Antifungal Activity of Phloroglucinol Derivatives against Botrytis cinerea and Monilinia fructicola.

Naturally derived compounds show promise as treatments for microbial infections. Polyphenols, abundantly found in various plants, fruits, and vegetables, are noted for their physiological benefits including antimicrobial effects. This study introduced a new set of acylated phloroglucinol derivatives, synthesized and tested for their antifungal activity in vitro against seven different pathogenic fungi. The standout compound, 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one (2b), exhibited remarkable fungicidal strength, with EC50 values of 1.39 µg/mL against Botrytis cinerea and 1.18 µg/mL against Monilinia fructicola, outperforming previously screened phenolic compounds. When tested in vivo, 2b demonstrated effective antifungal properties, with cure rates of 76.26% for brown rot and 83.35% for gray mold at a concentration of 200 µg/mL, rivaling the commercial fungicide Pyrimethanil in its efficacy against B. cinerea. Preliminary research suggests that 2b's antifungal mechanism may involve the disruption of spore germination, damage to the fungal cell membrane, and leakage of cellular contents. These results indicate that compound 2b has excellent fungicidal properties against B. cinerea and holds potential as a treatment for gray mold.

Efficacy of Lung Ultrasound vs Chest X-Ray in Detecting Lung Consolidation and Edema in Premature Infants in the NICU.

BACKGROUND The incidence of lung diseases in premature newborns is significantly higher than in full-term newborns due to their underdeveloped lungs. Ultrasound and X-ray are commonly-used bedside examinations in neonatology. This study primarily compares the efficacy of chest X-ray (CXR) and lung ultrasound (LUS) images in evaluating lung consolidation and edema in premature newborns at Neonatal Intensive Care Units (NICU). MATERIAL AND METHODS A retrospective analysis was conducted on LUS and CXR examination results, along with clinical records of premature newborns admitted to our hospital's NICU from November 1, 2019, to December 31, 2021. CXR and LUS scans were performed on the same newborn within a day. We evaluated the consolidations and edema by interpreting the CXR and LUS images, then compared the findings. RESULTS Out of 75 cases, 34 showed lung consolidations on LUS (45%), while only 14 exhibited consolidations on CXR (19%). The detection rate of consolidations by LUS was significantly higher compared to CXR (34/75 vs 14/75, P<0.001). Differences were observed between the 2 bedside examinations in identifying consolidations, with some cases seen only on LUS. CXR struggled to accurately assess the severity of lung edema visible on LUS, showing significant disparity in detecting interstitial edema (53/75 vs 21/75, P<0.001). CONCLUSIONS LUS outperforms chest CXR for bedside assessment of lung consolidation and edema in premature newborns.

Plastid phylogenomics provides new insights into the systematics, diversification, and biogeography of Cymbidium (Orchidaceae).

Cymbidium (Orchidaceae: Epidendroideae), with around 60 species, is widely-distributed across Southeast Asia, providing a nice system for studying the processes that underlie patterns of biodiversity in the region. However, phylogenetic relationships of Cymbidium have not been well resolved, hampering investigations of species diversification and the biogeographical history of this genus. In this study, we construct a plastome phylogeny of 56 Cymbidium species, with four well-resolved major clades, which provides a framework for biogeographical and diversification rate analyses. Molecular dating and biogeographical analyses show that Cymbidium likely originated in the region spanning northern Indo-Burma to the eastern Himalayas during the early Miocene (∼21.10 Ma). It then rapidly diversified into four major clades in East Asia within approximately a million years during the middle Miocene. Cymbidium spp. migration to the adjacent regions (Borneo, Philippines, and Sulawesi) primarily occurred during the Pliocene-Pleistocene period. Our analyses indicate that the net diversification rate of Cymbidium has decreased since its origin, and is positively associated with changes in temperature and monsoon intensity. Favorable hydrothermal conditions brought by monsoon intensification in the early Miocene possibly contributed to the initial rapid diversification, after which the net diversification rate was reduced with the cooling climate after the middle Miocene. The transition from epiphytic to terrestrial habits may have enabled adaptation to cooler environments and colonization of northern niches, yet without a significant effect on diversification rates. This study provides new insights into how monsoon activity and temperature changes affected the diversification dynamics of plants in Southeast Asia.

Polymeric immunoglobulin receptor promotes Th2 immune response in the liver by increasing cholangiocytes derived IL-33: a diagnostic and therapeutic biomarker of biliary atresia.

