MSMTSeg: Multi-Stained Multi-Tissue Segmentation of Kidney Histology Images via Generative Self-Supervised Meta-Learning Framework.

Accurately diagnosing chronic kidney disease requires pathologists to assess the structure of multiple tissues under different stains, a process that is timeconsuming and labor-intensive. Current AI-based methods for automatic structure assessment, like segmentation, often demand extensive manual annotation and focus on single stain domain. To address these challenges, we introduce MSMTSeg, a generative self-supervised meta-learning framework for multi-stained multi-tissue segmentation in renal biopsy whole slide images (WSIs). MSMTSeg incorporates multiple stain transform models for style translation of inter-stain domains, a self-supervision module for obtaining pre-trained models with the domain-specific feature representation, and a meta-learning strategy that leverages generated virtual data and pre-trained models to learn the domain-invariant feature representation across multiple stains, thereby enhancing segmentation performance. Experimental results demonstrate that MSMTSeg achieves superior and robust performance, with mDSC of 0.836 and mIoU of 0.718 for multiple tissues under different stains, using only one annotated training sample for each stain. Our ablation study confirms the effectiveness of each component, positioning MSMTSeg ahead of classic advanced segmentation networks, recent few-shot segmentation methods, and unsupervised domain adaptation methods. In conclusion, our proposed few-shot cross-domain technology offers a feasible and cost-effective solution for multi-stained renal histology segmentation, providing convenient assistance to pathologists in clinical practice. The source code and conditionally accessible data are available at https://github.com/SnowRain510/MSMTSeg.

G protein subunit alpha i2's pivotal role in angiogenesis.

Here we explored the potential role of Gαi2 (G protein subunit alpha i2) in endothelial cell function and angiogenesis. Methods: Genetic methodologies such as shRNA, CRISPR/Cas9, dominant negative mutation, and overexpression were utilized to modify Gαi2 expression or regulate its function. Their effects on endothelial cell functions were assessed in vitro. In vivo, the endothelial-specific Gαi2 shRNA adeno-associated virus (AAV) was utilized to silence Gαi2 expression. The impact of this suppression on retinal angiogenesis in control mice and streptozotocin (STZ)-induced diabetic retinopathy (DR) mice was analyzed. Results: Analysis of single-cell RNA sequencing data revealed Gαi2 (GNAI2) was predominantly expressed in retinal endothelial cells and expression was increased in retinal endothelial cells following oxygen-induced retinopathy (OIR) in mice. Moreover, transcriptome analysis linking Gαi2 to angiogenesis-related processes/pathways, supported by increased Gαi2 expression in experimental OIR mouse retinas, highlighted its possible role in angiogenesis. In various endothelial cell types, shRNA-induced silencing and CRISPR/Cas9-mediated knockout (KO) of Gαi2 resulted in substantial reductions in cell proliferation, migration, invasion, and capillary tube formation. Conversely, Gαi2 over-expression in endothelial cells induced pro-angiogenic activities, enhancing cell proliferation, migration, invasion, and capillary tube formation. Furthermore, our investigation revealed a crucial role of Gαi2 in NFAT (nuclear factor of activated T cells) activation, as evidenced by the down-regulation of NFAT-luciferase reporter activity and pro-angiogenesis NFAT-targeted genes (Egr3, CXCR7, and RND1) in Gαi2-silenced or -KO HUVECs, which were up-regulated in Gαi2-overexpressing endothelial cells. Expression of a dominant negative Gαi2 mutation (S48C) also down-regulated NFAT-targeted genes, slowing proliferation, migration, invasion, and capillary tube formation in HUVECs. Importantly, in vivo experiments revealed that endothelial Gαi2 knockdown inhibited retinal angiogenesis in mice, with a concomitant down-regulation of NFAT-targeted genes in mouse retinal tissue. In contrast, Gαi2 over-expression in endothelial cells enhanced retinal angiogenesis in mice. Single-cell RNA sequencing data confirmed increased levels of Gαi2 specifically in retinal endothelial cells of mice with streptozotocin (STZ)-induced diabetic retinopathy (DR). Importantly, endothelial Gαi2 silencing ameliorated retinal pathological angiogenesis in DR mice. Conclusion: Our study highlights a critical role for Gαi2 in NFAT activation, endothelial cell activation and angiogenesis, offering valuable insights into potential therapeutic strategies for modulating these processes.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Unveiling the molecular regulatory mechanisms underlying sucrose accumulation and oil reduction in peanut kernels through genetic mapping and transcriptome analysis.

