning analyses. The correlation between biomarkers and clinical indicators was validated in impatient cohort. A nomogram was generated using early-warning biomarkers for predicting the CAD progression. The molecular subtypes landscape of AMI was detected by consensus clustering. A higher fraction of exosomes derived from spleen and blood cells was revealed in plasma exosomes, while a lower fraction of heart-exosomes was detected. The gene ontology revealed that heart-exosomes genetic-signatures was associated with the heart development, cardiac function and cardiac response to stress. We ultimately identified three genes associated with heart-exosomes defining early-warning biomarkers for AMI. The early-warning biomarkers mediated molecular clusters presented heterogeneous metabolism preference in AMI. Our study introduced three early-warning biomarkers associated with heart-exosome genetic-signatures, which reflected the genetic information of heart-exosomes carrying AMI signals and provided new insights for exosomes research in CAD progression and prevention.

Transposition mechanism of ISApl1-the determinant of colistin resistance dissemination.

Multidrug-resistant Enterobacteriaceae, a prominent family of gram-negative pathogenic bacteria, causes a wide range of severe diseases. Strains carrying the mobile colistin resistance (mcr-1) gene show resistance to polymyxin, the last line of defense against multidrug-resistant gram-negative bacteria. However, the transmission of mcr-1 is not well understood. In this study, genomes of mcr-1-positive strains were obtained from the NCBI database, revealing their widespread distribution in China. We also showed that ISApl1, a crucial factor in mcr-1 transmission, is capable of self-transposition. Moreover, the self-cyclization of ISApl1 is mediated by its own encoded transposase. The electrophoretic mobility shift assay experiment validated that the transposase can bind to the inverted repeats (IRs) on both ends, facilitating the cyclization of ISApl1. Through knockout or shortening of IRs at both ends of ISApl1, we demonstrated that the cyclization of ISApl1 is dependent on the sequences of the IRs at both ends. Simultaneously, altering the ATCG content of the bases at both ends of ISApl1 can impact the excision rate by modifying the binding ability between IRs and ISAPL1. Finally, we showed that heat-unstable nucleoid protein (HU) can inhibit ISApl1 transposition by binding to the IRs and preventing ISAPL1 binding and expression. In conclusion, the regulation of ISApl1-self-circling is predominantly controlled by the inverted repeat (IR) sequence and the HU protein. This molecular mechanism deepens our comprehension of mcr-1 dissemination.

IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

BACKGROUND: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated. METHODS: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis. RESULTS: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo. CONCLUSIONS: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.

Comparison of AirSeal versus conventional insufflation system for retroperitoneal robot-assisted laparoscopic partial nephrectomy: a randomized controlled trial.

PURPOSE: AirSeal is a valve-less trocar insufflation system which is widely used in robotic urologic surgeries. More evidence is needed concerning the application and cost of AirSeal in retroperitoneal robot-assisted laparoscopic partial nephrectomy. METHODS: We conducted a randomized controlled trial enrolling 62 patients who underwent retroperitoneal robot-assisted laparoscopic partial nephrectomy from February 2022 to February 2023 in the Peking Union Medical College Hospital. Patients were randomly assigned into AirSeal insufflation (AIS) group and conventional insufflation (CIS) group. The primary outcome was the rate of subcutaneous emphysema (SCE). RESULTS: The SCE rate in the AIS group (12.9%) was significantly lower than that in the CIS group (35.5%) (P = 0.038). Lower maximum end-tidal carbon dioxide (CO2) (41 vs 45 mmHg, P = 0.011), PaCO2 at the end of the operation (40 vs 45 mmHg, P < 0.001), maximum tidal volume (512 vs 570 ml, P = 0.003), frequency of lens cleaning (3 vs 5, P < 0.001), pain score at 8 h (3 vs 4, P = 0.025), 12 h (2 vs 3, P = 0.029) postoperatively and at time of discharge (1 vs 2, P = 0.002) were observed in the AIS group, despite a higher hospitalization cost (68,197 vs 64658RMB, P < 0.001). Logistic regression analysis identified insufflation approach was the only influencing factor for the occurrence of SCE events. CONCLUSION: AirSeal insufflation system exhibited similar efficacy and improved safety for retroperitoneal robot-assisted laparoscopic partial nephrectomy than conventional insufflation system, despite an affordable increase of hospitalization costs.

Zn-Catalyzed Dehydroxylative Phosphorylation of Allylic Alcohols with P(III)-Nucleophiles.