BACKGROUND: Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging. METHODS: Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis. FINDINGS: Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial-mesenchymal transition, and reduced the apoptosis of BECs. INTERPRETATION: PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA. FUNDING: This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022).

The irregular developmental duration mainly caused by the broad-complex in Chilo suppressalis.

Chilo suppressalis, a critical rice stem borer pest, poses significant challenges to rice production due to its overlapping generations and irregular developmental duration. These characteristics complicate pest management strategies. According to the dynamic analysis of the overwintering adults of C. suppressalis in fields, it indicates that the phenomenon of irregular development of C. suppressalis exists widely and continuously. This study delves into the potential role of the Broad-Complex (Br-C) gene in the developmental duration of C. suppressalis. Four isoforms of Br-C, named CsBr-C Z1, CsBr-C Z2, CsBr-C Z4, and CsBr-C Z7, were identified. After CsBr-Cs RNAi, the duration of larva development spans extended obviously. And, the average developmental duration of dsCsBr-Cs feeding individuals increased obviously. Meanwhile, the average developmental duration of the dsCsBr-C Z2 feeding group was the longest among all the RNAi groups. After dsCsBr-Cs feeding continuously, individuals pupated at different instars changed obviously: the proportion of individuals pupated at the 5th instar decreased and pupated at the 7th instar or higher increased significantly. Moreover, the pupation rate of dsCsBr-Cs (except dsCsBr-C Z7) were significantly lower than that of dsGFP. The same results were obtained from the mutagenesis in CsBr-C genes mediated by CRISPR/Cas9. The average developmental duration of CsBr-Cs knockout individuals was significantly prolonged. And, the instar of pupation in knockout individuals was also delayed significantly. In conclusion, this work showed that CsBr-Cs played a crucial role in pupal commitment and affected the developmental duration of C. suppressalis significantly.

Efficacy and safety of concurrent chemoradiotherapy with paclitaxel-based or S-1 regimens in treating elderly patients with esophageal squamous cell carcinoma: A multi-center propensity-score matched study.

BACKGROUND: Elderly patients with esophageal cancer can benefit from concurrent chemoradiotherapy (CCRT). However, the optimal concurrent chemotherapy regimen remains undetermined. We aimed to compare the efficacy and safety of CCRT with paclitaxel-based or S-1 regimens in treating elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: From January 2016 to November 2022, a total of 349 patients aged 70 and above with ESCC were included. The patient population was divided into two treatment groups: patients receiving paclitaxel-based CCRT were allocated to the TP group, and those receiving S-1 regimen CCRT were allocated to the S-1 group. Propensity score matching (PSM) was used to balance potential biases. Survival outcomes, overall response rate, and treatment-related toxicities were assessed. RESULTS: After PSM, there were 82 patients in each group. The median follow up of the surviving patients was 42.6 months (IQR 28.0-58.8 months). The 2-year overall survival (OS) rate (71.4% vs 65.4%; log-rank P = 0.010) and progression-free survival (PFS) rate (64.4% vs 58.0%; log-rank P = 0.048) were significantly higher in the TP group. Compared with the S-1 group, the TP group experienced a higher rate of grade 3 and above hematologic toxicities, such as leukopenia (47.6% vs 15.9%, P < 0.001) and neutropenia (35.4% vs 6.1%, P < 0.001). One patient in the TP group and two patients in the S-1 group had grade 5 toxic effects. CONCLUSIONS: Our findings suggest that paclitaxel-based CCRT was well tolerated in elderly patients with ESCC and provided significant survival benefits over S-1 regimen.

Design, Synthesis, and Antimicrobial Activity Evaluation of Novel Isocryptolepine Derivatives against Phytopathogenic Fungi and Bacteria.

This research adopted the Fischer indole synthesis method to continue constructing a novel drug-like chemical entity based on the guidance of isocryptolepine and obtained four series of derivatives: Y, Da, Db, and Dc. The antimicrobial activity of these derivatives against plant pathogens was further evaluated. The results showed that Dc-2 had the best antifungal effect against Botrytis cinerea, and its EC50 value was up to 1.29 µg/mL. In addition, an in vivo activity test showed that the protective effect of Dc-2 on apples was 82.2% at 200 µg/mL, which was better than that of Pyrimethanil (45.4%). Meanwhile, it was found by scanning electron microscopy and transmission electron microscopy that the compound Dc-2 affected the morphology of mycelia. The compound Dc-2 was found to damage the cell membrane by PI and ROS staining. Through experiments such as leakage of cell contents, it was found that the compound Dc-2 changed the permeability of the cell membrane and caused the leakage of substances in the cell. According to the above studies, compound Dc-2 can be used as a candidate lead compound for further structural optimization and development.

