Fluoride removal from coal mining water using novel polymeric aluminum modified activated carbon prepared through mechanochemical process.

Defluoridation of coal mining water is of great significance for sustainable development of coal industry in western China. A novel one-step mechanochemical method was developed to prepare polymeric aluminum modified powder activated carbon (PAC) for effective fluoride removal from coal mining water. Aluminum was stably loaded on the PAC through facile solid-phase reaction between polymeric aluminum (polyaluminum chloride (PACl) or polyaluminum ferric chloride (PAFC)) and PAC (1:15 W/W). Fluoride adsorption on PACl and PAFC modified PAC (C-PACl and C-PAFC) all reached equilibrium within 5 min, at rate of 2.56 g mg-1 sec-1 and 1.31 g mg-1 sec-1 respectively. Larger increase of binding energy of Al on C-PACl (AlF bond: 76.64 eV and AlFOH bond: 77.70 eV) relative to that of Al on C-PAFC (AlF bond: 76.52 eV) explained higher fluoride uptake capacity of C-PACl. Less chloride was released from C-PACl than that from C-PAFC due to its higher proportion of covalent chlorine and lower proportion of ionic chlorine. The elements mapping and atomic composition proved the stability of Al loaded on the PAC as well as the enrichment of fluoride on both C-PACl and C-PAFC. The Bader charge, formation energy and bond length obtained from DFT computational results explained the fluoride adsorption mechanism further. The carbon emission was 7.73 kg CO2-eq/kg adsorbent prepared through mechanochemical process, which was as low as 1:82.3 to 1:8.07 × 104 compared with the ones prepared by conventional hydrothermal methods.

A real-world study of tyrosine kinase inhibitors plus anti-PD-1 immunotherapy with or without chemoembolization for hepatocellular carcinoma patients with main portal vein invasion.

BACKGROUND: Although systemic therapies are recommended for hepatocellular carcinoma (HCC) patients with main portal vein (MPV) invasion and preserved liver function, the outcome is limited. In the real-world, chemoembolization is a commonly used local treatment for advanced HCC. PURPOSE: To evaluate whether the additional chemoembolization treatment yields survival benefits compared to systemic therapy for HCC patients with MPV invasion and preserved liver function (Child-Pugh score ≤ B7) in a real-world study from multiple centers. PATIENTS AND METHODS: Between January 2020 and December 2022, 91 consecutive HCC patients with MPV invasion who received either systemic medical therapy (i.e., tyrosine kinase inhibitors (TKIs) plus anti-PD-1 immunotherapy, S group, n = 43) or in combination with chemoembolization treatment (S-T group, n = 48) from five centers were enrolled in the study. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and treatment response. Adverse events (AEs) related to treatment were also recorded. Survival curves were constructed with the Kaplan-Meier method and compared using the log-rank test. RESULTS: The baseline characteristics were comparable between the two groups. The mean number of chemoembolization sessions per patient was 2.1 (range 1-3). The median OS was 10.0 months and 8.0 months in the S-T group and S group, respectively (P = 0.254). The median PFS between the two groups was similar (4.0 months vs. 4.0 months, P = 0.404). The disease control rate between the S-T and S groups were comparable (60.4% vs. 62.8%, P = 0.816). Although no chemoembolization-related deaths occurred, 13 grade 3-4 AEs occurred in the S-T group. CONCLUSIONS: The results of the real-world study demonstrated that additional chemoembolization treatment did not yield survival benefits compared to TKIs plus anti-PD-1 immunotherapy for the overall patients with advanced HCC and MPV invasion.

The Analgesic Effect of a Transdermal Lappaconitine Patch Combined With Ibuprofen Suspension for Children After Adenoidectomy and Tonsillectomy: A Randomized Clinical Trial.

