Designing NIR AIEgens for lysosomes targeting and efficient photodynamic therapy of tumors.

Cancer is the most severe health problem facing most people today. Photodynamic therapy (PDT) for tumors has attracted attention because of its non-invasive nature, negligible adverse reactions, and high spatiotemporal selectivity. Developing biocompatible photosensitizers that can target, guide, and efficiently kill cancer cells is desirable in PDT. Here, two amphiphilic organic compounds, PS-I and PSS-II, were synthesized based on the D-π-A structure with a positive charge. The two AIEgens exhibited near-infrared emission, large Stokes shift, high 1O2 and O2-∙ generation efficiency, good biocompatibility, and photostability. They were co-incubated with cancer cells and eventually accumulated to lysosomes by cell imaging experiments. In vitro and in vivo experiments demonstrated that PS-I and PSS-II could effectively kill cancer cells and sufficiently inhibit tumor growth under light irradiation. PS-I had a higher fluorescence quantum yield in the aggregated state, which made it better for bio-imaging in imaging-guided photodynamic therapy. In contrast, PSS-II with a longer conjugated structure had more ROS generation to kill tumor cells under illumination, and the tumor growth inhibition of mice reached 71.95% during the treatment. No observable injury or undesirable outcomes were detected in the vital organs of the mice within the treatment group, suggesting that PSS-II/PS-I had a promising future in efficient imaging-guided PDT for cancer.

Intermolecular copigmentation of anthocyanins with phenolic compounds improves color stability in the model and real blueberry fermented beverage.

To improve the color stability of anthocyanins (ACNs) in blueberry fermented beverage, the intermolecular copigmentation between ACNs and 3 different phenolic compounds, including (-)-epigallocatechin gallate (EGCG), ferulic acid (FA), and gallic acid (GA) as copigments, was compared in the model and the real blueberry fermented beverage, respectively. The copigmented ACNs by EGCG presented a high absorbance (0.34 a.u.) and redness (27.09 ± 0.17) in the model blueberry fermented beverage. The copigmentation by the participation of the 3 different phenolic compounds showed all a spontaneous exothermic reaction, and the Gibbs free energy (ΔG°) of the system was lowest (-5.90 kJ/mol) using EGCG as copigment. Furthermore, the molecular docking model verified that binary complexes formed between ACNs and copigments by hydrogen bonds and π-π stacking. There was a high absorbance (1.02 a.u.), percentage polymeric color (PC%, 68.3 %), and good color saturation (C*ab, 43.28) in the real blueberry fermented beverage aged for 90 days, and more malvidin-3-O-glucoside had been preserved in the wine using EGCG as copigment. This finding may guide future industrial production of blueberry fermented beverage with improved color.

A meta-analysis of elevated O3 effects on herbaceous plants antioxidant oxidase activity.

Increases in near-surface ozone (O3) concentrations is a global environmental problem. High-concentration O3 induces stress in plants, which can lead to visible damage to plants, reduced photosynthesis, accelerated aging, inhibited growth, and can even plant death. However, its impact has not been comprehensively evaluated because of the response differences between individual plant species, environmental O3 concentration, and duration of O3 stress in plants. We used a meta-analysis approach based on 31 studies 343 observations) to examine the effects of elevated O3 on malondialdehyde (MDA), superoxide dismutase (SOD), and peroxidase (POD) activities in herbaceous plants. Globally, important as they constitute the majority of the world's food crops. We partitioned the variation in effect size found in the meta-analysis according to the presence of plant species (ornamental herb, rice, and wheat), O3 concentration, and duration of O3 stress in plants. Our results showed that the effects of elevated O3 on plant membrane lipid peroxidation depending on plant species, O3 concentration, and duration of O3 stress in plants. The wheat SOD and POD activity was significantly lower compared to the herbs and rice (P<0.01). The SOD activity of all herbaceous plants increased by 34.6%, 10.5%, and 26.3% for exposure times to elevated O3 environments of 1-12, 13-30, and 31-60 days, respectively. When the exposure time was more than 60 days, SOD activity did not increase but significantly decreased by 12.1%. However, the POD activity of herbaceous plants increased by 30.4%, 57.3%, 21.9% and 5.81%, respectively, when exposure time of herbaceous plants in elevated O3 environment was 1-12, 13-30, 31-60 and more than 60 days. Our meta-analysis revealed that (1) rice is more resistant to elevated O3 than wheat and ornamental herbs likely because of the higher activity of antioxidant components (e.g., POD) in the symplasts, (2) exposure to elevated O3 concentrations for >60 days, may result in antioxidant SOD lose its regulatory ability, and the antioxidant component POD in the symplast is mainly used to resist O3 damage, and (3) the important factors affected the activity of SOD and POD in plants were not consistent: the duration of O3 stress in plants was more important than plant species and O3 concentration for SOD activity. However, for POD activity, plant species was the most important factor.