Characteristics of pomegranate (Punica granatum L.) peel polyphenols encapsulated with whey protein isolate and ß-cyclodextrin by spray-drying.

Pomegranate peel polyphenols (PPPs) are recognized as promising food additives due to their diverse bioactivities; however, their application is limited by poor stability. To address this critical issue, three types of PPPs microcapsules were prepared using ß-cyclodextrin (CD), whey protein isolate (WPI), and a composite material of CD-WPI through ultrasound treatment (US). Results revealed that ultrasound treatment can enhance the PPPs-wall material interaction, as evidenced by MD simulations. The encapsulation efficiency of CD-WPI-PPPs was 93.73 %, which was significantly higher than that of CD-PPPs and WPI-PPPs (p < 0.05). The degradation rate constant of CD-WPI-PPPs was reduced by 95.83 %, and its t1/2 was extended by 23-fold compared to that of unencapsulated PPPs. Furthermore, CD-WPI-PPPs exhibited greater DPPH scavenging activity and inhibited polyphenol release during oral and gastric digestion while promoting release during intestinal digestion. These outcomes were attributed to enhanced integrity and interactions between PPPs and composite materials in the microcapsules formed through ultrasound treatment, as supported by SEM images and FT-IR spectra. Consequently, the application of US in the preparation of PPPs microcapsules presents a promising strategy for developing natural nutrient additives for food applications, thereby enhancing the functional properties of food products.

Adaptive control strategy for microgrid inverters based on Narendra model.

In recent years, microgrid technology has been widely studied and applied. However, with times developing, the installed capacity of distributed power generation devices has been improved, and work is being carried out in increasingly complex situations, resulting in a decline in the control performance of microgrids. In view of this, to effectively improve inverter's control performance, research is conducted on the fusion of Narendra model and adaptive control strategies for real-time voltage correction and compensation in complex situations. Compared to traditional inverters, inverters under research methods have faster voltage recovery speed when encountering load switching, and can recover in about one cycle, with good control performance. In the comparison between the improved inverter adaptive control system and the inverter adaptive system, the improved inverter voltage recovery speed is faster, can be restored within one cycle, and the control effect of the inverter is better. The harmonic rate of the port voltage has decreased from 10.43 to 1.92%. The applicability of the research method was verified. It indicats that the research method can improve inverter's control effect and solve problems such as voltage deviation, three-phase asymmetry, harmonic pollution, etc. that are easily generated by the output terminal voltage. Simultaneously, research has provided theoretical basis and data support for the research of microgrids.

The preliminary study of the effects of individual musculoskeletally stable position in the treatment of temporomandibular disorders.

BACKGROUND: Temporomandibular Disorders (TMD) is the dysfunction of group of muscles and bones in the joint area, the main symptoms of TMD are the pain of the chewing muscles and (or) the temporomandibular joints, mandibular movement disorders and joint noise. This study was designed to explore the therapeutic effects following Individual Musculoskeletally Stable (IMS) position stabilization splint therapy for TMD patients using Fricton index, cone beam computed tomography (CBCT) and surface-Electromyogram (sEMG). METHODS: In this study, we enrolled 31 TMD patients (ranging from 18 to 26 years old, including 7 males and 24 females), first Fricton index was used to evaluate the clinical curative effect of TMD with the treatment of IMS stabilization splint; then CBCT was used to observe the TMJ condylar position changes of TMD before and after the treatment of IMS stabilization splint; finally sEMG was used to observe the changes of electromyography of anterior temporalis (AT) and masseter muscles (MM) of TMD before and after the treatment of IMS stabilization splint. RESULTS: The course of treatment was 6-8 months, with an average of 7.6 months. After the IMS stabilization splint treatment, TMD symptoms relieved, especially in pain, mandibular movement disorder, but still slightly inferior in the treatment of joint noise. And there was a statistically significant difference in the anterior and inner joint space, the condyle had the tendency of moving forward and outward. AT presented reduction significantly of EMG value at rest position after treatment. CONCLUSIONS: IMS stabilization splint is a therapeutic reversible treatment for TMD, especially for pain and mandibular movement disorder; it produces effects of forward and outward condylar movement and elimination of the masticatory muscles antagonism.