PURPOSE: To study the analgesic effects and side effects of a transdermal lappaconitine (TLA) patch, ibuprofen suspension (IS), and TLA combined with IS (TLACIS) after adenoidectomy and tonsillectomy. DESIGN: Prospective, randomized clinical trial. METHODS: The patients were randomized into three groups defined by different analgesic drug regimens: the TLA group, the IS group, and the TLACIS group. Pain scores at 2, 12, and 24 hours after surgery and adverse-event reports within the first postoperative week were collected. RESULTS: Ultimately, this study included 102 cases in the TLA group, 101 cases in the IS group, and 101 cases in the TLACIS group. At 2 hours after surgery, the pain scores of the TLA and the TLACIS groups were both significantly lower than that of the IS group (all P < .05). At 12 and 24 hours after surgery, the pain score of the TLACIS group was significantly lower than those of the TLA and IS groups (all P < .05); furthermore, the pain score of the IS group was significantly lower than that of the TLA group (P < .05). Within 1 week after the operation, there was no significant difference in the incidence of adverse events. CONCLUSIONS: The addition of a TLA patch can speed the onset of analgesia. In terms of analgesic effects, IS alone is more advantageous than TLA alone, while the combination of TLA and IS has the best analgesic effect. No significant differences were found in the incidence of adverse events among the three regimens.

Engineered CARD11-PIK3R3 T-cell therapies as weapons of cancer mass destruction.

Garcia et al. discover a novel immunotherapy approach by engineering naturally occurring mutations in therapeutic T cells to strongly elevate anti-tumor activity. The authors identify a gene fusion, CARD11-PIK3R3, to increase activator protein 1 and nuclear factor-κB signaling, interleukin-2 production, and tumor death in vitro and in vivo .

Value analysis of ITLN1 in the diagnostic and prognostic assessment of colorectal cancer.

Background: Colorectal cancer (CRC) remains the leading cause of cancer death worldwide. Less than half of the patients are diagnosed when the cancer is locally advanced. Several studies have shown that intelectin-1 (ITLN1) can serve as a key prognostic and therapeutic target for CRC. The purpose of this study was to investigate the clinical value of ITLN1 in CRC and to analyse its potential as a predictive biomarker for CRC. Methods: Colon adenocarcinoma (COAD) is the main type of CRC. COAD project in The Cancer Genome Atlas (TCGA) database served as the training cohort, and GSE39582 series in the Gene Expression Omnibus (GEO) database served as the external independent validation cohort. First, the difference in the expression level of ITLN1 between COAD tissue and normal tissue was analysed, and the results were verified via immunohistochemistry. The relationship between ITLN1 expression and the prognosis of COAD patients was evaluated via the heatmap and the Kaplan-Meier (KM) curve. The ITLN1 coexpressed gene set obtained by Pearson correlation analysis was used. The prognostic signatures that were significantly correlated with survival status were screened by Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Finally, a nomogram related to ITLN1 was constructed based on the risk score of the prognostic signature and routine clinicopathological variables. Results: ITLN1 is significantly underexpressed in tumour tissues and can be used as a valuable tool to distinguish COAD. The high-expression group of ITLN1 was verified to have a greater survival rate. ITLN1 is significantly associated with a good prognosis in COAD patients. Six candidate genes (ITLN1 and MORC2, SH2D7, LGALS4, ATOH1, and NAT2) were selected for use in the Cox-LASSO regression analysis to calculate the risk score. Finally, a nomogram was constructed with a comprehensive risk score and clinicopathologic factors to successfully predict and verify the 1-year, 3-year, and 5-year survival probability. Conclusions: Our study established ITLN1 as an effective tool for CRC screening, diagnosis, and prognostic assessment, provided a basis for further study of the molecular function of ITLN1, and provided new insights for the mechanistic exploration and treatment of CRC.

Inhibitors and PROTACs of CDK2: challenges and opportunities.

INTRODUCTION: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors. AREA COVERED: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments. EXPERT OPINION: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

Hemifacial Spasm Associated With the Specific Offending Vein.

BACKGROUND AND OBJECTIVES: Hemifacial spasm (HFS) caused by venous compression is a rare occurrence. Currently, there is no relevant research on the venous characteristics and potential pathogenic mechanisms causing venous HFS. Exploring the venous characteristics in venous-type HFS may reduce the likelihood of repeated surgery. METHODS: The authors presented 4 cases of HFS caused by veins of middle cerebellar peduncle (V. of Mid.Cer.Ped) successfully treated with microvascular decompression. RESULTS: Based on intraoperative observations and abnormal muscle response (AMR) monitoring, it was determined that V. of Mid.Cer.Ped were offending vessels in these patients. Moreover, veins crossed between the facial and vestibulocochlear nerves, and then surrounded the ventral aspect of the facial nerve root. Microvascular decompression for the offending vessel was successfully performed, and AMR disappeared for each patient. These patients were discharged without any complications and involuntary contractions or twitching of facial muscles. CONCLUSION: The study demonstrated that veins can indeed induce HFS. The characteristic of the V. of Mid.Cer.Ped that leads to HFS is that these veins traverse between the facial nerve and the vestibulocochlear nerve, and then surround the ventral aspect of the facial nerve root. The dynamic influence of cerebrospinal fluid leads to pulsatile impingement of the facial nerve on the vein, resulting in facial nerve bending and deformation at the location of the vein. Significantly, in the context of surgery, if it is noticed that the V. of Mid.Cer.Ped surrounds the ventral aspect of the facial nerve root and the facial nerve is compressed and deformed, when AMR disappears after decompression of the artery, it may be necessary to perform vein decompression.

