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Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.

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Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

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OBJECTIVE: To explore the effect of acupotomy intervention on autophagy of chondrocytes in rabbits with knee osteoarthritis (KOA), and to determine the possible mechanisms of acupotomy to alleviate cartilage degeneration. METHODS: The modified Videman method was used to construct a KOA rabbit model. After modeling, 40 rabbits were randomly divided into 4 groups by a random number table: control; KOA (model); KOA + acupotomy (acupotomy), and KOA + sham acupotomy (sham), 10 in each group. After a 3-week treatment course, the knee joint activity was determined by the modified Lequesne MG index. Hematoxylin-eosin staining staining was used to examine the morphological changes of chondrocytes. Autophagy of chondrocytes was observed by transmission electron microscopy. The surface morphology of cartilage tissue was observed by scanning electron microscope. The mRNA and protein levels of AMP kinase/mammalian target of rapamycin/Unc-51 (AMPK/mTOR/ULK1) signal pathway key proteins, autophagy-related factor Beclin-1 and microtubule-associated protein 1A/1B light chain 3 (LC3) in rabbit knee cartilage were assessed by real-time fluorescence quantitative polymerase chain reaction and Western blot, respectively. RESULTS: The modified Lequesne MG score of acupotomy group was significantly lower than that of model group (P<0.05). Pathological results showed that chondrocyte autophagy decreased and cartilage surface was rough in the model group, which recovered after acupotomy treatment. The mRNA expressions of AMPK, ULK1, Beclin-1 and the protein levels of p-AMPK, p-ULK1, Beclin-1, and LC3 II/LC3 I were decreased in the model group, while the mRNA and protein expressions of mTOR were increased (P<0.01). However, acupotomy treatment reversed these abnormal changes (P<0.05). CONCLUSIONS: Acupotomy could effectively up-regulate the expressions of AMPK, ULK1 and Beclin1, reduce the expression of mTOR, promote autophagy, and alleviate joint degeneration. Acupotomy is a promising complementary and alternative therapy for KOA.

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Electrocatalysts undergo structural evolution under operating electrochemical CO2 reduction reaction (CO2RR) conditions. This dynamic reconstruction correlates with variations in CO2RR activity, selectivity, and stability, posing challenges in catalyst design for electrochemical CO2RR. Despite increased research on the reconstruction behavior of CO2RR electrocatalysts, a comprehensive understanding of their dynamic structural evolution under reaction conditions is lacking. This review summarizes recent developments in the dynamic reconstruction of catalysts during the CO2RR process, covering fundamental principles, modulation strategies, and in situ/operando characterizations. It aims to enhance understanding of electrocatalyst dynamic reconstruction, offering guidelines for the rational design of CO2RR electrocatalysts.

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Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

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Introduction: Myocardial injury in elderly Omicron variant patients is a leading cause of severe disease and death. This study focuses on elucidating the clinical characteristics and potential risk factors associated with myocardial injury in elderly patients infected with the Omicron variant. Methods: Myocardial injury was defined based on elevated cardiac troponin concentrations exceeding the 99th percentile upper reference limit. Among 772 elderly Omicron-infected patients, categorized into myocardial injury (n = 263) and non-myocardial injury (n = 509) groups. The stratified log-rank statistic was used to compare the probability of patients developing intensive care. Receiver operating characteristic curves were used to determine the best cut-off values of clinical and laboratory data for predicting myocardial injury. Univariate and multivariate logistic regression was adopted to analyze the risk factors for myocardial injury. Results: The occurrence of myocardial injury in Omicron variant-infected geriatric patients was up to 34.07% and these patients may have a higher rate of requiring intensive care (P < 0.05). By comparing myocardial injury patients with non-myocardial injury patients, notable differences were observed in age, pre-existing medical conditions (e.g., hypertension, coronary heart disease, cerebrovascular disease, arrhythmia, chronic kidney disease, and heart failure), and various laboratory biomarkers, including cycle threshold-ORF1ab gene (Ct-ORF1ab), cycle threshold-N gene (Ct-N), white blood cell count, neutrophil (NEUT) count, NEUT%, lymphocyte (LYM) count, LYM%, and D-dimer, interleukin-6, procalcitonin, C-reactive protein, serum amyloid A, total protein, lactate dehydrogenase, aspartate aminotransferase, glomerular filtration rate, blood urea nitrogen, and serum creatinine (sCr) levels (P < 0.05). Furthermore, in the multivariable logistic regression, we identified potential risk factors for myocardial injury in Omicron variant-infected elderly patients, including advanced age, pre-existing coronary artery disease, interleukin-6 > 22.69 pg/ml, procalcitonin > 0.0435 ng/ml, D-dimer > 0.615 mg/L, and sCr > 81.30 µmol/L. Conclusion: This study revealed the clinical characteristics and potential risk factors associated with myocardial injury that enable early diagnosis of myocardial injury in Omicron variant-infected elderly patients, providing important reference indicators for early diagnosis and timely clinical intervention.

