Tailoring near-infrared amyloid-ß probes with high-affinity and low background based on CN and amphipathic regulatory strategies and in vivo imaging of AD mice.

Amyloid-ß (Aß) species (Aß fibrils and Aß plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aß probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aß probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aß. Notably, the probes containing CN group display the ability of binding two distinct sites of Aß, which dramatically enhanced the affinity to Aß species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aß species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aß probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aß probes with low background in vivo/in vitro imaging for Aß species.

Accumulated inflammation and fibrosis participate in atrazine induced ovary toxicity in mice.

Atrazine is a widely used herbicide in agricultural production. Previous studies have shown that atrazine affects hormone secretion and oocyte maturation in female reproduction. However, the specific mechanism by which atrazine affects ovarian function remains unclear. In this study, using a mouse gastric lavage model, we report that four weeks of atrazine exposure affects body growth, interferes with the estrous cycle, and increases the number of atretic follicles in mice. The expression levels of follicle development related factors StAR, BMP15, and AMH decreased. Metabolomic analysis revealed that atrazine activates an inflammatory response in ovarian tissue. Further studies confirmed that the expression levels of TNF-α, IL-6, and NF-κB increased in the ovaries of mice exposed to atrazine. Additionally, α-smooth muscle actin (α-SMA) accumulated in ovarian tissue, and transforming growth factor-ß (TGF-ß) signaling was activated, indicating the occurrence of tissue fibrosis. Moreover, mice exposed to atrazine produced fewer oocytes and exhibited reduced embryonic development. Furthermore, mice exposed to atrazine exhibited altered gut microbiota abundance and a disrupted colon barrier. Collectively, these findings suggest that atrazine exposure induces ovarian inflammation and fibrosis, disrupts ovarian homeostasis, and impairs follicle maturation, ultimately reducing oocyte quality.

An Antiferromagnetic Neuromorphic Memory Based on Perpendicularly Magnetized CoO.

Antiferromagnets (AFMs) are ideal materials to boost neuromorphic computing toward the ultrahigh speed and ultracompact integration regime. However, developing a suitable AFM neuromorphic memory remains an aspirational but challenging goal. In this work, we construct such a memory based on the CoO/Pt heterostructure, in which the collinear insulating AFM CoO shows a strong perpendicular anisotropy facilitating its electrical readout and writing. Utilizing the unique nonlinear response and bipolar fading memory properties of the device, we demonstrate a multidimensional reservoir computing beyond the traditional binary paradigm. These results are expected to pave the way toward next-generation fast and massive neuromorphic computing.

Preconception mitochondrial DNA copy number plays a crucial role in linking prenatal air pollution with the risk of preterm birth.

The relationship between maternal peripheral blood mitochondrial DNA and adverse pregnancy outcomes, specifically preterm birth (PTB), remains uncertain. To investigate the effects of preconception mitochondrial DNA copy number (mtDNAcn) on the association between prenatal air pollutants exposure and PTB risk, a total of 1871 expectant mothers from six regions in Henan Province were recruited. Information regarding air pollutants was obtained from 151 environmental monitoring sites, and relative mtDNAcn was evaluated using real-time PCR analysis. After adjusting for potential confounding variables, it was determined that the risk of PTB increased with elevated levels of inhalable particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) exposure (P < 0.05) but decreased with higher nitrogen dioxide (NO2) exposure (0.05 < P < 0.10) during the entire pregnancy. Additionally, the preconception relative mtDNAcn was lower in the PTB group (0.82 ± 0.23) compared to the term group (0.92 ± 0.29). Furthermore, for each 0.1-unit increase in preconception mtDNAcn, the risk of PTB decreased by 14.8%. Stratified analyses revealed that the risk of PTB rose with increasing O3 concentrations, regardless of the relative mtDNAcn. Moreover, the study found a significant association between PTB risk and prenatal exposure to elevated PM10, PM2.5, SO2, and CO, particularly in mothers with low mtDNAcn (≤0.88) (P < 0.05). Conversely, a decrease in the PTB risk was observed with elevated NO2 exposure in mothers with high mtDNAcn (>0.88). Interaction analysis revealed that exposure to PM10, PM2.5, SO2, NO2, and CO interacted with mtDNAcn, respectively, affecting PTB risk (P-interaction<0.05). These findings indicate a noteworthy association between PTB risk and prenatal air pollutants exposure, which is influenced by the preconception mtDNAcn.