A novel highly virulent nephropathogenic QX-like infectious bronchitis virus originating from recombination of GI-13 and GI-19 genotype strains in China.

Infectious bronchitis virus (IBV) is one of the most widely spread RNA viruses, causing respiratory, renal, and intestinal damage, as well as decreased reproductive performance in hens, leading to significant economic losses in the poultry industry. In this study, a new IBV strain designated as CK/CH/GX/LA/071423 was successfully isolated from the 60-day-old Three-Yellow chicken vaccinated with H120 and QXL87 vaccines. The complete genome sequence analysis revealed that the CK/CH/GX/LA/071423 strain shared a high similarity of 96.7% with the YX10 strain belonging to the GI-19 genotype. Genetic evolution analysis based on the IBV S1 gene showed that the CK/CH/GX/LA/071423 isolate belonged to the GI-19 genotype. Recombination analysis of the virus genome using RDP and Simplot software indicated that CK/CH/GX/LA/071423 was derived from recombination events between the YX10 and 4/91 vaccine strains, which was supported by phylogenetic analysis using gene sequences from the 3 regions. Furthermore, the S1 protein tertiary structure differences were observed between the CK/CH/GX/LA/071423 and the QXL87 and H120 vaccine strains. Pathogenicity studies revealed that the CK/CH/GX/LA/071423 caused death and led to pale and enlarged kidneys with abundant urate deposits, indicative of a nephropathogenic IBV strain. High virus titers were detected in the trachea, kidneys, and cecal tonsils, demonstrating broad tissue tropism. Throughout the experimental period, the virus positive rate in throat swabs of the infected group reached to 100%. These findings highlight the continued predominance of the QX genotype IBV in Guangxi of China and the ongoing evolution of different genotypes through genetic recombination, raising concerns about the efficacy of current IBV vaccines in providing effective protection to poultry.

Photochromic radical states in 3D covalent organic frameworks with zyg topology for enhanced photocatalysis.

Covalent-organic frameworks (COFs) with photoinduced donor-acceptor (D-A) radical pairs show enhanced photocatalytic activity in principle. However, achieving long-lived charge separation in COFs proves challenging due to the rapid charge recombination. Here, we develop a novel strategy by combining [6 + 4] nodes to construct zyg-type 3D COFs, first reported in COF chemistry. This structure type exhibits a fused Olympic-rings-like shape, which provides a platform for stabilizing the photoinduced D-A radical pairs. The zyg-type COFs containing catalytically active moieties such as triphenylamine and phenothiazine (PTZ) show superior photocatalytic production rates of hydrogen peroxide (H2O2). Significantly, the photochromic radical states of these COFs show up to 400% enhancement in photocatalytic activity compared to the parent states, achieving a remarkable H2O2 synthesis rate of 3324 µmol g-1 h-1, which makes the PTZ-COF one of the best crystalline porous photocatalysts in H2O2 production. This work will shed light on the synthesis of efficient 3D COF photocatalysts built on topologies that can facilitate photogenerating D-A radical pairs for enhanced photocatalysis.

CD47, a novel YAP target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet.

Activated hepatic stellate cells (HSCs) have been widely recognized as a primary source of pathological myofibroblasts, leading to the accumulation of extracellular matrix and liver fibrosis. CD47, a transmembrane glycoprotein expressed on the surface of various cell types, has been implicated in non-alcoholic fatty liver disease. However, the precise role of CD47 in HSC activation and the underlying regulatory mechanisms governing CD47 expression remain poorly understood. In this study, we employed single-cell RNA sequencing analysis to investigate CD47 expression in HSCs from mice subjected to a high-fat diet. CD47 silencing in HSCs markedly inhibited the expression of fibrotic genes and promoted apoptosis. Mechanistically, we found that Yes-associated protein (YAP) collaborates with TEAD4 to augment the transcriptional activation of CD47 by binding to its promoter region. Notably, disruption of the interaction between YAP and TEAD4 caused a substantial decrease in CD47 expression in HSCs and reduced the development of high-fat diet-induced liver fibrosis. Our findings highlight CD47 as a critical transcriptional target of YAP in promoting HSC activation in response to a high-fat diet. Targeting the YAP/TEAD4/CD47 signaling axis may hold promise as a therapeutic strategy for liver fibrosis.

