LINC01320 facilitates cell proliferation and migration of ovarian cancer via regulating PURB/DDB2/NEDD4L/TGF-ß axis.

Ovarian cancer (OC) is one of the most prevalent and lethal malignancies affecting the female reproductive system, due to its tendency for metastasis and recurrence. This study identified the overexpression of LINC01320 (or long intergenic nonprotein coding RNA 1320) in tissues of ovarian cancer through the analysis of patient samples and online datasets. In vitro and in vivo experiments demonstrate that silencing of LINC01320 expression led to inhibition of proliferation and metastasis of OC cells. RNA pull-down followed by liquid chromatography tandem mass spectrometry (RNA pull-down-LC-MS/MS) revealed that LINC01320 interacted with purine-rich element binding protein B (PURB), a transcriptional repressor. Furthermore, the RNA-seq analysis identified damage-specific DNA binding protein 2 (DDB2) as a major common target of LINC01320 and PURB. Mechanistically, LINC01320 could recruit PURB to the promoter region of DDB2 to repress DDB2 transcription; thus, promoting the expression of NEDD4L and impeding the TGF-ß/SMAD signaling pathway, and ultimately facilitating the progression of OC. Finally, rescue experiments confirmed the involvement of the DDB2/NEDD4L/TGF-ß axis in LINC01320-mediated OC progression. In conclusion, this study unveils for the first time the pivotal function of the LINC01320/PURB/DDB2/NEDD4L/TGF-ß axis and explores its prospective clinical implications in OC.

An intelligent device with double fluorescent carbon dots based on smartphone for visual and point-of-care testing of Copper(II) in water and food samples.

The excessive presence of Cu2+ could be harmful to human health. Therefore, a ratiometric fluorescence sensor based on multicolor fluorescent carbon dots (CDs) was developed for Cu2+ detection. The blue and yellow carbon dots (B-CDs/Y-CDs) were synthesized by one-step hydrothermal method. After adding Cu2+, it is captured by the amino groups of B-CDs to form complexes, resulting in a strong fluorescence quenching via photoinduced electron transfer (PET). Meanwhile, the amino groups from Y-CDs also binds with Cu2+ that inhibit the internal PET thus enhancing the fluorescence of Y-CDs. The sensor has the merits in rapid, visual, and selective with a low limit of detection (LOD) at 2.29 nM. Furthermore, an intelligent device composed of portable optical detector and smartphone is constructed, which realizes the visual point-of-care testing (POCT) of Cu2+ with a LOD of 7.51 nM. The strategy provides an accessible approach for monitoring heavy metal pollution and food safety.

Titanium Dioxide Nanomaterials: Progress in Synthesis and Application in Drug Delivery.

Background: Recent developments in nanotechnology have provided efficient and promising methods for the treatment of diseases to achieve better therapeutic results and lower side effects. Titanium dioxide (TiO2) nanomaterials are emerging inorganic nanomaterials with excellent properties such as low toxicity and easy functionalization. TiO2 with special nanostructures can be used as delivery vehicles for drugs, genes and antigens for various therapeutic options. The exploration of TiO2-based drug delivery systems shows great promise for translating nanotechnology into clinical applications; Methods: Comprehensive data on titanium dioxide were collected from reputable online databases including PubMed, GreenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration; Results: In this review, we discuss the synthesis pathways and functionalization strategies of TiO2. Recent advances of TiO2 as a drug delivery system, including sustained and controlled drug release delivery systems were introduced. Rigorous long-term systematic toxicity assessment is an extremely critical step in application to the clinic, and toxicity is still a problem that needs to be closely monitored; Conclusions: Despite the great progress made in TiO2-based smart systems, there is still a great potential for development. Future research may focus on developing dual-reaction delivery systems and single-reaction delivery systems like redox and enzyme reactions. Undertaking thorough in vivo investigations is necessary prior to initiating human clinical trials. The high versatility of these smart drug delivery systems will drive the development of novel nanomedicines for personalized treatment and diagnosis of many diseases with poor prognosis.

A Highly Tumor-Permeating DNA Nanoplatform for Efficient Remodeling of Immunosuppressive Tumor Microenvironments.

The immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure-based nanoplatform with striking tumor-penetrating capability for targeted remodeling of the immunosuppressive tumor microenvironment in vivo. In our design, chemo-immunomodulator (gemcitabine) can be precisely grafted on DNA sequences through a reactive oxygen species (ROS)-sensitive linker. After self-assembly, the gemcitabine-grafted DNA structure can site-specifically organize legumain-activatable melittin pro-peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi-type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.