A novel and efficient protocol for the synthesis of diarylallyl-functionalized phosphonates, phosphinates, and phosphine oxides through the zinc-catalyzed dehydroxylative phosphorylation of allylic alcohols with P(III)-nucleophiles via a Michaelis-Arbuzov-type rearrangement is reported. A broad range of allylic alcohols and P(III)-nucleophiles (P(OR)3, ArP(OR)2, and Ar2P(OR)) are well tolerated in this reaction, and the expected dehydroxylative phosphorylation products could be synthesized with good to excellent yields under the optimal reaction conditions. The reaction can be easily scaled up at a gram-synthesis level. Furthermore, through the step-by-step control experiments, kinetic study experiments, and 31P NMR tracking experiments, we acquired insights into the reaction and proposed the possible mechanism for this transformation.

Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.

Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.

The role of antimicrobial prophylaxis in laparoscopic nephrectomy for renal cell carcinoma.

BACKGROUND: To investigate the role of antimicrobial prophylaxis in laparoscopic nephrectomy for renal cell carcinoma. METHODS: We retrospectively enrolled 1000 patients who underwent laparoscopic nephrectomy from August 2019 to November 2021 in the Peking Union Medical College Hospital. Patients were divided into group without antimicrobial prophylaxis (n = 444) and group with antimicrobial prophylaxis (n = 556). Outcomes including 30-day postoperative infection rate, the increase rate of pre- and post-operative white blood cell counts and hospital stay were analyzed. RESULTS: The overall infection rate was 5.0% (28/556) in the group with antimicrobial prophylaxis, which was similar to 4.1% (18/444) in the group without antimicrobial prophylaxis (P = 0.461). The increase rate of pre- and post-operative white blood cell counts was significantly lower (85.5% versus 97.0%) in the group with antimicrobial prophylaxis (P = 0.004). The postoperative hospital stay was 5 (4, 6) days in both groups (P = 0.483). Logistic regression analyses identified the use of antimicrobial prophylaxis had no influence on the occurrence of infection events (odds ratio = 0.797; 95% confidence interval, 0.435-1.460; P = 0.462). Hemoglobin (odds ratio = 0.430; 95% confidence interval, 0.257-0.719; P = 0.001) and partial nephrectomy (odds ratio = 2.292; 95% confidence interval, 1.724-3.046; P < 0.001) influenced the use of antimicrobial prophylaxis independently. CONCLUSIONS: The use of antimicrobial prophylaxis had no impact on postoperative infection in patients receiving laparoscopic nephrectomy for renal cell carcinoma.

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target.

Neutrophil extracellular traps (NETs) are implicated in gastric cancer (GC) growth, metastatic dissemination, cancer-associated thrombosis, etc. This work is conducted to elucidate the heterogeneity of NETs in GC. The transcriptome heterogeneity of NETs is investigated in TCGA-STAD via a consensus clustering algorithm, with subsequent external verification in the GSE88433 and GSE88437 cohorts. Clinical and molecular traits, the immune microenvironment, and drug response are characterized in the identified NET-based clusters. Based upon the feature genes of NETs, a classifier is built for estimating NET-based clusters via machine learning. Multiple experiments are utilized to verify the expressions and implications of the feature genes in GC. A novel NET-based classification system is proposed for reflecting the heterogeneity of NETs in GC. Two NET-based clusters have unique and heterogeneous clinical and molecular features, immune microenvironments, and responses to targeted therapy and immunotherapy. A logistic regression model reliably differentiates the NET-based clusters. The feature genes C5AR1, CSF1R, CSF2RB, CYBB, HCK, ITGB2, LILRB2, MNDA, MPEG1, PLEK, SRGN, and STAB1 are proven to be aberrantly expressed in GC cells. Specific knockdown of C5AR1 effectively hinders GC cell growth and elicits intracellular ROS accumulation. In addition, its suppression suppresses the aggressiveness and EMT phenotype of GC cells. In all, NETs are the main contributors to intratumoral heterogeneity and differential drug sensitivity in GC, and C5AR1 has been shown to trigger GC growth and metastatic spread. These findings collectively provide a theoretical basis for the use of anti-NETs in GC treatment.

αO-Conotoxin GeXIVA[1,2] Suppresses In Vivo Tumor Growth of Triple-Negative Breast Cancer by Inhibiting AKT-mTOR, STAT3 and NF-κB Signaling Mediated Proliferation and Inducing Apoptosis.

Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.

Study on the Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactone Derivatives.