Exploration and Validation of Ferroptosis-Associated Genes in ADAR1 Deletion-Induced NAFLD through RNA-seq Analysis.

BACKGROUND: Ferroptosis, characterized by excessive iron ions and lipid peroxides accumulation, contributes to Nonalcoholic Fatty Liver Disease (NAFLD) development. The role of ADAR1, crucial for lipid metabolism and immune regulation, in ferroptosis-related NAFLD remains unexplored. METHODS: In this study, we analyzed the expression of ADAR1 in NAFLD patients using the GSE66676 database. Subsequently, We investigated the effects of ADAR1 knockdown on mitochondrial membrane potential (MMP), Fe2+ levels, oxidation products, and ferroptosis in NAFLD cells through in vitro and in vivo experiments. Additionally, RNA-seq analysis was performed following ADAR1 depletion in an NAFLD cell model. Overlapping and ferroptosis-related genes were identified using a Venn diagram, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted as well. Furthermore, a protein-protein interaction (PPI) network was constructed to identify hub genes associated with ferroptosis. RESULTS: We found the expression level of ADAR1 was downregulated in NAFLD patients and 22 ferroptosis-associated genes were differentially expressed in a NAFLD cell model upon ADAR1 knockdown. Based on PPI network, we identified NOS2, PTGS2, NOX4, ALB, IL6, and CCL5 as the central genes related to ferroptosis. ADAR1 deletion-related NAFLD was found to be involved in the ferroptosis signaling pathway. NOS2, PTGS2, ALB, and IL6 can serve as potential biomarkers. These findings offer new insights and expanded targets for NAFLD prevention and treatment. CONCLUSION: These findings provide new strategies and potential targets for preventing and treating NAFLD. NOS2, PTGS2, ALB, and IL6 may serve as biomarkers for ADAR1 deletion-related NAFLD, which could help for developing its new diagnostic and therapeutic strategies.

Structural characterization of a polymorphic repeat at the CACNA1C schizophrenia locus.

Genetic variation within intron 3 of the CACNA1C calcium channel gene is associated with schizophrenia and bipolar disorder, but analysis of the causal variants and their effect is complicated by a nearby variable-number tandem repeat (VNTR). Here, we used 155 long-read genome assemblies from 78 diverse individuals to delineate the structure and population variability of the CACNA1C intron 3 VNTR. We categorized VNTR sequences into 7 Types of structural alleles using sequence differences among repeat units. Only 12 repeat units at the 5' end of the VNTR were shared across most Types, but several Types were related through a series of large and small duplications. The most diverged Types were rare and present only in individuals with African ancestry, but the multiallelic structural polymorphism Variable Region 2 was present across populations at different frequencies, consistent with expansion of the VNTR preceding the emergence of early hominins. VR2 was in complete linkage disequilibrium with fine-mapped schizophrenia variants (SNPs) from genome-wide association studies (GWAS). This risk haplotype was associated with decreased CACNA1C gene expression in brain tissues profiled by the GTEx project. Our work suggests that sequence variation within a human-specific VNTR affects gene expression, and provides a detailed characterization of new alleles at a flagship neuropsychiatric locus.

Tracheobronchopathia osteochondroplastica concurrent with peripheral lung cancer: a case report and perioperative considerations.