Ciprofloxacin Versus Levofloxacin Prophylaxis in Hematopoietic Stem Cell Transplantation: A Randomized Trial.

OBJECTIVES: We aimed to assess whether there is a difference between ciprofloxacin and levofloxacin as prophylaxis in hematopoietic stem cell transplant (SCT) recipients. METHODS: This is a prospective, randomized trial in patients receiving SCT at Henry Ford Health in the United States of America. We randomly assigned patients (1:1) to receive ciprofloxacin or levofloxacin. The primary outcome was incidence of bloodstream bacterial infections (BSI) up to day 60 after SCT. RESULTS: Between June 4, 2018, and May 23, 2022, we randomly assigned 308 consecutive patients to receive ciprofloxacin (154 patients) or levofloxacin (154 patients). BSI was similar in both the ciprofloxacin and levofloxacin groups (18 [11.7%] vs 18 [11.7%]). Pneumonia was more frequent in the ciprofloxacin group compared to the levofloxacin group (18 [18%] vs 7 [23%]; relative risk 2.57, 95% CI 1.11-5.98; p = 0.028). There were no differences in neutrophil engraftment, fever, Clostridium difficile infection, relapse incidence, overall survival, non-relapse mortality, length of stay post-SCT, or intensive care unit admission. CONCLUSIONS: Although both prophylaxis regimens demonstrated the same efficacy in SCT recipients, levofloxacin prophylaxis led to less pneumonia in the first 60 days post-SCT. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, NCT03850379.

Fgf9 regulates bone marrow mesenchymal stem cell fate and bone-fat balance in osteoporosis by PI3K/AKT/Hippo and MEK/ERK signaling.

Bone-fat balance is crucial to maintain bone homeostasis. As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal stem cells (BMSCs) are delicately balanced for their differentiation commitment. However, the exact mechanisms governing BMSC cell fate are unclear. In this study, we discovered that fibroblast growth factor 9 (Fgf9), a cytokine expressed in the bone marrow niche, controlled bone-fat balance by influencing the cell fate of BMSCs. Histomorphology and cytodifferentiation analysis showed that Fgf9 loss-of-function mutation (S99N) notably inhibited bone marrow adipose tissue (BMAT) formation and alleviated ovariectomy-induced bone loss and BMAT accumulation in adult mice. Furthermore, in vitro and in vivo investigations demonstrated that Fgf9 altered the differentiation potential of BMSCs, shifting from osteogenesis to adipogenesis at the early stages of cell commitment. Transcriptomic and gene expression analyses demonstrated that FGF9 upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. Mechanistic studies revealed that FGF9, through FGFR1, promoted adipogenic gene expression via PI3K/AKT/Hippo pathways and inhibited osteogenic gene expression via MAPK/ERK pathway. This study underscores the crucial role of Fgf9 as a cytokine regulating the bone-fat balance in adult bone, suggesting that FGF9 is a potentially therapeutic target in the treatment of osteoporosis.

Polystyrene nanoplastics of different particle sizes regulate the polarization of pro-inflammatory macrophages.