Bacterial pneumonia patients with elevated globulin levels did not get infected with SARS-CoV-2: two case reports.

Background: COVID-19 began in December 2019, rapidly spreading worldwide. China implemented a dynamic zero-COVID strategy and strict control measures after the outbreak. However, Guangzhou city ended closed-off management by the end of November 2022, leading to exposure to SARS-CoV-2. Despite most hospitalized patients being infected or co-infected with SARS-CoV-2, some remained uninfected. We report two cases of bacterial pneumonia with elevated globulin levels not infected with SARS-CoV-2, aiming to identify protection factors of SARS-CoV-2 infection and provide a scientific basis for SARS-CoV-2 prevention. Case presentation: Case 1, a 92-year-old male, admitted on October 21, 2022, developed worsening cough and sputum after aspiration, diagnosed with bacterial pneumonia with Pseudomonas aeruginosa, Escherichia coli (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB) infections. He was treated with imipenem anti-infective therapy and mechanical ventilation, then switched to a combination of meropenem, voriconazole and amikacin anti-infective therapy due to recurrent infections and septic shock, and died of sepsis on 8 January 2023. Case 2 is an 82-year-old male admitted on 30 September 2022, with recurrent cough, sputum, and shortness of breath, diagnosed with bacterial pneumonia with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Mycobacterium pneumoniae infections. He was treated with ventilator-assisted ventilation, meropenem, amikacin, tigecycline and mucomycin nebulization and discharged with improvement on 26 October. He was readmitted on 21 November 2022 and diagnosed with bacterial pneumonia. He was treated with cefoperazone sulbactam, amikacin, meropenem and fluconazole and discharged on 31 December. Neither patient was infected with SARS-CoV-2 during hospitalization. Notably, their globulin levels were elevated before SARS-CoV-2 exposure, gradually decreasing afterward. Conclusions: Patients with bacterial pneumonia with high globulin levels likely have large amounts of immunoglobulin, and that immunoglobulin cross-reactivity causes this protein to be involved in clearing SARS-CoV-2 and preventing infection. Therefore, bacterial pneumonia patients with high globulin levels included in this study were not infected with SARS-CoV-2. After exposure to SARS-CoV-2, the amount of globulin in the patient's body was reduced because it was used to clear SARS-CoV-2. The results of this study are expected to provide a theoretical basis for the study of the mechanism of prevention and treatment of SARS-CoV-2 infection.

When anaphylactic shock meets epinephrine and blood lactate increases: A case report.

RATIONALE: Anaphylactic shock, a severe and rapid systemic allergic reaction, poses significant treatment challenges. Epinephrine, the first-line treatment, effectively reverses symptoms but can complicate the clinical picture by elevating lactate levels, blurring the distinction between shock-induced hypoperfusion and drug-induced metabolic effects. PATIENT CONCERNS: A 26-year-old female presented with anaphylactic shock following an antibiotic infusion, experiencing chest tightness, hypotension, and pulmonary edema, without significant past medical history apart from a noted allergy to fish and shrimp. DIAGNOSES: Anaphylaxis was diagnosed based on clinical presentation and supported by imaging that revealed pulmonary edema, despite normal troponin levels and electrocardiogram. INTERVENTIONS: Treatment included 0.5 mg of intramuscular epinephrine and 5 mg of intravenous dexamethasone, with subsequent intubation and mechanical ventilation in the intensive care unit. An intravenous epinephrine infusion was also administered for hemodynamic support. OUTCOMES: While epinephrine resolved the pulmonary edema and stabilized circulation, it led to a significant, albeit transient, increase in lactate levels, which normalized following discontinuation of epinephrine, indicating the metabolic effect of the drug rather than ongoing tissue hypoperfusion. LESSONS: This case illustrates the importance of recognizing epinephrine-induced lactate elevation in anaphylactic shock, necessitating a nuanced interpretation of lactate dynamics. Clinicians must differentiate between lactate elevations due to tissue hypoperfusion and those arising from epinephrine's pharmacologic effects to optimize patient care.

A pan-cancer analysis of Wnt family member 7B in human cancers.