TRIM59 is required for mouse GC-1 cell maintenance through modulating the ubiquitination of AXIN1.

Tripartite motif-containing protein 59 (TRIM59) is a biomarker for multiple tumors with crucial roles. However, the specific role of TRIM59 in germ cells remains largely unknown. Here, we investigated the effects and underlying regulatory mechanisms of TRIM59 on germ cells using the mouse spermatogonial cell line GC-1. Our results demonstrated that TRIM59 promoted proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, TRIM59 maintained GC-1 cell behaviors through ubiquitination of AXIN1 to activate ß-catenin signaling. Furthermore, activation of ß-catenin signaling reversed the effects mediated by Trim59 knockdown in GC-1 cells. Collectively, our study revealed a major role and regulatory mechanism of TRIM59 in GC-1 cells, which sheds new light on the molecular pathogenesis of defects in spermatogenesis and may provide therapeutic targets for treatment of male infertility.

[Study of the effect of different methods on the removal of calcium hydroxide in root canal by micro-computed tomography in vivo].

PURPOSE: To establish molar root canal model with micro-computed tomography (Micro-CT) and evaluate the removal efficiency of calcium hydroxide by different methods. METHODS: Eight molar teeth (24 root canals) extracted from the Department of General Dentistry, Shanghai Ninth People's Hospital from October 2023 to February 2024 were collected. Root canal preparation was instrumented by M3 according to standard root canal treatment procedures, then calcium hydroxide was injected into the root canal. One week later, the samples were randomly divided into 3 groups according to different irrigation methods(n=8): lateral opening syringe group, ultrasonic group and sonic vibration group. Micro-CT was used to reconstruct the root canal system before and after irrigation, and independent root canals were marked with different colors. The root canals were divided into upper root segment, middle root segment and apex segment. The volume of calcium hydroxide in each canal was calculated, and the clearance rate of calcium hydroxide was compared among the groups. SPSS 19.0 software package was used for statistical analysis. RESULTS: None of the three methods could completely remove calcium hydroxide from the root canal. When sodium hypochlorite was used as the flushing solution, the removal effect of ultrasonic group and sonic vibration group was significantly better than that of lateral opening syringe group(P＜0.05). The removal efficiency of calcium hydroxide by ultrasonic group and sonic vibration group was similar, and the difference was not statistically significant(P＞0.05). The removal rate of calcium hydroxide in apical segment was low. CONCLUSIONS: Micro-CT can reconstruct the molar root canal model efficiently for evaluating the removal effect of calcium hydroxide. The removal efficiency of calcium hydroxide in ultrasonic group and sonic vibration group is similar, and both are better than that in lateral syringe group.

GLIM Achieves Best Diagnostic Performance in Non-Cancer Patients with Low BMI: A Hierarchical Bayesian Latent-Class Meta-Analysis.

CONTEXT: Global Leadership Initiative on Malnutrition (GLIM) and Patient-Generated Subjective Global Assessment (PG-SGA) are commonly used nutrition assessment tools, whose performance does not reach a consensus due to different and imperfect reference standards. OBJECTIVE: This study aimed to evaluate and compare the diagnostic accuracy of GLIM and PG-SGA, using a hierarchical Bayesian latent class model, in the absence of a gold standard. DATA SOURCES: A systematic search was undertaken in PubMed, Embase, and Web of Science from inception to October 2022. Diagnostic test studies comparing (1) the GLIM and/or (2) PG-SGA with "semi-gold" standard assessment tools for malnutrition were included. DATA EXTRACTION: Two authors independently extracted data on sensitivity, specificity, and other key characteristics. The methodological quality of each included study was appraised according to the criteria in the Quality Assessment of Diagnostic Accuracy Studies-2. DATA ANALYSIS: A total of 45 studies, comprising 20 876 individuals evaluated for GLIM and 11 575 for PG-SGA, were included. The pooled sensitivity was 0.833 (95% CI 0.744 to 0.896) for GLIM and 0.874 (0.797 to 0.925) for PG-SGA, while the pooled specificity was 0.837 (0.780 to 0.882) for GLIM and 0.778 (0.707 to 0.836) for PG-SGA. GLIM showed slightly better performance than PG-SGA, with a higher diagnostic odds ratio (25.791 vs 24.396). The diagnostic performance of GLIM was most effective in non-cancer patients with an average body mass index (BMI) of <24 kg/m2, followed by non-cancer patients with an average age of ≥60 years. PG-SGA was most powerful in cancer patients with an average age of <60 years, followed by cancer patients with an average BMI of <24 kg/m2. CONCLUSION: Both GLIM and PG-SGA had moderately high diagnostic capabilities. GLIM was most effective in non-cancer patients with a low BMI, while PG-SGA was more applicable in cancer patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42022380409.