Microplastics (MPs) are defined as plastic particles smaller than 5 mm in size, and nanoplastics (NPs) are those MPs with a particle size of less than 1000 nm or 100 nm. The prevalence of MPs in the environment and human tissues has raised concerns about their potential negative effects on human health. Macrophages are the major defence against foreign substances in the intestine, and can be polarized into two types: the M1 phenotype and the M2 phenotype. However, the effect of NPs on the polarization of macrophages remains unclear. Herein, we selected polystyrene, one of the most plastics in the environment and controlled the particle sizes at 50 nm and 500 nm respectively to study the effects on the polarization of macrophages. We used mouse RAW264.7 cell line models in this macrophage-associated study. Experiments on cell absorption showed that macrophages could quickly ingest polystyrene nanoplastics of both diameters with time-dependent uptake. Compared to the untreated group and 10 µg/mL treatment group, macrophages exposed to 50 µg/mL groups (50 nm and 500 nm) had considerably higher levels of CD86, iNOS, and TNF-α, but decreased levels of aCD206, IL-10, and Arg-1. According to these findings, macrophage M1 and M2 polarization can both be induced and inhibited by 50 µg/mL 50 nm and 500 nm polystyrene nanoplastics. This work provided the first evidence of a possible MPs mode of action with appropriate concentration and size through the production of polarized M1, providing dietary and environmental recommendations for people, particularly those with autoimmune and autoinflammatory illnesses.

The association between different impact exercises and osteoporosis: an analysis of data from the Taiwan biobank.

Osteoporosis is a prevalent condition marked by reduced bone density and an elevated risk of fractures, especially among postmenopausal women. Exercise plays a crucial role in preventing and managing osteoporosis, with weight-bearing and impact exercises being particularly effective in enhancing bone density and mitigating disease risk. This study investigated the relationship between various types of impact exercises and osteoporosis using data from the Taiwan Biobank (TWB). The study sample comprised 5,123 individuals without osteoporosis and 1,770 individuals with the condition. Student's t-test and logistic regression analyses were utilized to assess the associations between exercise types and osteoporosis risk. Results indicated that high-impact exercise significantly reduced the likelihood of developing osteoporosis compared to no exercise (odds ratio; OR = 0.573, 95% CI: 0.406-0.810, P = 0.002). Conversely, low-impact exercises did not show a significant overall association with osteoporosis (OR = 1.160, 95% CI: 0.932-1.445, P = 0.184). Stratified analysis by sex revealed that high-impact exercise was protective against osteoporosis in men (OR = 0.391, 95% CI: 0.202-0.755, P = 0.005), but not significantly so in women (OR = 0.671, 95% CI: 0.438-1.027, P = 0.066). These findings suggest that high-impact exercise is associated with a reduced risk of osteoporosis, particularly among Taiwanese men aged 30 to 70.

Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy.

BACKGROUND: The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. METHODS: Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. RESULTS: The abscopal effect was further amplified in the "cold" tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. CONCLUSIONS: Bi was used as an artificially implanted anaerobic target to cause a transient "infection" at the tumor, causing the tumor to become locally inflamed and "hot", and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Liquid-liquid phase separation in diseases.

Liquid-liquid phase separation (LLPS), an emerging biophysical phenomenon, can sequester molecules to implement physiological and pathological functions. LLPS implements the assembly of numerous membraneless chambers, including stress granules and P-bodies, containing RNA and protein. RNA-RNA and RNA-protein interactions play a critical role in LLPS. Scaffolding proteins, through multivalent interactions and external factors, support protein-RNA interaction networks to form condensates involved in a variety of diseases, particularly neurodegenerative diseases and cancer. Modulating LLPS phenomenon in multiple pathogenic proteins for the treatment of neurodegenerative diseases and cancer could present a promising direction, though recent advances in this area are limited. Here, we summarize in detail the complexity of LLPS in constructing signaling pathways and highlight the role of LLPS in neurodegenerative diseases and cancers. We also explore RNA modifications on LLPS to alter diseases progression because these modifications can influence LLPS of certain proteins or the formation of stress granules, and discuss the possibility of proper manipulation of LLPS process to restore cellular homeostasis or develop therapeutic drugs for the eradication of diseases. This review attempts to discuss potential therapeutic opportunities by elaborating on the connection between LLPS, RNA modification, and their roles in diseases.

Current Applications and Future Directions of Circulating Tumor Cells in Colorectal Cancer Recurrence.