Background: Tracheobronchopathia osteochondroplastica (TPO) is a rare, benign, chronic disorder of unknown etiology. It is characterized by submucosal nodules, often calcified, which predominantly affect the anterolateral aspects of the trachea and main bronchi, while sparing the posterior bronchial wall. The co-occurrence of TPO and lung cancer is exceedingly rare. This report presents a case of TPO association with early-stage lung cancer, which was managed through surgical intervention. No active treatment was undertaken for the TPO. Case Description: A patient presented with a nodule in the right upper lobe, which was identified during a computed tomography (CT) scan of the chest, suggestive of early-stage lung cancer. Concurrently, multiple calcifications in the cartilaginous rings of the trachea were noted. Bronchoscopy revealed distinctive "pebblestone" nodules along the anterior and lateral tracheal walls, indicative of extensive TPO. The patient underwent bronchofiberscopy, which showed patency in the bronchial lumen of the right lung's upper lobe. A biopsy was not undertaken during this procedure. Comprehensive preoperative tests, including a blood biochemical examination, tumor-marker tests, lung-function tests, head-enhanced magnetic resonance imaging, abdominal ultrasound, and whole-body bone emission CT revealed no significant abnormalities. Despite this, the patient declined a whole-body positron emission tomography (PET)-CT scan. Given the potential malignancy of nodules in the right lung's upper lobe, the lobectomy for lung cancer was carried out, a procedure that would have proceeded irrespective of the presence or absence of TPO. Preoperative planning for potential tracheal intubation difficulties involved consultation with the anesthesiologist, resulting in a smooth intraoperative process. The pathology confirmed invasive adenocarcinoma. Post-surgery, the patient developed an infection in the right lung's lower lobe, identified as pseudomonas aeruginosa and Klebsiella pneumoniae through sputum culture and bronchoscopic lavage. Treatment with meropenem for 2 weeks, as guided by drug sensitivity results and respiratory advice, led to an improvement, allowing for discharge. A follow-up lung CT four months post-operation showed inflammation absorption in the right lower lobe. Conclusions: Surgical resection in cases of TPO association with lung cancer may have an increased risk of postoperative pulmonary infection. Proactive intraoperative sputum aspiration by anesthesiologists and the postoperative reinforcement of anti-infection measures, guided by drug sensitivity results, are recommended.

Integrative analysis of transcriptome and target metabolites uncovering flavonoid biosynthesis regulation of changing petal colors in Nymphaea 'Feitian 2'.

BACKGROUND: Nymphaea (waterlily) is known for its rich colors and role as an important aquatic ornamental plant globally. Nymphaea atrans and some hybrids, including N. 'Feitian 2,' are more appealing due to the gradual color change of their petals at different flower developmental stages. The petals of N. 'Feitian 2' gradually change color from light blue-purple to deep rose-red throughout flowering. The mechanism of the phenomenon remains unclear. RESULTS: In this work, flavonoids in the petals of N. 'Feitian 2' at six flowering stages were examined to identify the influence of flavonoid components on flower color changes. Additionally, six cDNA libraries of N. 'Feitian 2' over two blooming stages were developed, and the transcriptome was sequenced to identify the molecular mechanism governing petal color changes. As a result, 18 flavonoid metabolites were identified, including five anthocyanins and 13 flavonols. Anthocyanin accumulation during flower development is the primary driver of petal color change. A total of 12 differentially expressed genes (DEGs) in the flavonoid biosynthesis pathway were uncovered, and these DEGs were significantly positively correlated with anthocyanin accumulation. Six structural genes were ultimately focused on, as their expression levels varied significantly across different flowering stages. Moreover, 104 differentially expressed transcription factors (TFs) were uncovered, and three MYBs associated with flavonoid biosynthesis were screened. The RT-qPCR results were generally aligned with high-throughput sequencing results. CONCLUSIONS: This research offers a foundation to clarify the mechanisms underlying changes in the petal color of waterlilies.

Fungi play a crucial role in sustaining microbial networks and accelerating organic matter mineralization and humification during thermophilic phase of composting.

Fungi play an important role in the mineralization and humification of refractory organic matter such as lignocellulose during composting. However, limited research on the ecological role of fungi in composting system hindered the development of efficient microbial agents. In this study, six groups of lab-scale composting experiments were conducted to reveal the role of fungal community in composting ecosystems by comparing them with bacterial community. The findings showed that the thermophilic phase was crucial for organic matter degradation and humic acid formation. The Richness index of the fungal community peaked at 1165 during this phase. PCoA analysis revealed a robust thermal stability in the fungal community. Despite temperature fluctuations, the community structure, predominantly governed by Pichia and Candida, remained largely unaltered. The stability of fungal community and the complexity of ecological networks were 1.26 times and 5.15 times higher than those observed in bacterial community, respectively. Fungi-bacteria interdomain interaction markedly enhanced network complexity, contributing to maintain microbial ecological functions. The core fungal species belonging to the family Saccharomycetaceae drove interdomain interaction during thermophilic phase. This study demonstrated the key role of fungi in the composting system, which would provide theoretical guidance for the development of high efficiency composting agents to strengthen the mineralization and humification of organic matter.

High-Level Extracellular Production of a Trisaccharide-Producing Alginate Lyase AlyC7 in Escherichia coli and Its Agricultural Application.