Sucrose content is a key factor for the flavor of edible peanut, which determines the sweet taste of fresh peanut and also attribute to pleasant flavor of roasted peanut. To explore the genetic mechanism of the sucrose content in peanut, an F2 population was created by crossing the sweet cultivar Zhonghuatian 1 (ZHT1) with Nanyangbaipi (NYBP). A genomic region spanning 28.26 kb on chromosome A06 was identified for the sucrose content through genetic mapping, elucidating 47.5% phenotypic variance explained. As the sucrose content had a significantly negative correlation with the oil content, this region was also found to be related to the oil content explaining 37.2% of phenotype variation. In this region, Arahy.42CAD1 was characterized as the most likely candidate gene through a comprehensive analysis. The nuclear localization of Arahy.42CAD1 suggests its potential involvement in the regulation of gene expression for sucrose and oil contents in peanut. Transcriptome analysis of the developing seeds in both parents revealed that genes involved in glycolysis and triacylglycerol biosynthesis pathways were not significantly down-regulated in ZHT1, indicating that the sucrose accumulation was not attributed to the suppression of triacylglycerol biosynthesis. Based on the WGCNA analysis, Arahy.42CAD1 was co-expressed with the genes involved in vesicle transport and oil body assembly, suggesting that the sucrose accumulation may be caused by disruptions in TAG transportation or storage mechanisms. These findings offer new insights into the molecular mechanisms governing sucrose accumulation in peanut, and also provide a potential gene target for enhancing peanut flavor.

Identification of Putative Quantitative Trait Loci for Improved Seed Oil Quality in Peanuts.

Improving seed oil quality in peanut (Arachis hypogaea) has long been an aim of breeding programs worldwide. The genetic resources to achieve this goal are limited. We used an advanced recombinant inbred line (RIL) population derived from JH5 × KX01-6 to explore quantitative trait loci (QTL) affecting peanut oil quality and their additive effects, epistatic effects, and QTL × environment interactions. Gas chromatography (GC) analysis suggested seven fatty acids components were obviously detected in both parents and analyzed in a follow-up QTL analysis. The major components, palmitic acid (C16:0), oleic acid (C18:1), and linoleic acid (C18:2), exhibited considerable phenotypic variation and fit the two major gene and minor gene mixed-inheritance model. Seventeen QTL explained 2.57-38.72% of the phenotypic variation in these major components, with LOD values of 4.12-37.56 in six environments, and thirty-five QTL explained 0.94-32.21% of the phenotypic variation, with LOD values of 5.99-150.38 in multiple environments. Sixteen of these QTL were detected in both individual and multiple environments. Among these, qFA_08_1 was a novel QTL with stable, valuable and major effect. Two other major-effect QTL, qFA_09_2 and qFA_19_3, share the same physical position as FAD2A and FAD2B, respectively. Eleven stable epistatic QTL involving nine loci explained 1.30-34.97% of the phenotypic variation, with epistatic effects ranging from 0.09 to 6.13. These QTL could be valuable for breeding varieties with improved oil quality.

TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors.