Sensitive and accurate monitoring of urinary albumin and point-of-care testing using a fluorescent probe with anti-interference capacity against exogenous drugs.

Fluorescent probes have been reported for monitoring urinary albumin (u-ALB) to enable early diagnosis of kidney diseases and facilitate regular point-of-care testing (POCT) for chronic kidney disease (CKD) patients. However, the albumin can bind hydrophobic drugs through host-guest interactions, which may result in decreased accuracy of probes at regular drug sites and hamper POCT of albuminuria since CKD patients often need to take medications routinely. Herein, we reported a novel fluorescent probe (NC-2) by molecular engineering of a reported AIEgen (NC-1). The introduction of a non-conjugated ring moiety to the molecular rotor granted the NC-2 enhanced sensitivity with a limit of detection in urine of 8.7 mg/L, which is below l the threshold of microalbuminuria (30 mg/L). Moreover, the NC-2 was found to preferentially bind to the FA1 site of ALB, conferring it with excellent anti-interference capacities against exogenous drug molecules and metabolites. Simulation experiments using lab-spiked urine samples containing common drugs taken by CKD patients demonstrated that the probe could provide satisfied detecting accuracy (80-90 %). Furthermore, a paper-based device was constructed and achieved on-site detection of u-ALB in qualitative and semi-quantitative manners. Findings in this work were of great significance to the development of fluorescent probes for accurate detection of ALB in complex urine samples and the further achievement of fluorescence-based POCT for CKD.

Instant in situ highlighting of latent fingerprints by a green fluorescent probe based on aggregation-induced emission.

Fluorescence sensing of latent fingerprints (LFPs) has gained extensive attention due to its high sensitivity, non-destructive testing, low biotoxicity, ease of operation, and the potential for in situ visualization. However, the realization of in situ visualization of LFPs especially with green emission and rapid speed is still a challenge. Herein, we synthesized an amphibious green-emission AIE-gen TPE-NI-AOH (PLQY = 62%) for instant in situ LFP detecting, which integrates the excellent fluorescence properties of naphthalimide (NI) with a hydrophilic head and the AIE character as well as the donating property of tetraphenylethene (TPE). TPE-NI-AOH in ethanol/water binary solvent was used as an environmentally friendly LFP developer and achieved in situ green-fluorescence visualization of LFPs. The fluorescence signal achieves its 60% saturated intensity in 0.37 s and nearly 100% in 2.50 s, which is an instant process for the naked eye. Moreover, level 3 details and super-resolution images of LFPs could be observed clearly. Besides, the TPE-NI-AOH developer could be stored for at least 6 months, suitable for long-term storage. This instant in situ highlighting method does not require post-processing operations, providing a more convenient, rapid, and efficient detection method of LFPs. This work would inspire the further advancement of fluorescent sensors for fingerprint imaging.

SART3 reads methylarginine-marked glycine- and arginine-rich motifs.

Glycine- and arginine-rich (GAR) motifs, commonly found in RNA-binding and -processing proteins, can be symmetrically (SDMA) or asymmetrically (ADMA) dimethylated at the arginine residue by protein arginine methyltransferases. Arginine-methylated protein motifs are usually read by Tudor domain-containing proteins. Here, using a GFP-Trap, we identify a non-Tudor domain protein, squamous cell carcinoma antigen recognized by T cells 3 (SART3), as a reader for SDMA-marked GAR motifs. Structural analysis and mutagenesis of SART3 show that aromatic residues lining a groove between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains are essential for SART3 to recognize and bind to SDMA-marked GAR motif peptides, as well as for the interaction between SART3 and the GAR-motif-containing proteins fibrillarin and coilin. Further, we show that the loss of this reader ability affects RNA splicing. Overall, our findings broaden the range of potential SDMA readers to include HAT domains.

Polyhydroxy structure orchestrates the intrinsic antibacterial property of acrylamide hydrogel as a versatile wound-healing dressing.