Alginate oligosaccharides (AOS), products of alginate degradation by endotype alginate lyases, possess favorable biological activities and have broad applications. Although many have been reported, alginate lyases with homogeneous AOS products and secretory production by an engineered host are scarce. Herein, the alginate lyase AlyC7 from Vibrio sp. C42 was characterized as a trisaccharide-producing lyase exhibiting high activity and broad substrate specificity. With PelB as the signal peptide and 500 mM glycine as the additive, the extracellular production of AlyC7 in Escherichia coli reached 1122.8 U/mL after 27 h cultivation in Luria-Bertani medium. The yield of trisaccharides from sodium alginate degradation by the produced AlyC7 reached 758.6 mg/g, with a purity of 85.1%. The prepared AOS at 20 µg/mL increased the root length of lettuce, tomato, wheat, and maize by 27.5%, 25.7%, 9.7%, and 11.1%, respectively. This study establishes a robust foundation for the industrial and agricultural applications of AlyC7.

Synergetic Catalytic Effect between Ni and Co in Bimetallic Phosphide Boosting Hydrogen Evolution Reaction.

The application of electrochemical hydrogen evolution reaction (HER) for renewable energy conversion contributes to the ultimate goal of a zero-carbon emission society. Metal phosphides have been considered as promising HER catalysts in the alkaline environment, which, unfortunately, is still limited owing to the weak adsorption of H* and easy dissolution during operation. Herein, a bimetallic NiCoP-2/NF phosphide is constructed on nickel foam (NF), requiring rather low overpotentials of 150 mV and 169 mV to meet the current densities of 500 and 1000 mA cm-2, respectively, and able to operate stably for 100 h without detectable activity decay. The excellent HER performance is obtained thanks to the synergetic catalytic effect between Ni and Co, among which Ni is introduced to enhance the intrinsic activity and Co increases the electrochemically active area. Meanwhile, the protection of the externally generated amorphous phosphorus oxide layer improves the stability of NiCoP/NF. An electrolyser using NiCoP-2/NF as both cathode and anode catalysts in an alkaline solution can produce hydrogen with low electric consumption (overpotential of 270 mV at 500 mA cm-2).

A first-principles study of the BC3N2 monolayer and a BC3N2/graphene heterostructure as promising anode materials for sodium-ion batteries.

High-performance sodium-ion batteries (SIBs) require anode materials with high capacity and fast kinetics. Based on first-principles calculations, we propose BC3N2 and BC3N2/graphene (B/G) heterostructure as potential SIB anode materials. The BC3N2 monolayer exhibits intrinsic metallic behavior. In addition, BC3N2 possesses a low Na+ diffusion barrier (0.15 eV), a high storage capacity (777 mA h g-1), a low open-circuit voltage (0.72 V), and a tiny axial expansion (0.36%). Compared with the BC3N2 monolayer, the B/G heterostructure exhibits a lower diffusion barrier of 0.027 eV, suggesting a much faster diffusion. More importantly, although the B/G heterostructure possesses heavier molar weight, its theoretical capacity (689 mA h g-1) is comparable to that of the BC3N2 monolayer. Based on the above-mentioned properties, we hope both the BC3N2 monolayer and the B/G heterostructure would be promising anodes for SIBs.

[Resources and utilization of medicinal plants in countries and regions involved in "the Belt and Road" Initiative].

The protection, development, and utilization of medicinal plant resources are important cornerstones of maintaining human health. However, due to factors such as the reduction of high-quality land resources, deterioration of ecological environments, and excessive and disorderly resource development, medicinal plant resources are becoming scarce, and some of them are insufficiently supplied. With the proposal of "the Belt and Road" Initiative, the cooperation between China and "the Belt and Road" partners(the countries and regions involved in "the Belt and Road" Initiative)is increasingly close, which provides a new opportunity for carrying out trade of medicinal plant resources and alleviating the problem of imbalance and relative inadequacy of medicinal plant resources in countries. This study first determined the distribution and species information of plant resources in countries and regions involved in "the Belt and Road" Initiative by investigating the database of plant distribution and that of medicinal plant resources. Then, according to the published data from the International Union for Conservation of Nature(IUCN) and the Convention on International Trade in Endangered Species of Wild Fauna and Flora(CITES), this study identified the rare and endangered medicinal plants and the medicinal plants under trade control in countries and regions involved in "the Belt and Road" Initiative and finally sorted out the list of potential medicinal plant resources in countries and regions involved in "the Belt and Road" Initiative that can be used by China. This data resource can not only be used for the overall protection of important endangered species but also scientifically guide the development and utilization of medicinal resources, providing guidance and a theoretical basis for the sustainable development of medicinal plant resources in countries and regions involved in "the Belt and Road" Initiative.