BACKGROUND: Imatinib has become an exceptionally effective targeted drug for treating gastrointestinal stromal tumors (GISTs). Despite its efficacy, the resistance to imatinib is common in GIST patients, posing a significant challenge to the effective treatment. METHODS: The expression profiling of TRIM21, USP15, and ACSL4 in GIST patients was evaluated using Western blot and immunohistochemistry. To silence gene expression, shRNA was utilized. Biological function of TRIM21, USP15, and ACSL4 was examined through various methods, including resistance index calculation, colony formation, shRNA interference, and xenograft mouse model. The molecular mechanism of TRIM21 and USP15 in GIST was determined by conducting Western blot, co-immunoprecipitation, and quantitative real-time PCR (qPCR) analyses. RESULTS: Here we demonstrated that downregulation of ACSL4 is associated with imatinib (IM) resistance in GIST. Moreover, clinical data showed that higher levels of ACSL4 expression are positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that the reduced expression of ACSL4 in GIST is attributed to excessive protein degradation mediated by the E3 ligase TRIM21 and the deubiquitinase USP15. CONCLUSION: These findings demonstrate that the TRIM21 and USP15 control ACSL4 stability to maintain the IM sensitive/resistant status of GIST.

A novel approach for transforming breast cancer stem cells into endothelial cells.

Tumor vascular endothelial cells play a pivotal in the tumor microenvironment, influencing the proliferation, invasion, and metastasis of tumor progression. The present study investigated a novel method for inducing the transformation of breast cancer stem cells into endothelial cells, providing a cellular model investigating anti-angiogenic mechanisms in vitro. The breast cancer cell line MCF-7 was used, and the expression of CD133 was initially detected using flow cytometry. CD133+ breast cancer cells were purified using immunomagnetic bead sorting technology, yielding an MCF-7CD133+ subpopulation. The proliferation ability of these cells was assessed using an MTT assay, while their microsphere formation ability was evaluated using a microsphere formation assay. Post-transformation in an optimized endothelial cell culture medium, expression of endothelial cell markers CD31 and CD105 were detected using flow cytometry. Endothelial cell tube formation assays and DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL) assays were employed to analyze the endothelial cell function of the MCF-7CD133+ cells. MDM2/CEN12 gene amplification was detected through fluorescence in situ hybridization (FISH). The MCF-7 breast cancer cell line exhibited 1.7±0.3% trace cells expressing the stem cell surface marker CD133. After anti-CD133 immunomagnetic bead sorting, MCF-7CD133+ and MCF-7CD133- subpopulation cells were obtained, with CD133 expression rates of 85.6±2.8 and 0.18±0.08%, respectively. MTT assay results demonstrated that, after 7 days, the proliferation rate of MCF-7CD133+ cells was significantly higher compared with MCF-7CD133- cells. MCF-7CD133+ subpopulation cells displayed strong stem cell characteristics, growing in suspension in serum-free media and forming tumor cell spheres. In contrast, MCF-7CD133- cells failed to form microspheres. After culturing cells in endothelial cell differentiation and maintenance media, the percentage of MCF-7CD133+ cells before and after endothelial cell culture was 0.3±0.16 and 81.4±8.37% for CD31+ cells and 0.2±0.08 and 83.8±7.24% for CD105+ cells, respectively. Vascular-like structure formation and Ac-LDL phagocytosis with red fluorescence in the tube formation assays confirmed endothelial cell function in the MCF-7CD133+ cells. FISH was used to verify MDM2/CEN12 gene amplification in the induced MCF-7CD133+ cells, indicating tumor cell characteristics. The modified endothelial cell transformation medium effectively induced differentiated tumor stem cells to express vascular endothelial cell markers and exhibit endothelial functions, ideal for in vitro anti-angiogenesis research.

Prediction Model for Unfavorable Outcome in Spontaneous Intracerebral Hemorrhage Based on Machine Learning.

OBJECTIVE: The spontaneous intracerebral hemorrhage (ICH) remains a significant cause of mortality and morbidity throughout the world. The purpose of this retrospective study is to develop multiple models for predicting ICH outcomes using machine learning (ML). METHODS: Between January 2014 and October 2021, we included ICH patients identified by computed tomography or magnetic resonance imaging and treated with surgery. At the 6-month check-up, outcomes were assessed using the modified Rankin Scale. In this study, four ML models, including Support Vector Machine (SVM), Decision Tree C5.0, Artificial Neural Network, Logistic Regression were used to build ICH prediction models. In order to evaluate the reliability and the ML models, we calculated the area under the receiver operating characteristic curve (AUC), specificity, sensitivity, accuracy, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR). RESULTS: We identified 71 patients who had favorable outcomes and 156 who had unfavorable outcomes. The results showed that the SVM model achieved the best comprehensive prediction efficiency. For the SVM model, the AUC, accuracy, specificity, sensitivity, PLR, NLR, and DOR were 0.91, 0.92, 0.92, 0.93, 11.63, 0.076, and 153.03, respectively. For the SVM model, we found the importance value of time to operating room (TOR) was higher significantly than other variables. CONCLUSION: The analysis of clinical reliability showed that the SVM model achieved the best comprehensive prediction efficiency and the importance value of TOR was higher significantly than other variables.