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Catalyst surface dynamics drive the generation of active species for electrocatalytic reactions. Yet, the understanding of dominant site formation and reaction mechanisms is limited. In this study, we thoroughly investigate the dynamic reconstruction of two-dimensional defective Bi nanosheets from exfoliated Bi2Se3 nanosheets under electrochemical CO2 and nitrate (NO3 -) reduction conditions. The ultrathin Bi2Se3 nanosheets obtained by NaBH4-assisted cryo-mediated liquid-phase exfoliation are more easily reduced and reconstructed to Bi nanosheets with high-density grain boundaries (GBs; GB-rich Bi). The reconstructed GB-rich Bi catalyst affords a remarkable yield rate of 4.6 mmol h-1 mgcat. -1 and Faradaic efficiency of 32 % for urea production at -0.40 V vs. RHE. Notably, this yield rate is 2 and 8.2 times higher than those of the low-GB Bi and bulk Bi catalysts, respectively. Theoretical analysis demonstrates that the GB sites significantly reduce the *CO and *NH2 intermediate formation energy and C-N coupling energy barrier, enabling selective urea electrosynthesis on the GB-rich Bi catalyst. This work will trigger further research into the structure-activity interplay in dynamic processes using in situ techniques.

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Aims: The aim of this study was to develop and validate a prognostic model based on clinical laboratory biomarkers for the early identification of high-risk patients who require intensive care unit (ICU) admission among those hospitalized with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complicated with myocardial injury (MI). Methods: This single-center study enrolled 263 hospitalized patients with confirmed Omicron variant infection and concurrent MI. The patients were randomly divided into training and validation cohorts. Relevant variables were collected upon admission, and the least absolute shrinkage and selection operator (LASSO) was used to select candidate variables for constructing a Cox regression prognostic model. The model's performance was evaluated in both training and validating cohorts based on discrimination, calibration, and net benefit. Results: Of the 263 eligible patients, 210 were non-ICU patients and 53 were ICU patients. The prognostic model was built using four selected predictors: white blood cell (WBC) count, procalcitonin (PCT) level, C-reactive protein (CRP) level, and blood urea nitrogen (BUN) level. The model showed good discriminative ability in both the training cohort (concordance index: 0.802, 95% CI: 0.716-0.888) and the validation cohort (concordance index: 0.799, 95% CI: 0.681-0.917). For calibration, the predicted probabilities and observed proportions were highly consistent, indicating the model's reliability in predicting outcomes. In the 21-day decision curve analysis, the model had a positive net benefit for threshold probability ranges of 0.2 to 0.8 in the training cohort and nearly 0.2 to 1 in the validation cohort. Conclusion: In this study, we developed a clinically practical model with high discrimination, calibration, and net benefit. It may help to early identify severe and critical cases among Omicron variant-infected hospitalized patients with MI.