Background: Previous studies have highlighted the crucial role of Wnt7B in the development of various cancers, including breast, pancreatic, and gastric cancers. However, research into the involvement of Wnt7B is often confined to specific tumor types, with a noticeable lack of comprehensive studies spanning multiple cancer forms. The potential of Wnt7B as a diagnostic or prognostic cancer biomarker has not been fully explored. Methods: In this study, we combined bioinformatics and immunohistochemistry analyses to examine the expression patterns and functions of Wnt7B in cancerous and adjacent noncancerous tissues across a range of tumors. Results: Our data indicate that Wnt7B may serve as a novel prognostic biomarker and therapeutic target in certain cancers. Conclusion: We found significant upregulation of Wnt7B expression levels in the majority of cancer cases examined. Furthermore, Wnt7B can influence cancer prognosis by modulating the tumor microenvironment, immune cell infiltration, and tumor stemness, among other factors. Additionally, we examined the associations between anticancer drug sensitivity and Wnt7B expression, which could aid in the development of more precise clinical therapies.

Highly-Efficient Selection of Aptamers for Quantitative Fluorescence Detecting Multiple IAV Subtypes.

Influenza A virus (IAV) can cause infectious respiratory diseases in humans and animals. IAVs mutate rapidly through antigenic drift and shift, resulting in the emergence of numerous IAV subtypes and significant challenges for IAV detection. Therefore, achieving the simultaneous detection of multiple IAVs is crucial. In this work, three specific aptamers targeting the hemagglutination (HA) protein of the influenza A H5N1, H7N9, and H9N2 viruses were screened using a multichannel magnetic microfluidic chip. The aptamers exhibit nanomolar affinity and excellent specificity for the HA protein of H5N1, H7N9, and H9N2 viruses. Furthermore, three specific aptamers were truncated and labeled with different fluorescence markers to realize fluorescence quantitative detection of influenza A H5N1, H7N9, and H9N2 viruses through an aptamer sandwich assay in 1 h. The limit of detection (LOD) of the developed method is 0.38 TCID50/mL for the H5N1 virus, 0.75 TCID50/mL for the H7N9 virus, and 1.14 TCID50/mL for the H9N2 virus. The detection method has excellent specificity, strong anti-interference ability, and good reproducibility. This work provides a sensitive quantitative detection method for the H5N1, H7N9, and H9N2 viruses, enabling quantitative fluorescence detection for multiple IAV subtypes.

Chiral Macrocycles for Enantioselective Recognition.

The efficient synthesis of chiral macrocycles with highly enantioselective recognition remains a challenge. We have addressed this issue by synthesizing a pair of chiral macrocycles, namely, R/S-BINOL[2], achieving total isolated yields of up to 62% through a two-step reaction sequence. These macrocycles are readily purified by column chromatography over silica gel without the need for chiral separation, thus streamlining the overall synthesis. R/S-BINOL[2] demonstrated enantioselective recognition toward chiral ammonium salts, with enantioselectivity (KS/KR) values reaching up to 13.2, although less favorable separations were seen for other substrates. R/S-BINOL[2] also displays blue circularly polarized luminescence with a |glum| value of up to 2.2 × 10-3. The R/S-BINOL[2] macrocycles of this study are attractive as chiral hosts in that they both display enantioselective guest recognition and benefit from a concise, high-yielding synthesis. As such, they may have a role to play in chiral separations.

CRISPR/Gal4BD-Cas donor adapting systems based on miniaturized Cas proteins for improved gene editing.

Targeted precise point editing and knock-in can be achieved by homology-directed repair(HDR) based gene editing strategies in mammalian cells. However, the inefficiency of HDR strategies seriously restricts their application in precision medicine and molecular design breeding. In view of the problem that exogenous donor DNA cannot be efficiently recruited autonomously at double-stranded breaks(DSBs) when using HDR strategies for gene editing, the concept of donor adapting system(DAS) was proposed and the CRISPR/Cas9-Gal4BD DAS was developed previously. Due to the large size of SpCas9 protein, its fusion with the Gal4BD adaptor is inconvenient for protein expression, virus vector packaging and in vivo delivery. In this study, two novel CRISPR/Gal4BD-SlugCas9 and CRISPR/Gal4BD-AsCas12a DASs were further developed, using two miniaturized Cas proteins, namely SlugCas9-HF derived from Staphylococcus lugdunensis and AsCas12a derived from Acidaminococcus sp. Firstly, the SSA reporter assay was used to assess the targeting activity of different Cas-Gal4BD fusions, and the results showed that the fusion of Gal4BD with SlugCas9 and AsCas12a N-terminals had minimal distraction on their activities. Secondly, the HDR efficiency reporter assay was conducted for the functional verification of the two DASs and the corresponding donor patterns were optimized simultaneously. The results demonstrated that the fusion of the Gal4BD adaptor binding sequence at the 5'-end of intent dsDNA template (BS-dsDNA) was better for the CRISPR/Gal4BD-AsCas12a DAS, while for the CRISPR/Gal4BD-SlugCas9 DAS, the dsDNA-BS donor pattern was recommended. Finally, CRISPR/Gal4BD-SlugCas9 DAS was used to achieve gene editing efficiency of 24%, 37% and 31% respectively for EMX1, NUDT5 and AAVS1 gene loci in HEK293T cells, which was significantly increased compared with the controls. In conclusion, this study provides a reference for the subsequent optimization of the donor adapting systems, and expands the gene editing technical toolbox for the researches on animal molecular design breeding.

Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a blood cancer that remains challenging to cure due to drug resistance and side effects from current BCR-ABL inhibitors. There is an urgent need for novel and more effective BCR-ABL targeting inhibitors and therapeutic strategies to combat this deadly disease. METHOD: We disclose an "OH-implant" strategy to improve a noncovalent BCR-ABL inhibitor, PPY-A, by adding a hydroxyl group to its scaffold. By taking advantage of this OH "hot spot", we designed a panel of irreversible covalent kinase inhibitors and hypoxia-responsive pro-/dual-drugs, and their biological activities were studied in vitro, in cellulo and in vivo. RESULT: The resulting compound B1 showed enhanced solubility and biological activity. B4 achieved sustained BCR-ABL inhibition by forming a stable covalent bond with ABL kinase. Hypoxia-responsive prodrug P1 and dual-drugs D1/D2/D3 demonstrated significant anti-tumor effects under hypoxic conditions. The in vivo studies using K562-xenografted mice showed that B1 displayed superior antitumor activity than PPY-A, while P1 and D3 offered better safety profiles alongside significant tumor control. CONCLUSION: We have successfully developed a chemical biology approach to convert a known noncovalent BCR-ABL inhibitor into more potent and safer inhibitors through covalent and pro-/dual-drug targeting strategies. Our "OH-implant" approach and the resulting drug design strategies have general applicability and hold promise for improvement the performance of various other reported drugs/drug candidates, thereby providing advanced medicines for disease treatment.

Merging semi-crystallization and multispecies iodine intercalation at photo-redox interfaces for dual high-value synthesis.

The artificial photocatalytic synthesis based on graphitic carbon nitride (g-C3N4) for H2O2 production is evolving rapidly. However, the simultaneous production of high-value products at electron and hole sites remains a great challenge. Here, we use transformable potassium iodide to obtain semi-crystalline g-C3N4 integrated with the I-/I3- redox shuttle mediators for efficient generation of H2O2 and benzaldehyde. The system demonstrates a prominent catalytic efficiency, with a benzaldehyde yield of 0.78 mol g-1 h-1 and an H2O2 yield of 62.52 mmol g-1 h-1. Such a constructed system can achieve an impressive 96.25% catalytic selectivity for 2e- oxygen reduction, surpassing previously reported systems. The mechanism study reveals that the strong crystal electric field from iodized salt enhances photo-generated charge carrier separation. The I-/I3- redox mediators significantly boost charge migration and continuous electron and proton supply for dual-channel catalytic synthesis. This groundbreaking work in photocatalytic co-production opens neoteric avenues for high-value synthesis.

Consideration on immunotherapy of liver metastases of malignant tumors.

In this editorial, we comment on the article "Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis" by Liu et al that was published in the recent issue of the World Journal of Gastrointestinal Surgery. It has prompted us to think and summarize some thoughts on immunotherapy for malignant tumor liver metastasis. Immunotherapy plays a crucial role in the treatment of malignant tumors; however, the presence of liver metastases in advanced tumors may impact its efficacy. Although patients with liver metastases can still benefit from immunotherapy, multiple clinical studies have indicated that, compared to other sites of metastasis, liver metastases may diminish the effectiveness of immunotherapy. The efficacy of immune checkpoint inhibitors in patients with liver metastases often fails to reach the ideal level, primarily due to the liver metastases exploiting the host's peripheral immune tolerance mechanisms to promote systemic CD8(+) T cell exhaustion, resulting in a systemic immune-tolerant environment. This article aims to summarize the reasons for the decreased efficacy of immunotherapy following liver metastasis in various malignant tumors and propose potential clinical strategies for management.