Porcine circovirus type 2 and Glaesserella parasuis serotype 4 co-infection activates Snail1 to disrupt the intercellular junctions and facilitate bacteria translocation across the tracheal epithelium.

Clinically, Porcine circovirus type 2 (PCV2) often causes disease through coinfection with other bacterial pathogens, including Glaesserella parasuis (G. parasuis), which causes high morbidity and mortality. However, the mechanism of PCV2 and G. parasuis serotype 4 (GPS4) co-infection is still not fully understood. In this study, swine tracheal epithelial cells (STEC) were used as a barrier model, and our results showed that PCV2 infection increased the adhesion of GPS4 to STEC, while decreasing the levels of ZO-1, Occludin and increasing tracheal epithelial permeability, and ultimately facilitated GPS4 translocation. Snail1 is a transcriptional repressor, and has been known to induce epithelial-to-mesenchymal transition (EMT) during development or in cancer metastasis. Importantly, we found that Snail1, as a transcriptional repressor, was crucial in destroying the tracheal epithelial barrier induced by PCV2, GPS4, PCV2 and GPS4 coinfection. For the first time, we found that PCV2, GPS4, PCV2 and GPS4 coinfection cross-activates TGF-ß and p38/MAPK signaling pathways to upregulate the expression of Snail1, down-regulate the levels of ZO-1 and Occludin, and thus disrupt the integrity of tracheal epithelial barrier then promoting GPS4 translocation. Finally, PCV2 and GPS4 co-infection also can activate TGF-ß and p38/MAPK signaling pathways in vivo and upregulate Snail1, ultimately down-regulating the expression of ZO-1 and Occludin. Our study elucidates how PCV2 infection promotes GPS4 to breach the tracheal epithelial barrier and aggravate clinical manifestations.

METTL3/IGF2BP3-regulated m6A modification of HYOU1 confers doxorubicin resistance in breast cancer.

Chemoresistance is a main reason for therapeutic failure and poor prognosis for breast cancer (BC) patients, especially for triple-negative BC patients. How the molecular mechanisms underlying the chemoresistance to doxorubicin (Dox) in BC is not well understood. Here, we revealed that METTL3/IGF2BP3-regulated m6A modification of HYOU1 increased Dox resistance in BC cells. CCK-8 and Annexin V-FITC/PI staining assays were employed to measure viability and cell death. Western blotting and qRT-PCR assays were applied to assay the expression of genes. Knockdown and rescue experiments were used to assay the role of METTL3, IGF2BP3 and HYOU1 in regulating BC cell responses to Dox. RIP, MeRIP and dual-luciferase activity assays were applied to examine the function of METTL3/IGF2BP3 in the m6A modification of HYOU1 mRNA. It was found that global mRNA m6A methylation levels were upregulated in Dox-resistant BC cell lines. The methyltransferase METTL3 was upregulated in Dox-resistant BC cell lines, and downregulation of METTL3 could overcome this resistance. Furthermore, HYOU1 was identified as a downstream target of METTL3-mediated m6A modification. Downregulation of HYOU1 could overcome Dox resistance, while forced expression of HYOU1 resulted in Dox resistance in BC cells. METTL3 cooperated with IGF2BP3 to modulate the m6A modification of HYOU1 mRNA and increase its stability. Collectively, our findings unveiled the key roles of the METTL3/IGF2BP3/HYOU1 axis in modulating Dox sensitivity in BC cells; thus, targeting this axis might be a potential strategy to increase Dox efficacy in the treatment of BC.