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Interaction between Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) protein heptad repeat-1 domain (HR1) and heptad repeat-2 domain (HR2) is critical for the MERS-CoV fusion process. This interaction is mediated by the α-helical region from HR2 and the hydrophobic groove in a central HR1 trimeric coiled coil. We sought to develop a short peptidomimetic to act as a MERS-CoV fusion inhibitor by reproducing the key recognition features of HR2 helix. This was achieved by the use of helix-stabilizing strategies, including substitution with unnatural helix-favoring amino acids, introduction of ion pair interactions, and conjugation of palmitic acid. The resulting 23-mer lipopeptide, termed AEEA-C16, inhibits MERS-CoV S protein-mediated cell-cell fusion at a low micromolar level comparable to that of the 36-mer HR2 peptide HR2P-M2. Collectively, our studies provide new insights into developing short peptide-based antiviral agents to treat MERS-CoV infection.

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The unceasing global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls for the development of novel therapeutics. Although many newly developed antivirals and repurposed antivirals have been applied to the treatment of coronavirus disease 2019 (COVID-19), antivirals showing satisfactory clinical efficacy are few in number. In addition, the loss of sensitivity to variants of concern (VOCs) and lack of oral bioavailability have also limited the clinical application of some antivirals. These facts remind us to develop more potent and broad-spectrum antivirals with better pharmacokinetic/pharmacodynamic properties to fight against infections from SARS-CoV-2, its variants, and other human coronaviruses (HCoVs). In this review, we summarize the latest advancements in the clinical development of antivirals against infections by SARS-CoV-2 and its variants.

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Along with the long pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has come the dilemma of emerging viral variants of concern (VOC), particularly Omicron and its subvariants, able to deftly escape immune surveillance and the otherwise protective effect of current vaccines and antibody drugs. We previously identified a peptide-based pan-CoV fusion inhibitor, termed as EK1, able to bind the HR1 region in viral spike (S) protein S2 subunit. This effectively blocked formation of the six-helix bundle (6-HB) fusion core and, thus, showed efficacy against all human coronaviruses (HCoVs). EK1 is now in phase 3 clinical trials. However, the peptide drug generally lacks oral availability. Therefore, we herein performed a structure-based virtual screening of the libraries of biologically active molecules and identified nine candidate compounds. One is Navitoclax, an orally active anticancer drug by inhibition of Bcl-2. Like EK1 peptide, it could bind HR1 and block 6-HB formation, efficiently inhibiting fusion and infection of all SARS-CoV-2 variants tested, as well as SARS-CoV and MERS-CoV, with IC50 values ranging from 0.5 to 3.7 µM. These findings suggest that Navitoclax is a promising repurposed drug candidate for development as a safe and orally available broad-spectrum antiviral drug to combat the current SARS-CoV-2 and its variants, as well as other HCoVs.

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BACKGROUND AND AIMS: Recompensation between patients with ascites and bleeding was unknown in treatment-naïve HBV-related decompensated cirrhosis. METHODS: In this retrospective multi-center study, treatment-naïve HBV-related decompensated patients were enrolled at first decompensating event of ascites and/or variceal bleeding. Further complications and clinical characteristics were collected using standard case report form every 6 months to year-5 of antiviral treatment. Recompensation was defined as maintaining free of decompensation for one year and achieving liver function within Child-Pugh A and/or MELD < 10. RESULTS: Totally, 170 (170/298, 57.0%) patients in ascites group of 298 (298/383, 77.8%) treatment-naïve decompensated patients and 33 (33/85, 38.8%) in bleeding group of 85 (85/383, 22.2%) patients, achieved recompensation. Ascites group had higher 5-year rate of recompensation than bleeding group (63.3% vs. 46.5%, p = 0.012), respectively. Patients achieving recompensation in ascites group maintained lower rate of second decompensation than these in bleeding group (at year-5: 26.7% vs. 43.3%, p = 0.032). Specifically, recompensated patients in ascites group had predominantly 5-year rate of further ascites (24.0%) and lower rate of further bleeding (6.0%), which differed from the pattern of these in bleeding group, with lower rate of further ascites (16.0%, p = 0.599) and significantly higher rate of further bleeding (33.9%, p < 0.001). Both patients had superior long-term prognosis (death/LT rate at year-5: 0.6% vs. 3.0%, p = 0.196). CONCLUSION: Ascites patients could achieve higher rate of recompensation through antiviral therapy than bleeding patients. Recompensated patients in ascites group had better prognosis in terms of preventing further bleeding.