The ability to predict or detect colorectal cancer (CRC) recurrence early after surgery enables physicians to apply appropriate treatment plans and different follow-up strategies to improve patient survival. Overall, 30-50% of CRC patients experience cancer recurrence after radical surgery, but current surveillance tools have limitations in the precise and early detection of cancer recurrence. Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and enter the bloodstream. These can provide real-time information on disease status. CTCs might become novel markers for predicting CRC recurrence and, more importantly, for making decisions about additional adjuvant chemotherapy. In this review, the clinical application of CTCs as a therapeutic marker for stage II CRC is described. It then discusses the utility of CTCs for monitoring cancer recurrence in advanced rectal cancer patients who undergo neoadjuvant chemoradiotherapy. Finally, it discusses the roles of CTC subtypes and CTCs combined with clinicopathological factors in establishing a multimarker model for predicting CRC recurrence.

Thymol improves the growth performance of blue foxes by regulating the gut microbiota.

Introduction: The drawbacks of using antibiotics as feed additives for blue foxes have gradually become apparent; moreover, thymol has wide-spectrum antimicrobial activity and has the potential to replace antibiotics in various animals. However, there are few reports on the effects of thymol on blue foxes. Methods: This study aimed to investigate the effects of different concentrations of thymol on the growth performance, apparent nutrient digestibility, serum biochemical indicators, intestinal morphology, and gut microbiota of blue foxes. Twenty-four male blue foxes (120 ± 5 d) of similar weight (6.05 ± 0.16 kg) were randomly divided into 4 groups. 0, 100, 200, and 300 mg/kg thymol were added to the basal diets of groups C, L, M, and H, respectively. Results: Compared with those in the C group, the addition of 100 mg/kg thymol to the diet significantly increased organic matter (OM) digestibility, crude protein (CP) digestibility, immunoglobulin (Ig) A, IgM, the VH of the duodenum, the CD of the jejunum, the VH of the ileum, and the VH/CD of the ileum (P < 0.05) and strongly significantly increased IgG (P < 0.01). The addition of 200 mg/kg thymol to the diet increased the VH/CD of the duodenum (P < 0.05). The addition of 300 mg/kg thymol to the diet significantly increased the VH and CD of the jejunum (P < 0.05). The addition of 200 mg/kg and 300 mg/kg thymol to the diets increased the final weight (FW) (P < 0.05). Adding 100 mg/kg thymol significantly increased the levels of interleukin-4 (IL-4) and catalase (CAT) compared with those in the other groups (P < 0.05). 16S rRNA gene detection revealed that thymol can change the abundances of Bifidobacterium, Fusobacterium, Allobaculum, Streptococcus, Megasphaera, and Lactobacillus in the gut. Conclusion: The addition of thymol to diets can increase the abundance of Bifidobacterium, Fusobacterium, and Allobaculum, which may contribute to improving the growth performance of blue foxes.

Correlated Charge Density Wave Insulators in Chirally Twisted Triple Bilayer Graphene.

Electrons residing in a flat-band system can play a vital role in triggering spectacular phenomenology due to relatively large interactions and spontaneous breaking of different degeneracies. In this work, we demonstrate chirally twisted triple bilayer graphene, a new moiré structure formed by three pieces of helically stacked Bernal bilayer graphene, as a highly tunable flat-band system. In addition to the correlated insulators showing at integer moiré fillings, commonly attributed to interaction induced symmetry broken isospin flavors in graphene, we observe abundant insulating states at half-integer moiré fillings, suggesting a longer-range interaction and the formation of charge density wave insulators which spontaneously break the moiré translation symmetry. With weak out-of-plane magnetic field applied, as observed half-integer filling states are enhanced and more quarter-integer filling states appear, pointing toward further quadrupling moiré unit cells. The insulating states at fractional fillings combined with Hartree-Fock calculations demonstrate the observation of a new type of correlated charge density wave insulators in graphene and points to a new accessible twist manner engineering correlated moiré electronics.

Physiologic Network-Based Brain-Heart Interaction Quantification During Visual Emotional Elicitation.

In recent years, there has been a surge in interest regarding the intricate physiological interplay between the brain and the heart, particularly during emotional processing. This has led to the development of various signal processing techniques aimed at investigating Brain-Heart Interactions (BHI), reflecting a growing appreciation for their bidirectional communication and influence on each other. Our study contributes to this burgeoning field by adopting a network physiology approach, employing time-delay stability as a quantifiable metric to discern and measure the coupling strength between the brain and the heart, specifically during visual emotional elicitation. We extract and transform features from EEG and ECG signals into a 1 Hz format, facilitating the calculation of BHI coupling strength through stability analysis on their maximal cross-correlation. Notably, our investigation sheds light on the critical role played by low-frequency components in EEG, particularly in the δ , θ , and α bands, as essential mediators of information transmission during the complex processing of emotion-related stimuli by the brain. Furthermore, our analysis highlights the pivotal involvement of frontal pole regions, emphasizing the significance of δ - θ coupling in mediating emotional responses. Additionally, we observe significant arousal-dependent changes in the θ frequency band across different emotional states, particularly evident in the prefrontal cortex. By offering novel insights into the synchronized dynamics of cortical and heartbeat activities during emotional elicitation, our research enriches the expanding knowledge base in the field of neurophysiology and emotion research.