The Role of ZNF275/AKT Pathway in Carcinogenesis and Cisplatin Chemosensitivity of Cervical Cancer Using Patient-Derived Xenograft Models.

Zinc finger protein 275 (ZNF275) is a C2H2-type transcription factor that is localized on chromosome Xq28. Whether ZNF275 participates in modulating the biological behaviors of cervical cancer has not been determined to our knowledge. The present study employed CCK-8, BrdU, flow cytometry, and a transwell assay to investigate the cell viability, proliferation, apoptosis, migration, and invasion of cervical cancer cells. The application of Western blotting and immunohistochemistry (IHC) aims to assess ZNF275 protein expression and identify the signaling pathway relevant to ZNF275-mediated effects on cervical cancer. The therapeutic impact of the combined therapy of the AKT inhibitor triciribine and cisplatin was evaluated on cervical cancer patient-derived xenograft (PDX) models expressing high ZNF275. The current research illustrated that cervical cancer tissue exhibited a higher expression of ZNF275 in contrast to the surrounding normal cervical tissue. The downregulation of ZNF275 suppressed cell viability, migration, and invasion, and facilitated the apoptosis of SiHa and HeLa cells via weakening AKT/Bcl-2 signaling pathway. Moreover, triciribine synergized with cisplatin to reduce cell proliferation, migration, and invasion, and enhanced the apoptosis of SiHa cells expressing high ZNF275. In addition, the combination treatment of triciribine and cisplatin was more effective in inducing tumor regression than single agents in cervical cancer PDX models expressing high ZNF275. Collectively, the current findings demonstrated that ZNF275 serves as a sufficiently predictive indicator of the therapeutic effectiveness of the combined treatment of triciribine and cisplatin on cervical cancer. Combining triciribine with cisplatin greatly broadens the therapeutic options for cervical cancer expressing high ZNF275, but further research is needed to confirm these results.

Diagnostic value of circRNA in coronary heart disease: a meta-analysis.

Aim: Studies have indicated that circRNAs have diagnostic value for coronary heart disease (CHD), but the efficacy varies greatly; therefore, a meta-analysis was conducted to assess the diagnostic value of circRNAs in CHD. Materials & methods: 16 studies with 3962 subjects (2239 cases and 1723 controls) were included by searching PubMed, Web of Science and MEDLINE. The pooled sensitivity and specificity, summary receiver operating characteristic and area under the curve, positive likelihood ratio and negative likelihood ratio were calculated. Results: The pooled area under the curve of circRNAs for the diagnosis of CHD was 0.80 (sensitivity and specificity were 0.77 and 0.68, respectively), and more indexes were calculated. Conclusion: circRNAs may be good biomarkers for diagnosing CHD.

Exploring the Release of Elastin Peptides Generated from Enzymatic Hydrolysis of Bovine Elastin via Peptide Mapping.

To enhance the understanding of enzymatic hydrolysis and to accelerate the discovery of key bioactive peptides within enzymatic products, this research focused on elastin as the substrate and investigated the variations in peptide profiles and the production of key bioactive peptides (those exceeding 5% of the total) and their impacts on the biological activity of the hydrolysates. Through the application of advanced analytical techniques, such as stop-flow two-dimensional liquid chromatography and ultra-high-performance liquid chromatography-tandem mass spectrometry, the research tracks the release and profiles of peptides within elastin hydrolysates (EHs). Despite uniform peptide compositions, significant disparities in peptide concentrations were detected across the hydrolysates, hinting at varying levels of bioactive efficacy. A comprehensive identification process pinpointed 403 peptides within the EHs, with 18 peptides surpassing 5% in theoretical maximum content, signaling their crucial role in the hydrolysate's bioactivity. Of particular interest, certain peptides containing sequences of alanine, valine, and glycine were released in higher quantities, suggesting Alcalase® 2.4L's preference for these residues. The analysis not only confirms the peptides' dose-responsive elastase inhibitory potential but also underscores the nuanced interplay between peptide content, biological function, and their collective synergy. The study sets the stage for future research aimed at refining enzymatic treatments to fully exploit the bioactive properties of elastin.