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Disinfection by-products (DBPs), a series of undesired secondary contaminants formed during the disinfection processes, deteriorate water quality, threaten human health and endanger ecological safety. Membrane-filtration technologies are commonly used in the advanced water treatment and have shown a promising performance for removing trace contaminants. In order to gain a clearer understanding of the behavior of DBPs in membrane-filtration processes, this work dedicated to: (1) comprehensively reviewed the retention efficiency of microfiltration (MF), ultrafiltration (UF), nanofiltration (NF) and reverse osmosis (RO) for DBPs. (2) summarized the mechanisms involved size exclusion, electrostatic repulsion and adsorption in the membrane retention of DBPs. (3) In conjunction with principal component analysis, discussed the influence of various factors (such as the characteristics of membrane and DBPs, feed solution composition and operating conditions) on the removal efficiency. In general, the characteristics of the membranes (salt rejection, molecular weight cut-off, zeta potential, etc.) and DBPs (molecular size, electrical property, hydrophobicity, polarity, etc.) fundamentally determine the membrane-filtration performance on retaining DBPs, and the actual operating environmental factors (such as solute concentration, coexisting ions/NOMs, pH and transmembrane pressure) exert a positive/negative impact on performance to some extent. Current researches indicate that NF and RO can be effective in removing DBPs, and looking forward, we recommend that multiple factors should be taken into account that optimize the existed membrane-filtration technologies, rationalize the selection of membrane products, and develop novel membrane materials targeting the removal of DBPs.

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OBJECTIVE: To observe the effect of acupotomy on mitophagy mediated by PINK1/Parkin pathway in cartilage of rabbits with knee osteoarthritis (KOA), so as to explore its mechanism in inhibiting cartilage damage. METHODS: Twenty-one New Zealand rabbits were randomly divided into normal, model, and acupotomy groups, with 7 rabbits in each group. The KOA rabbit model was established by using the Videman method. Rabbits in the acupotomy group received regular acupotomy treatment around the knee joint nodules or tendons once a week for 3 consecutive weeks. HE staining and transmission electron microscopy were used to observe the morphological and ultrastructural changes in knee joint cartilage of rabbits. Flow cytometry was used to measure the mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) average fluorescence intensity in chondrocytes. Immunofluorescence was performed to detect the fluorescence intensity of LC3B, PINK1 and Parkin in cartilage tissue. Western blot was conducted to measure the protein expression levels of p62, LC3Ⅱ/Ⅰ, PINK1, and Parkin in cartilage tissue. RESULTS: Compared to the normal group, the model group showed fissures and tissue fibrosis on the surface of rabbit knee joint cartilages, loose distribution of chondrocytes, decreased autophagosomes, and abnormal mitochondrial morphology. The fluorescence intensity of LC3B, PINK1 and Parkin, the expression levels of LC3Ⅱ/Ⅰ, PINK1 and Parkin proteins in cartilage tissue were significantly decreased (P<0.01), while the percentage of chondrocytes with low Δψm, the average fluorescence intensity of ROS, and the expression of p62 protein in cartilage tissue were significantly increased (P<0.01). Compared to the model group, the acupotomy group showed no obvious defects on the surface of rabbit knee joint cartilage, relatively dense distribution of chondrocytes, increased autophagosomes, and relatively normal mitochondrial morphology. The fluorescence intensity of LC3B, PINK1 and Parkin, the expression of LC3Ⅱ/Ⅰ, PINK1 and Parkin proteins in cartilage tissue were significantly increased (P<0.01, P<0.05), while the percentage of chondrocytes with low Δψm, the average fluorescence intensity of ROS, and the expression of p62 protein in cartilage tissue were significantly decreased (P<0.01). CONCLUSION: Acupotomy may promote mitophagy by regulating the PINK1/Parkin pathway, thereby improving cartilage damage in rabbits with KOA.