An intratumor bacteria-targeted DNA nanocarrier for multifaceted tumor microenvironment intervention.

Intratumor bacteria, which are involved with complex tumor development mechanisms, can compromise the therapeutic efficiencies of cancer chemotherapeutics. Therefore, the development of anti-tumor agents targeting intratumor bacteria is crucial in overcoming the drug inactivation induced by bacteria colonization. In this study, a double-bundle DNA tetrahedron-based nanocarrier is developed for intratumor bacteria-targeted berberine (Ber) delivery. The combination of aptamer modification and high drug loading efficacy endow the DNA nanocarrier TA@B with enhanced delivery performance in anti-tumor therapy without obvious systemic toxicity. The loaded natural isoquinoline alkaloid Ber exhibits enhanced antimicrobial, anticancer, and immune microenvironment regulation effects, ultimately leading to efficient inhibition of tumor proliferation. This intratumor bacteria-targeted DNA nanoplatform provides a promising strategy in intervening the bacteria-related microenvironment and facilitating tumor therapy.

Clonal growth characteristics and diversity patterns of different Clintonia udensis (Liliaceae) diploid and tetraploid cytotypes in the Hualongshan Mountains.

Polyploidization plays an important role in plant evolution and biodiversity. However, intraspecific polyploidy compared to interspecific polyploidy received less attention. Clintonia udensis (Liliaceae) possess diploid (2n = 2x = 14) and autotetraploid (2n = 4x = 28) cytotypes. In the Hualongshan Mountains, the autotetraploids grew on the northern slope, while the diploids grew on the southern slopes. The clonal growth characteristics and clonal architecture were measured and analyzed by field observations and morphological methods. The diversity level and differentiation patterns for two different cytotypes were investigated using SSR markers. The results showed that the clonal growth parameters, such as the bud numbers of each rhizome node and the ratio of rhizome branches in the autotetraploids were higher than those in the diploids. Both the diploids and autotetraploids appeared phalanx clonal architectures with short internodes between ramets. However, the ramets or genets of the diploids had a relatively scattered distribution, while those of the autotetraploids were relatively clumping. The diploids and autotetraploids all allocated more biomass to their vegetative growth. The diploids had a higher allocation to reproductive organs than that of autotetraploids, which indicated that the tetraploids invested more resources in clonal reproduction than diploids. The clone diversity and genetic diversity of the autotetraploids were higher than that of the diploids. Significant genetic differentiation between two different cytotypes was observed (P < 0.01). During establishment and evolution, C. udensis autotetraploids employed more clumping phalanx clonal architecture and exhibited more genetic variation than the diploids.

Antimicrobial and Antibiofilm Effects of Bithionol against Mycobacterium abscessus.

Mycobacterium abscessus (M. abscessus) is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 µM against M. abscessus type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against M. abscessus were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of M. abscessus from 0.625 µM to 2.5 µM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time-kill curve study and also electron microscopy study. Interestingly, it was found that at 128 µg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 µg/mL, 99% at 32 µg/mL, and 90% at 16 µg/mL. Therefore, bithionol may be a potential candidate for the treatment of M. abscessus infections due to its significant antimicrobial and antibiofilm activities.

E3 ligase FBXO22 is not significant for spermatogenesis and male fertility in mice.

BACKGROUND: F-box-only protein 22 (FBXO22), an important substrate receptor of the SKP1-Cullin-F-box (SCF) ubiquitin ligases, has been reported to be involved in many biological processes, including tumorigenesis, neurological disorders, cellular senescence, and DNA damage. However, the specific role of FBXO22 during spermatogenesis is poorly understood. METHODS: We produced Fbxo22 conditional knockout (cKO) and global knockout (KO) mice and assessed their sperm masurements using a computer-assisted sperm analysis (CASA) system. Additionally, we conducted histologic staining and immunostaining to examine the impact of Fbxo22 loss on spermatogenesis. RESULTS: Our results revealed that there were no notable differences in semen quality, fertility test results, or histologic findings in Fbxo22-KO and Fbxo22-cKO mice compared to the control group. CONCLUSIONS: Our study demonstrated that Fbxo22 is not significant for spermatogenesis or male fertility in mice. These findings will help researchers avoid redundant efforts and serve as a foundational resource for genetic studies on human fertility.