Scalable Video Object Segmentation With Identification Mechanism.

This paper delves into the challenges of achieving scalable and effective multi-object modeling for semi-supervised Video Object Segmentation (VOS). Previous VOS methods decode features with a single positive object, limiting the learning of multi-object representation as they must match and segment each target separately under multi-object scenarios. Additionally, earlier techniques catered to specific application objectives and lacked the flexibility to fulfill different speed-accuracy requirements. To address these problems, we present two innovative approaches, Associating Objects with Transformers (AOT) and Associating Objects with Scalable Transformers (AOST). In pursuing effective multi-object modeling, AOT introduces the IDentification (ID) mechanism to allocate each object a unique identity. This approach enables the network to model the associations among all objects simultaneously, thus facilitating the tracking and segmentation of objects in a single network pass. To address the challenge of inflexible deployment, AOST further integrates scalable long short-term transformers that incorporate scalable supervision and layer-wise ID-based attention. This enables online architecture scalability in VOS for the first time and overcomes ID embeddings' representation limitations. Given the absence of a benchmark for VOS involving densely multi-object annotations, we propose a challenging Video Object Segmentation in the Wild (VOSW) benchmark to validate our approaches. We evaluated various AOT and AOST variants using extensive experiments across VOSW and five commonly used VOS benchmarks, including YouTube-VOS 2018 & 2019 Val, DAVIS-2017 Val & Test, and DAVIS-2016. Our approaches surpass the state-of-the-art competitors and display exceptional efficiency and scalability consistently across all six benchmarks. Moreover, we notably achieved the 1st position in the 3 rd Large-scale Video Object Segmentation Challenge. Project page: https://github.com/yoxu515/aot-benchmark.

Proteinase 3 depletion attenuates leukemia by promoting myeloid differentiation.

Hematopoietic stem and progenitor cells (HSPCs) that have impaired differentiation can transform into leukemic blasts. However, the mechanism that controls differentiation remains elusive. Here, we show that the genetic elimination of Proteinase 3 (PRTN3) in mice led to spontaneous myeloid differentiation. Mechanistically, our findings indicate that PRTN3 interacts with the N-terminal of STAT3, serving as a negative regulator of STAT3-dependent myeloid differentiation. Specifically, PRTN3 promotes STAT3 ubiquitination and degradation, while simultaneously reducing STAT3 phosphorylation and nuclear translocation during G-CSF-stimulated myeloid differentiation. Strikingly, pharmacological inhibition of STAT3 (Stattic) partially counteracted the effects of PRTN3 deficiency on myeloid differentiation. Moreover, the deficiency of PRTN3 in primary AML blasts promotes the differentiation of those cells into functional neutrophils capable of chemotaxis and phagocytosis, ultimately resulting in improved overall survival rates for recipients. These findings indicate PRTN3 exerts an inhibitory effect on STAT3-dependent myeloid differentiation and could be a promising therapeutic target for the treatment of acute myeloid leukemia.

A Long-Retention Cell Membrane-Targeting AIEgen for Boosting Tumor Theranostics.

Designing and developing photosensitizers with cell membrane specificity is crucial for achieving effective multimodal therapy of tumors compared to other organelles. Here, we designed and screened a photosensitizer CM34 through donor/receptor regulation strategies, and it is able to achieve long-retention cell membrane targeting. It is not only an extremely excellent cell membrane targeted tumor theranostic agent, but also found to be a promising potential immune activator. Specifically, CM34 with a larger intramolecular twist angle is more likely to form larger aggregates in aqueous solutions, and the introduction of cyanide group also enhances its interaction with cell membranes, which were key factors hindering molecular penetration of the cell membrane and prolonging its residence time on the cell membrane, providing conditions for further membrane targeted photodynamic therapy. Furthermore, the efflux of contents caused by cell necrosis directly activates the immune response. In summary, this study realizes to clarify and refine all potential mechanisms of action through density functional theory calculations, photophysical property measurements, and cellular level mechanism exploration, providing a new direction for the clinical development of cell membrane targeted anti-tumor immune activators.

The suppressive effect of the specific KCC2 modulator CLP290 on seizure in mice.

Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl- cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl-]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.