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid and efficient screening of bioactive compounds. The 14-membered resorcylic acid lactones (RALs) have a wide range of bioactivities such as antibacterial, antifouling and antimalarial activity. In order to further study their bioactivities, we initially constructed a 14-membered RALs library, which contains 16 new derivatives. The anti-M. marinum activity was evaluated in vitro. Derivatives 12, 19, 20 and 22 exhibited promising activity with MIC90 values of 80, 90, 80 and 80 µM, respectively. The preliminary structure-activity relationships showed that the presence of a chlorine atom at C-5 was a key factor to improve activity. Further studies showed that 12 markedly inhibited the survival of M. marinum and significantly reduced the dosage of positive drugs isoniazid and rifampicin when combined with them. These results suggest that 12 is a bioactive compound capable of enhancing the potency of existing positive drugs, and its effective properties make it a very useful leads for future drug development in combating TB resistance.

Isolation and Characterization of Antimicrobial Metabolites from the Sophora tonkinensis-Associated Fungus Penicillium sp. GDGJ-N37.

Chemical investigation of Penicillium sp. GDGJ-N37, a Sophora tonkinensis-associated fungus, yielded two new azaphilone derivatives, N-isoamylsclerotiorinamine (1) and 7-methoxyl-N-isoamylsclerotiorinamine (2), and four known azaphilones (3-6), together with two new chromone derivatives, penithochromones X and Y (7 and 8). Their structures were elucidated based on spectroscopic data, CD spectrum, and semi-synthesis. Sclerotioramine (3) showed significant antibacterial activities against B. subtilis and S. dysentery, and it also showed most potent anti-plant pathogenic fungi activities against P. theae, C. miyabeanus, and E. turcicum.

Rice ubiquitin-conjugating enzyme OsUbc13 negatively regulates immunity against pathogens by enhancing the activity of OsSnRK1a.

Ubc13 is required for Lys63-linked polyubiquitination and innate immune responses in mammals, but its functions in plant immunity still remain largely unknown. Here, we used molecular biological, pathological, biochemical, and genetic approaches to evaluate the roles of rice OsUbc13 in response to pathogens. The OsUbc13-RNA interference (RNAi) lines with lesion mimic phenotypes displayed a significant increase in the accumulation of flg22- and chitin-induced reactive oxygen species, and in defence-related genes expression or hormones as well as resistance to Magnaporthe oryzae and Xanthomonas oryzae pv oryzae. Strikingly, OsUbc13 directly interacts with OsSnRK1a, which is the α catalytic subunit of SnRK1 (sucrose non-fermenting-1-related protein kinase-1) and acts as a positive regulator of broad-spectrum disease resistance in rice. In the OsUbc13-RNAi plants, although the protein level of OsSnRK1a did not change, its activity and ABA sensitivity were obviously enhanced, and the K63-linked polyubiquitination was weaker than that of wild-type Dongjin (DJ). Overexpression of the deubiquitinase-encoding gene OsOTUB1.1 produced similar effects with inhibition of OsUbc13 in affecting immunity responses, M. oryzae resistance, OsSnRK1a ubiquitination, and OsSnRK1a activity. Furthermore, re-interfering with OsSnRK1a in one OsUbc13-RNAi line (Ri-3) partially restored its M. oryzae resistance to a level between those of Ri-3 and DJ. Our data demonstrate OsUbc13 negatively regulates immunity against pathogens by enhancing the activity of OsSnRK1a.

B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen.

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Soilborne bacterium Klebsiella pneumoniae promotes cluster root formation in white lupin through ethylene mediation.

Cluster roots of white lupin are induced by low phosphorus (LP) to efficiently access unavailable P, but how soilborne microbes are associated with cluster root formation (CRF) is unclear. We investigated the roles of soilborne bacteria in CRF response to LP by high-throughput sequencing and root-bacteria interactions. Cluster root number was significantly decreased in plants grown in sterilized soil compared with nonsterilized soil. Proteobacteria was enriched in CR, as shown by microbiome analysis of soil (bulk, rhizosphere, and rhizosheath) and roots (main, lateral, and CR). Large-scale gene expression level implicated ethylene mediation in CRF. Klebsiella pneumoniae (P7), a soilborne bacterium belonging to Proteobacteria, was isolated from CR. Among 11 isolated strains, P7 exhibited the highest 1-aminocyclopropane-1-carboxylate deaminase (ACCD) activity; this enzyme inhibits the biosynthesis of ethylene in plants by the cleavage of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid and promotes CRF under LP. We constructed an ACCD-deficit mutant accd in the P7 genetic background. The loss-of-function mutation failed to promote CRF under LP conditions. Also, auxin responses may be involved in K. pneumoniae-ethylene-mediated CRF. Overall, we propose that the soilborne bacterium K. pneumoniae promotes CRF of white lupin in response to LP by ethylene mediation.