Exploring the association between congenital vertebral malformations and neural tube defects.

Congenital vertebral malformations (CVMs) and neural tube defects (NTDs) are common birth defects affecting the spine and nervous system, respectively, due to defects in somitogenesis and neurulation. Somitogenesis and neurulation rely on factors secreted from neighbouring tissues and the integrity of the axial structure. Crucial signalling pathways like Wnt, Notch and planar cell polarity regulate somitogenesis and neurulation with significant crosstalk. While previous studies suggest an association between CVMs and NTDs, the exact mechanism underlying this relationship remains unclear. In this review, we explore embryonic development, signalling pathways and clinical phenotypes involved in the association between CVMs and NTDs. Moreover, we provide a summary of syndromes that exhibit occurrences of both CVMs and NTDs. We aim to provide insights into the potential mechanisms underlying the association between CVMs and NTDs, thereby facilitating clinical diagnosis and management of these anomalies.

Diagnosis of diabetic kidney disease in whole slide images via AI-driven quantification of pathological indicators.

Diagnosis of diabetic kidney disease (DKD) mainly relies on screening the morphological variations and internal lesions of glomeruli from pathological kidney biopsy. The prominent pathological alterations of glomeruli for DKD include glomerular hypertrophy and nodular mesangial sclerosis. However, the qualitative judgment of these alterations is inaccurate and inconstant due to the intra- and inter-subject variability of pathologists. It is necessary to design artificial intelligence (AI) methods for accurate quantification of these pathological alterations and outcome prediction of DKD. In this work, we present an AI-driven framework to quantify the volume of glomeruli and degree of nodular mesangial sclerosis, respectively, based on an instance segmentation module and a novel weakly supervised Macro-Micro Aggregation (MMA) module. Subsequently, we construct classic machine learning models to predict the degree of DKD based on three selected pathological indicators via factor analysis. These corresponding modules are trained and tested on a total of 281 whole slide images (WSIs) digitized from two hospitals with different scanners. Our designed AI framework achieved inspiring results with 0.926 mIoU for glomerulus segmentation, and 0.899 F1 score for glomerulus classification in the external testing dataset. Meantime, the visualized results of the MMA module could reflect the location of the lesions. The performance of predicting disease achieved the F1 score of 0.917, which further proved the effectiveness of our AI-driven quantification of pathological indicators. Additionally, the interpretation of the machine learning model with the SHAP method showed similar accordance with the development of DKD in pathology. In conclusion, the proposed auxiliary diagnostic technologies have the feasibility for quantitative analysis of glomerular pathological tissues and alterations in DKD. Pathological quantitative indicators will also make it more convenient to provide doctors with assistance in clinical practice.

FDX1 inhibits thyroid cancer malignant progression by inducing cuprotosis.

Cuprotosis is a recently identified cell death form that caused by intracellular copper accumulation and regulated by FDX1. This work aimed to explore the role of cuprotosis and the pivotal regulatory gene FDX1 in thyroid cancer development. We observed that expression of FDX1 in tumor section was notably lower than that in non-tumor sections in clinical samples. Induction of cuprotosis by elesclomol (ES) significantly repressed the in vitro and in vivo growth of thyroid cancer cells, simultaneously elevated Cu level and expression of FDX1, whereas depletion of FDX1 abolished these effects. Knockdown of FDX1 decreased the lipoylation level of DLAT and DLST in thyroid cancer cells, alleviated cuprotosis-induced cell death, simultaneously upregulated the levels of PA and α-KG. These findings demonstrated that FDX1 promotes the cuprotosis of thyroid cancer cells via regulating the lipoylation of DLAT.

Self-template synthesis of mesoporous and biodegradable Fe3O4 nanospheres as multifunctional nanoplatform for cancer therapy.