Competition and synergy of Arp2/3 and formins in nucleating actin waves.

Actin assembly and dynamics are crucial for maintaining cell structure and changing physiological states. The broad impact of actin on various cellular processes makes it challenging to dissect the specific role of actin regulatory proteins. Using actin waves that propagate on the cortex of mast cells as a model, we discovered that formins (FMNL1 and mDia3) are recruited before the Arp2/3 complex in actin waves. GTPase Cdc42 interactions drive FMNL1 oscillations, with active Cdc42 and the constitutively active mutant of FMNL1 capable of forming waves on the plasma membrane independently of actin waves. Additionally, the delayed recruitment of Arp2/3 antagonizes FMNL1 and active Cdc42. This antagonism is not due to competition for monomeric actin but rather for their common upstream regulator, active Cdc42, whose levels are negatively regulated by Arp2/3 via SHIP1 recruitment. Collectively, our study highlights the complex feedback loops in the dynamic control of the actin cytoskeletal network.

Far-Red Aggregation-Induced Emission Hydrogel-Reinforced Tissue Clearing for 3D Vasculature Imaging of Whole Lung and Whole Tumor.

Understanding the vascular formation and distribution in metastatic lung tumors is a significant challenge due to autofluorescence, antibody/dye diffusion in dense tumor, and fluorophore stability when exposed to solvent-based clearing agents. Here, an approach is presented that redefines 3D vasculature imaging within metastatic tumor, peritumoral lung tissue, and normal lung. Specifically, a far-red aggregation-induced emission nanoparticle with surface amino groups (termed as TSCN nanoparticle, TSCNNP) is designed for in situ formation of hydrogel (TSCNNP@Gel) inside vasculatures to provide structural support and enhance the fluorescence in solvent-based tissue clearing method. Using this TSCNNP@Gel-reinforced tissue clearing imaging approach, the critical challenges are successfully overcome and comprehensive visualization of the whole pulmonary vasculature up to 2 µm resolution is enabled, including its detailed examination in metastatic tumors. Importantly, features of tumor-associated vasculature in 3D panoramic views are unveiled, providing the potential to determine tumor stages, predict tumor progression, and facilitate the histopathological diagnosis of various tumor types.

Membrane Disruption-Enhanced Photodynamic Therapy against Gram-Negative Bacteria by a Peptide-Photosensitizer Conjugate.

Photodynamic therapy (PDT) emerges as a promising strategy for combating bacteria with minimal drug resistance. However, a significant hurdle lies in the ineffectiveness of most photosensitizers against Gram-negative bacteria, primarily attributable to their characteristic impermeable outer membrane (OM) barrier. To tackle this obstacle, we herein report an amphipathic peptide-photosensitizer conjugate (PPC) with intrinsic outer membrane disruption capability to enhance PDT efficiency against Gram-negative bacteria. PPC is constructed by conjugating a hydrophilic ultrashort cationic peptide to a hydrophobic photosensitizer. PPC could efficiently bind to the OM of Gram-negative bacteria through electrostatic adsorption, and subsequently disrupt the structural integrity of the OM. Mechanistic investigations revealed that PPC triggers membrane disruption by binding to both lipopolysaccharide (LPS) and phospholipid leaflet in the OM, enabling effective penetration of PPC into the Gram-negative bacteria interior. Upon light irradiation, PPC inside bacteria generates singlet oxygen not only to effectively decrease the survival of Gram-negative bacteria P. aeruginosa and E. coli to nearly zero in vitro, but also successfully cure the full-thickness skin infection and bacterial keratitis (BK) induced by P. aeruginosa in animal models. Thus, this study provides a broad-spectrum antibacterial phototherapeutic design strategy by the synergistic action of membrane disruption and PDT to combat Gram-negative bacteria.