The Selectivity Origins in Ag-Catalyzed CO2 Electroreduction.

Ag exhibits high selectivity of electrochemical CO2 reduction (CO2R) toward C1 products, while the hydrogenation involving the concerted proton-electron transfer (CPET) or sequential electron-proton transfer (SEPT) mechanism is still in debate. Toward a better understanding of the Ag-catalyzed electrochemical CO2R, we employed a microkinetic model based on the Marcus electron transfer theory to thoroughly investigate the selectivity of C1 products of electrochemical CO2R over the Ag(111) surface. We found that at an acidic condition of pH = 1.94, formate is the main product when U < -0.94 V via the CPET mechanism, whereas CO becomes the primary product when U > -0.94 V via the SEPT mechanism. Conversely, at an alkaline condition of pH = 13.95, formate is the main product following the SEPT mechanism. Our findings provide novel insights into the influence of external factors (applied potential and pH) on the product selectivity and hydrogenation mechanism of electrochemical CO2R.

Heat shock protein HvHSP16.9 from wild barley enhances tolerance to salt stress.

Heat shock proteins (HSPs) are known to play a crucial role in the response of plants to environmental stress, particularly heat stress. Nevertheless, the function of HSPs in salt stress tolerance in plants, especially in barley, remains largely unexplored. Here, we aimed to investigate and compare the salt tolerance mechanisms between wild barley EC_S1 and cultivated barley RGT Planet through a comprehensive analysis of physiological parameters and transcriptomic profiles. Results demonstrated that the number of differentially expressed genes (DEGs) in EC_S1 was significantly higher than in RGT Planet, indicating that wild barley gene regulation is more adaptive to salt stress. KEGG enrichment analysis revealed that DEGs were mainly enriched in the processes of photosynthesis, plant hormone signal transduction, and reactive oxygen species metabolism. Furthermore, the application of weighted gene correlation network analysis (WGCNA) enabled the identification of a set of key genes, including small heat shock protein (sHSP), Calmodulin-like proteins (CML), and protein phosphatases 2C (PP2C). Subsequently, a novel sHSP gene, HvHSP16.9 encoding a protein of 16.9 kDa, was cloned from wild barley, and its role in plant response to salt stress was elucidated. In Arabidopsis, overexpression of HvHSP16.9 increased the salt tolerance. Meanwhile, barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) of HvHSP16.9 significantly reduced the salt tolerance in wild barley. Overall, this study offers a new theoretical framework for comprehending the tolerance and adaptation mechanisms of wild barley under salt stress. It provides valuable insights into the salt tolerance function of HSP, and identifies new candidate genes for enhancing cultivated barley varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01455-4.

High-entropy relaxor ferroelectric ceramics for ultrahigh energy storage.

Dielectric ceramic capacitors with ultrahigh power densities are fundamental to modern electrical devices. Nonetheless, the poor energy density confined to the low breakdown strength is a long-standing bottleneck in developing desirable dielectric materials for practical applications. In this instance, we present a high-entropy tungsten bronze-type relaxor ferroelectric achieved through an equimolar-ratio element design, which realizes a giant recoverable energy density of 11.0 J·cm-3 and a high efficiency of 81.9%. Moreover, the atomic-scale microstructural study confirms that the excellent comprehensive energy storage performance is attributed to the increased atomic-scale compositional heterogeneity from high configuration entropy, which modulates the relaxor features as well as induces lattice distortion, resulting in reduced polarization hysteresis and enhanced breakdown endurance. This study provides evidence that developing high-entropy relaxor ferroelectric material via equimolar-ratio element design is an effective strategy for achieving ultrahigh energy storage characteristics. Our results also uncover the immense potential of tetragonal tungsten bronze-type materials for advanced energy storage applications.

Cancer-associated fibroblast-derived periostin promotes papillary thyroid tumor growth through integrin-FAK-STAT3 signaling.