Inhibition of influenza A virus replication by a marine derived quinolone alkaloid targeting virus nucleoprotein.

Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, a novel quinolone alkaloid (QLA) derived from marine fungus was discovered with broad-spectrum anti-IAV activities with low toxicity. Distinct from current anti-IAV drugs, QLA may block virus replication and viral RNA (vRNA) export from the nucleus by targeting virus nucleoprotein (NP). QLA can block the binding of chromosome region maintenance 1 to nuclear export signal 3 of NP to inhibit the nuclear export of NP and vRNP. QLA may also affect vRNP assembly by interfering with the binding of NP to RNA rather than NP oligomerization. Arg305 and Phe488-Gly490 may be required for the interaction between QLA and NP, and the binding pocket around these amino acids may be a promising target for anti-IAV drugs. Importantly, oral administration of QLA can protect the mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. In summary, the marine derived compound QLA has the potential to be developed into a novel anti-IAV agent targeting virus NP protein in the future.

Root acid phosphatases and rhizobacteria synergistically enhance white lupin and rice phosphorus acquisition.

The rhizosheath is a belowground area that acts as a communication hub at the root-soil interface to promote water and nutrient acquisition. Certain crops, such as white lupin (Lupinus albus), acquire large amounts of phosphorus (P), owing partially to exudation of acid phosphatases (APases). Plant growth-promoting rhizobacteria also increase soil P availability. However, potential synergistic effects of root APases and rhizosheath-associated microbiota on P acquisition require further research. In this study, we investigated the roles of root purple APases (PAPs) and plant growth-promoting rhizobacteria in rhizosheath formation and P acquisition under conditions of soil drying (SD) and P treatment (+P: soil with P fertilizer; -P: soil without fertilizer). We expressed purple acid phosphatase12 (LaPAP12) in white lupin and rice (Oryza sativa) plants and analyzed the rhizosheath-associated microbiome. Increased or heterologous LaPAP12 expression promoted APase activity and rhizosheath formation, resulting in increased P acquisition mainly under SD-P conditions. It also increased the abundance of members of the genus Bacillus in the rhizosheath-associated microbial communities of white lupin and rice. We isolated a phosphate-solubilizing, auxin-producing Bacillus megaterium strain from the rhizosheath of white lupin and used this to inoculate white lupin and rice plants. Inoculation promoted rhizosheath formation and P acquisition, especially in plants with increased LaPAP12 expression and under SD-P conditions, suggesting a functional role of the bacteria in alleviating P deficit stress via rhizosheath formation. Together, our results suggest a synergistic enhancing effect of LaPAP12 and plant growth-promoting rhizobacteria on rhizosheath formation and P acquisition under SD-P conditions.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study.

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Copper-Catalyzed Aerobic Oxidative/Decarboxylative Phosphorylation of Aryl Acrylic Acids with P(III)-Nucleophiles.

A copper-catalyzed aerobic oxidative/decarboxylative phosphorylation of aryl acrylic acids with P(III)-nucleophiles via the Michaelis-Arbuzov rearrangement for the synthesis of ß-ketophosphine oxides, ß-ketophosphinates, and ß-ketophosphonates is reported. The present reaction could be conducted effectively without the use of a ligand and a base. Various kinds of aryl acrylic acids and P(III)-nucleophiles are tolerated in the transformation, generating the desired ß-keto-organophosphorus compounds as a valuable class of phosphorus-containing intermediates with good to excellent yields. In addition, the possible mechanism and kinetic studies for the reaction have been explored by step-by-step control experiments and competitive experiments, and the results proved that this transformation may follow second-order chemical kinetics as well as involve a radical process.

Ruthenium-Catalyzed 1,6-Hydroalkylation of para-Quinone Methides with Ketones via the in Situ Activation of C(sp3)-H Bonds.

A simple and efficient method for the ruthenium-catalyzed 1,6-hydroalkylation of para-quinone methides (p-QMs) with ketones via the in situ activation of C(sp3)-H bonds has been disclosed. Without the need for preactivation of the substrates and oxidant, a broad range of p-QMs and ketones are well tolerated, producing the expected 1,6-hydroalkylation products with moderate to good yields. Step-by-step control experiments and DFT calculation were conducted systematically to gain insights for the plausible reaction mechanism. This finding may have potential application in the selective diarylmethylation of ketones at the α-C position in organic synthesis.