Hydrogel is considered as a promising candidate for wound dressing due to its tissue-like flexibility, good mechanical properties and biocompatibility. However, traditional hydrogel dressings often fail to fulfill satisfied mechanical, antibacterial, and biocompatibility properties simultaneously, due to the insufficient intrinsic bactericidal efficacy and the addition of external antimicrobial agents. In this paper, hydroxyl-contained acrylamide monomers, N-Methylolacrylamide (NMA) and N-[Tris (hydroxymethyl)methyl] acrylamide (THMA), are employed to prepare a series of polyacrylamide hydrogel dressings xNMA-yTHMA, where x and y represent the mass fractions of NMA and THMA in the hydrogels. We have elucidated that the abundance of hydroxyl groups determines the antibacterial effect of the hydrogels. Particularly, hydrogel 35NMA-5THMA exhibits excellent mechanical properties, with high tensile strength of 259 kPa and large tensile strain of 1737%. Furthermore, the hydrogel dressing 35NMA-5THMA demonstrates remarkable inherent antibacterial without exogenous antimicrobial agents owing to the existence of abundant hydroxyl groups. Besides, hydrogel dressing 35NMA-5THMA possesses excellent biocompatibility, in view of marginal cytotoxicity, low hemolysis ratio, and negligible inflammatory response and organ toxicity to mice during treatment. Encouragingly, hydrogel 35NMA-5THMA drastically promote the healing of bacteria-infected wound in mice. This study has revealed the importance of polyhydroxyl in the antibacterial efficiency of hydrogels and provided a simplified strategy to design wound healing dressings with translational potential.

The characteristics and prognosis of different disease patterns of multiple primary lung cancers categorized according to the 8th edition lung cancer staging system.

INTRODUCTION: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. METHOD: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. RESULTS: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. CONCLUSIONS: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients.

Organoid Culture of Different Intestinal Segments from Human and Mouse.

The intestine comprises distinct segments, each characterized by unique cell populations and functions. Intestinal organoids faithfully replicate the cellular composition and functions of the intestine. Over the past decade, the organoid model has garnered considerable attention for its application in investigation of organ development, renewal and functional performance. While the organoid culture systems for mouse small intestine and human large intestine have widely adopted, a comparison summary for different segments of the human or mouse intestine is lacking. In this study, we present a systematically detailed culture methodology for intestinal organoids, encompassing both the small intestine and the large intestine from humans or mice. This method provides a robust in vitro tool for intestinal research, and expands the possible clinical application of organoids.

Explore the active ingredients and potential mechanism of action on Actinidia arguta leaves against T2DM by integration of serum pharmacochemistry and network pharmacology.

BACKGROUND: Actinidia arguta leaves (AAL) are traditionally consumed as a vegetable and as tea in folk China and Korea. Previous studies have reported the anti-diabetic effect of AAL, but its bioactive components and mechanism of action are still unclear. AIM OF THE STUDY: This study aims to identify the hypoglycemic active components of AAL by combining serum pharmacochemistry and network pharmacology and to elucidate its possible mechanism of action. METHODS: Firstly, the effective components in mice serum samples were characterized by UPLC-Q/TOF-MSE. Furthermore, based on these active ingredients, network pharmacology analysis was performed to establish an "H-C-T-P-D" interaction network and reveal possible biological mechanisms. Finally, the affinity between serum AAL components and the main proteins in the important pathways above was investigated through molecular docking analysis. RESULTS: Serum pharmacochemistry analysis showed that 69 compounds in the serum samples were identified, including 23 prototypes and 46 metabolites. The metabolic reactions mainly included deglycosylation, dehydration, hydrogenation, methylation, acetylation, glucuronidation, and sulfation. Network pharmacology analysis showed that the key components quercetin, pinoresinol diglucoside, and 5-O-trans-p-coumaroyl quinic acid butyl ester mainly acted on the core targets PTGS2, HRAS, RELA, PRKCA, and BCL2 targets and through the PI3K-Akt signaling pathway, endocrine resistance, and MAPK signaling pathway to exert a hypoglycemic effect. Likewise, molecular docking results showed that the three potential active ingredients had good binding effects on the five key targets. CONCLUSION: This study provides a basis for elucidating the pharmacodynamic substance basis of AA against T2DM and further exploring the mechanism of action.

HER2 phosphorylation induced by TGF-ß promotes mammary morphogenesis and breast cancer progression.