Background: Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown. Methods: Postn and Rag1 knock-out mice and orthotopic mouse models were used to determine the role of POSTN on papillary thyroid tumor progression. Immunofluorescence, cell co-culture, fluorescence in situ hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth. Results: POSTN is up-regulated in papillary thyroid tumors and negatively correlates with the overall survival of patients with thyroid cancer. Cancer-associated fibroblast (CAF)-derived POSTN promotes papillary thyroid tumor growth in vivo and in vitro. POSTN deficiency in CAFs significantly impairs CAF-promoted papillary thyroid tumor growth. POSTN promotes papillary thyroid tumor cell proliferation and IL-4 expression through integrin-FAK-STAT3 signaling. In turn, tumor cell-derived IL-4 induces the activation of CAFs and stimulates POSTN expression by activating STAT6. We reveal the crucial role of CAF-derived POSTN and tumor cell-derived IL-4 in driving the development of papillary thyroid tumors through the POSTN-integrin-FAK-STAT3-IL-4 pathway in tumor cells and IL-4-STAT6-POSTN signaling in CAFs. Conclusion: Our findings underscore the significance of POSTN and IL-4 as critical molecular mediators in the dynamic interplay between CAFs and tumor cells, ultimately supporting the growth of papillary thyroid tumors.

Recent advances of focused ultrasound induced blood-brain barrier opening for clinical applications of neurodegenerative diseases.

With the aging population on the rise, neurodegenerative disorders have taken center stage as a significant health concern. The blood-brain barrier (BBB) plays an important role to maintain the stability of central nervous system, yet it poses a formidable obstacle to delivering drugs for neurodegenerative disease therapy. Various methods have been devised to confront this challenge, each carrying its own set of limitations. One particularly promising noninvasive approach involves the utilization of focused ultrasound (FUS) combined with contrast agents-microbubbles (MBs) to achieve transient and reversible BBB opening. This review provides a comprehensive exploration of the fundamental mechanisms behind FUS/MBs-mediated BBB opening and spotlights recent breakthroughs in its application for neurodegenerative diseases. Furthermore, it addresses the current challenges and presents future perspectives in this field.

Carrier-Free Self-Assembly Nano-Sonosensitizers for Sonodynamic-Amplified Cuproptosis-Ferroptosis in Glioblastoma Therapy.

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half-life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier-free nanoparticles (Ce6@Cu NPs), which self-assembled by the coordination of Cu2+ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic-triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu+ concentration in tumor cells significantly increases as Cu2+ reacts with reductive GSH, resulting in the downregulation of ferredoxin-1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood-brain barrier, resulting in significant accumulation in orthotopic U87MG-Luc glioblastoma. The sonodynamic-triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis.

The potential of machine learning models to identify malnutrition diagnosed by GLIM combined with NRS-2002 in colorectal cancer patients without weight loss information.

BACKGROUND & AIMS: The key step of the Global Leadership Initiative on Malnutrition (GLIM) is nutritional risk screening, while the most appropriate screening tool for colorectal cancer (CRC) patients is yet unknown. The GLIM diagnosis relies on weight loss information, and bias or even failure to recall patients' historical weight can cause misestimates of malnutrition. We aimed to compare the suitability of several screening tools in GLIM diagnosis, and establish machine learning (ML) models to predict malnutrition in CRC patients without weight loss information. METHODS: This multicenter cohort study enrolled 4487 CRC patients. The capability of GLIM diagnoses combined with four screening tools in predicting survival probability was compared by Kaplan-Meier curves, and the most accurate one was selected as the malnutrition reference standard. Participants were randomly assigned to a training cohort (n = 3365) and a validation cohort (n = 1122). Several ML approaches were adopted to establish models for predicting malnutrition without weight loss data. We estimated feature importance and reserved the top 30% of variables for retraining simplified models. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to assess and compare model performance. RESULTS: NRS-2002 was the most suitable screening tool for GLIM diagnosis in CRC patients, with the highest hazard ratio (1.59; 95% CI, 1.43-1.77). A total of 2076 (46.3%) patients were malnourished diagnosed by GLIM combined with NRS-2002. The simplified random forest (RF) model outperformed other models with an AUC of 0.830 (95% CI, 0.805-0.854), and accuracy, sensitivity and specificity were 0.775, 0.835 and 0.742, respectively. We deployed an online application based on the simplified RF model to accurately estimate malnutrition probability in CRC patients without weight loss information (https://zzuwtt1998.shinyapps.io/dynnomapp/). CONCLUSIONS: Nutrition Risk Screening 2002 was the optimal initial nutritional risk screening tool in the GLIM process. The RF model outperformed other models, and an online prediction tool was developed to properly identify patients at high risk of malnutrition.