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The peptide-based pan-coronavirus fusion inhibitor EK1 is in phase III clinical trials, and it has, thus far, shown good clinical application prospects against SARS-CoV-2 and its variants. To further improve its in vivo long-acting property, we herein developed an Fc-binding strategy by conjugating EK1 with human immunoglobulin G Fc-binding peptide (IBP), which can exploit the long half-life advantage of IgG in vivo. The newly engineered peptide IBP-EK1 showed potent and broad-spectrum inhibitory activity against SARS-CoV-2 and its variants, including various Omicron sublineages and other human coronaviruses (HCoVs) with low cytotoxicity. In mouse models, IBP-EK1 possessed potent prophylactic and therapeutic efficacy against lethal HCoV-OC43 challenge, and it showed good safety profile and low immunogenicity. More importantly, IBP-EK1 exhibited a significantly extended in vivo half-life in rhesus monkeys of up to 37.7 h, which is about 20-fold longer than that reported for EK1. Strikingly, IBP-EK1 displayed strong in vitro or ex vivo synergistic anti-HCoV effect when combined with monoclonal neutralizing antibodies, including REGN10933 or S309, suggesting that IBP-conjugated EK1 can be further developed as a long-acting, broad-spectrum anti-HCoV agent, either alone or in combination with neutralizing antibodies, to combat the current COVID-19 pandemic or future outbreaks caused by emerging and re-emerging highly pathogenic HCoVs.

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The threat to global health caused by three highly pathogenic human coronaviruses (HCoV), SARS-CoV-2, MERS-CoV and SARS-CoV, calls for the development of pan-HCoV therapeutics and vaccines. This study reports the design and engineering of a recombinant protein designated HR1LS. It contains three linked molecules, each consisting of three structural domains, including a heptad repeat 1 (HR1), a central helix (CH), and a stem helix (SH) region, in the S2 subunit of SARS-CoV-2 spike (S) protein. It was found that HR1LS protein automatically formed a trimer able to bind with heptad repeat 2 (HR2) region in the SARS-CoV-2 S2 subunit, thus potently inhibiting HCoV fusion and entry into host cells. Furthermore, immunization of mice with HR1LS, when combined with CF501 adjuvant, resulted in the production of neutralizing antibodies against infection of SARS-CoV-2 and its variants, as well as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and MjHKU4r-CoV-1. These results suggest that HR1LS is a promising candidate for further development as a novel HR1-trimer-based pan-HCoV entry inhibitor or vaccine for the treatment and prevention of infection by SARS-CoV-2 and its variants, but also other HCoVs with the potential to cause future emerging and re-emerging infectious coronavirus diseases.

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Cationic photosensitizers have good binding ability with negatively charged bacteria and fungi, exhibiting broad applications potential in antimicrobial photodynamic therapy (aPDT). However, cationic photosensitizers often display unsatisfactory transkingdom selectivity between mammalian cells and pathogens, especially for eukaryotic fungi. It is unclear which biomolecular sites are more efficient for photodynamic damage, owing to the lack of systematic research with the same photosensitizer system. Herein, a series of cationic aggregation-induced emission (AIE) derivatives (CABs) (using berberine (BBR) as the photosensitizers core) with different length alkyl chains are successfully designed and synthesized for flexible modulation of cellular activities. The BBR core can efficiently produce reactive oxygen species (ROS) and achieve high-performance aPDT . Through the precise regulation of alkyl chain length, different bindings, localizations, and photodynamic killing effects of CABs are achieved and investigated systematically among bacteria, fungi, and mammalian cells. It is found that intracellular active substances, not membranes, are more efficient damage sites of aPDT. Moderate length alkyl chains enable CABs to effectively kill Gram-negative bacteria and fungi with light, while still maintaining excellent mammalian cell and blood compatibility. This study is expected to provide systematic theoretical and strategic research guidance for the construction of high-performance cationic photosensitizers with good transkingdom selectivity.

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