Transforming growth factor ß (TGF-ß) and HER2 signaling collaborate to promote breast cancer progression. However, their molecular interplay is largely unclear. TGF-ß can activate mitogen-activated protein kinase (MAPK) and AKT, but the underlying mechanism is not fully understood. In this study, we report that TGF-ß enhances HER2 activation, leading to the activation of MAPK and AKT. This process depends on the TGF-ß type I receptor TßRI kinase activity. TßRI phosphorylates HER2 at Ser779, promoting Y1248 phosphorylation and HER2 activation. Mice with HER2 S779A mutation display impaired mammary morphogenesis, reduced ductal elongation, and branching. Furthermore, wild-type HER2, but not S779A mutant, promotes TGF-ß-induced epithelial-mesenchymal transition, cell migration, and lung metastasis of breast cells. Increased HER2 S779 phosphorylation is observed in human breast cancers and positively correlated with the activation of HER2, MAPK, and AKT. Our findings demonstrate the crucial role of TGF-ß-induced S779 phosphorylation in HER2 activation, mammary gland development, and the pro-oncogenic function of TGF-ß in breast cancer progression.

Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.

PURPOSE: Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined. METHODS: We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS. RESULTS: Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS. CONCLUSION: NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

Turning Threat to Therapy: A Nanozyme-Patch in Surgical Bed for Convenient Tumor Vaccination by Sustained In Situ Catalysis.

Complete surgical resection of tumor is difficult as the invasiveness of cancer, making the residual tumor a lethal threat to patients. The situation is deteriorated by the immune suppression state after surgery, which further nourishes tumor recurrence and metastasis. Immunotherapy is promising to combat tumor metastasis, but is limited by severe toxicity of traditional immunostimulants and complexity of multiple functional units. Here, it is reported that the simple "trans-surgical bed" delivery of Cu2- xSe nanozyme (CSN) by a microneedle-patch can turn the threat to therapy by efficient in situ vaccination. The biocompatible CSN exhibits both peroxidase and glutathione oxidase-like activities, efficiently exhausting glutathione, boosting free radical generation, and inducing immunogenic cell death. The once-for-all inserting of the patch on surgical bed facilitates sustained catalytic action, leading to drastic decrease of recurrence rate and complete suppression of tumor-rechallenge in cured mice. In vivo mechanism interrogation reveals elevated cytotoxic T cell infiltration, re-educated macrophages, increased dendritic cell maturation, and memory T cells formation. Importantly, preliminary metabolism and safety evaluation validated that the metal accumulation is marginable, and the important biochemical indexes are in normal range during therapy. This study has provided a simple, safe, and robust tumor vaccination approach for postsurgical metastasis control.

Recent advances in super-resolution optical imaging based on aggregation-induced emission.

Super-resolution imaging has rapidly emerged as an optical microscopy technique, offering advantages of high optical resolution over the past two decades; achieving improved imaging resolution requires significant efforts in developing super-resolution imaging agents characterized by high brightness, high contrast and high sensitivity to fluorescence switching. Apart from technical requirements in optical systems and algorithms, super-resolution imaging relies on fluorescent dyes with special photophysical or photochemical properties. The concept of aggregation-induced emission (AIE) was proposed in 2001, coinciding with unprecedented advancements and innovations in super-resolution imaging technology. AIE probes offer many advantages, including high brightness in the aggregated state, low background signal, a larger Stokes shift, ultra-high photostability, and excellent biocompatibility, making them highly promising for applications in super-resolution imaging. In this review, we summarize the progress in implementation methods and provide insights into the mechanism of AIE-based super-resolution imaging, including fluorescence switching resulting from photochemically-converted aggregation-induced emission, electrostatically controlled aggregation-induced emission and specific binding-regulated aggregation-induced emission. Particularly, the aggregation-induced emission principle has been proposed to achieve spontaneous fluorescence switching, expanding the selection and application scenarios of super-resolution imaging probes. By combining the aggregation-induced emission principle and specific molecular design, we offer some comprehensive insights to facilitate the applications of AIEgens (AIE-active molecules) in super-resolution imaging.

U-shaped relationship between ozone exposure and preterm birth risk associated with preconception telomere length.