Superparamagnetic Fe3O4 nanospheres have demonstrated great potential as important components in nanomedicine for cancer imaging and therapy. One of the major obstacles that impedes their application is the slow degradation of ingested Fe3O4 nanospheres, which potentially causes long-term health risks. To tackle this issue, we proposed to fabricate Fe3O4 nanospheres with mesoporous structure via a simple self-template etching method. The mesoporous Fe3O4 nanospheres not only offered large specific surface area and weak-acidic responsive degradability, but also exhibited T2-weighted magnetic resonance contrast enhancement and magnetic targeting, which made them possible to serve as excellent cancer therapeutic nanoplatform. Both inorganic photothermal therapeutic Au nanoparticles and organic chemotherapeutic doxorubicin hydrochloride were demonstrated to be successfully loaded onto such kind of nanoplatform, and the hybrid nanomedicine demonstrated synergistic photothermal and chemotherapeutic activity for tumor elimination under near infrared irradiation and improved biodegradability in weak acidic tumor microenvironment. We believe that this study paved a simple way for designing multifunctional Fe3O4-based biodegradable nanomedicine.

Synthesis, characterization and performance of lignin carboxyl betaine zwitterionic surfactants for application in enhanced oil recovery.

The objective of this study was to synthesize lignin carboxyl betaine zwitterionic surfactants (LCBS) from alkali lignin through a three-step reaction involving epoxidation, amination, and quaternization. The synthesized LCBS were characterized using infrared spectroscopy (IR) and thermogravimetric (TG) analysis. To assess their potential for enhanced oil recovery (EOR), the physicochemical properties of the LCBS surfactants, such as surface tension, emulsification, temperature resistance, salt resistance, and interfacial properties, were evaluated using standard experimental methods for surfactants applied in oil displacement. The LCBS surfactants exhibited higher surface activity, with low surface tension values ranging from 29.65 mN m-1 to 31.85 mN m-1 at the corresponding critical micelle concentration (cmc), also the significant emulsifying performance of LCBS surfactants was proved in the emulsifying experiments. Moreover, the synthesized LCBS surfactants were found to be suitable for use in harsh reservoirs of high-salinity and high-temperature, as confirmed by the temperature and salt resistance measurements. The interfacial tension (IFT) tests between Huabei crude oil and LCBS surfactants suggested that these surfactants could effectively extract the crude oil containing heavy components such as colloid and asphaltene, and ultra-low IFT values could be achieved with the addition of weak alkali.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia.

BACKGROUND: Genetic mutations of IKZF1 have been frequently delineated in B-lineage acute leukaemia (B-ALL) but rarely elucidated in acute myeloid leukaemia (AML). IKZF1 mutations confer a poor prognosis in AML, and hotspot mutations of IKZF1, N159Y and N159S tend to occur in B-ALL and AML respectively. However, the pathogenesis of IKZF1 N159S in AML and IKZF1 lineage susceptibility are largely unknown. METHODS: The genetic and clinical characteristics of IKZF1-mutated AML patients were evaluated. Multi-omics analysis and functional assays were performed in vitro using IKZF1 mutations knock-in AML cell lines. RESULTS: 23 (4.84%) small sequence variants of IKZF1 were identified in 475 newly diagnosed AML (non-M3) patients. Based on RNA sequencing, three classes of IKZF1-related AML were defined, including 9 patients (39.13%) with IKZF1 N159S mutations, 10 (43.47%) with CEBPA mutations and 4 others (17.39%). IKZF1 N159S may define a unique subgroup with higher HOXA/B expression and native B-cell immune fractions. Gene expression data of multiple knock-in cell lines indicate that the lymphocyte differentiation-related MME and CD44 kept high expression in IKZF1 N159Y but were downregulated in N159S. CUT&TAG sequencing showed that IKZF1 N159S reshaped the binding profiles of IKZF1. Integration analysis suggested that the pathogenesis of IKZF1 N159S may depend on the deregulation of several cofactors, such as oncogenic MYC and CPNE7 targets. CONCLUSIONS: Collectively, we dissected the molecular spectrum and clinical features of IKZF1-related AML, which may promote an in-depth understanding of the pathogenesis, lineage susceptibility and clinical research of AML.