There are conflicting findings regarding the association of ozone (O3) exposure with preterm birth (PTB) occurrence. In the present study, two cohorts were combined to explore the relationship between maternal O3 exposure during pregnancy and PTB risk, and analyze the underlying mechanisms of this relationship in terms of alterations in the preconception telomere length. Cohort 1 included mothers who participated in the National Free Preconception Health Examination Project in Henan Province from 2014 to 2018 along with their newborns (n = 1,066,696). Cohort 2 comprised mothers who conceived between 2016 and 2018 and their newborns (n = 1871) from six areas in Henan Province. The telomere length was assessed in the peripheral blood of mothers at the preconception stage. Data on air pollutant concentrations were collected from environmental monitoring stations and individual exposures were assessed using an inverse distance-weighted model. O3 concentrations (100.60 ± 14.13 µg/m3) were lower in Cohort 1 than in Cohort 2 (114.09 ± 15.17 µg/m3). Linear analyses showed that PTB risk decreased with increasing O3 exposure concentrations in Cohort 1 but increased with increasing O3 exposure concentrations in Cohort 2. Nonlinear analyses revealed that PTB risk tended to decrease and then increase with increasing O3 exposure concentrations in both cohorts. Besides, PTB risk was reduced by 88% for each-unit increase in telomere length in those exposed to moderate O3 concentrations (92.4-123.7 µg/m3, P < 0.05). While no significant association was observed between telomere length and PTB at extreme O3 concentration exposure during entire pregnancy (<92.4 or >123.7 µg/m3, P > 0.05) in Cohort 2. These findings reveal a nonlinear (U-shaped) relationship between O3 exposure and PTB risk. Furthermore, telomere with elevated length was associated with decreased risk of PTB only when exposed to moderate concentrations of O3, but not when exposed to extreme concentrations of O3 during pregnancy.

Microenvironment responsive charge-switchable nanoparticles act on biofilm eradication and virulence inhibition for chronic lung infection treatment.

Chronic pulmonary infection caused by Pseudomonas aeruginosa (P. aeruginosa) is a common lung disease with high mortality, posing severe threats to public health. Highly resistant biofilm and intrinsic resistance make P. aeruginosa hard to eradicate, while powerful virulence system of P. aeruginosa may give rise to the recurrence of infection and eventual failure of antibiotic therapy. To address these issues, infection-microenvironment responsive nanoparticles functioning on biofilm eradication and virulence inhibition were simply prepared by electrostatic complexation between dimethylmaleic anhydride (DA) modified negatively charged coating and epsilon-poly(l-lysine) derived cationic nanoparticles loaded with azithromycin (AZI) (DA-AZI NPs). Charge reversal responsive to acidic condition enabled DA-AZI NPs to successively penetrate through both mucus and biofilms, followed by targeting to P. aeruginosa and permeabilizing its outer/inner membrane. Then in situ released AZI, which was induced by the lipase-triggered NPs dissociation, could easily enter into bacteria to take effects. DA-AZI NPs exhibited enhanced eradication activity against P. aeruginosa biofilms with a decrease of >99.999% of bacterial colonies, as well as remarkable inhibitory effects on the production of virulence factors and bacteria re-adhesion & biofilm re-formation. In a chronic pulmonary infection model, nebulization of DA-AZI NPs into infected mice resulted in prolonged retention and increased accumulation of the NPs in the infected sites of the lungs. Moreover, they significantly reduced the burden of P. aeruginosa, effectively alleviating lung tissue damages and inflammation. Overall, the proposed DA-AZI NPs highlight an innovative strategy for treating chronic pulmonary infection.

ICT-based fluorescent probes for intracellular pH and biological species detection.

Fluorescent probes, typically based on the intramolecular charge transfer (ICT) mechanism, have received considerable research attention in cell detection due to their non-invasiveness, fast response, easy regulation, high sensitivity, and low damage tolerance for in vivo bio-samples. Generally, intracellular pH and biological species such as various gases, metal ions, and anions constitute the foundation of cells and participate in the basic physiological processes, whose abnormal level can lead to poisoning, cardiovascular disease, and cancer in living organisms. Therefore, monitoring of their quantity plays an essential role in understanding the status of organisms and preventing, diagnosing, and treating diseases. In the last decades, remarkable progress has been made in developing ICT probes for the detection of biological elements. In this review, we highlight the recent ICT probes focusing primarily on the detection of intracellular pH, various gases (H2S, CO, H2O2, and NO), metal ions (Cu2+, Hg2+, Pb2+, Zn2+, and Al3+), and anions (ClO-, CN-, SO3 2-, and F-). In addition, we discuss the issues and limitations of ICT-based fluorescent probes for in vivo detection and explore the clinical translational potential and challenges of these materials, providing valuable guidance and insights for the design of fluorescent materials.

PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.