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Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles in tumour growth, angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 and M2 subtypes based on their differentiation and activities. M1 macrophages, characterized by a pro-inflammatory phenotype, exert anti-tumoural effects, while M2 macrophages, with an anti-inflammatory phenotype, function as protumoural regulators. These highly versatile cells respond to stimuli from tumour cells and other constituents within the tumour microenvironment (TME), such as growth factors, cytokines, chemokines, and enzymes. These stimuli induce their polarization towards one phenotype or another, leading to complex interactions with TME components and influencing both pro-tumour and anti-tumour processes. This review comprehensively and deeply covers the literature on macrophages, their origin and function as well as the intricate interplay between macrophages and the TME, influencing the dual nature of TAMs in promoting both pro- and anti-tumour processes. Moreover, the review delves into the primary pathways implicated in macrophage polarization, examining the diverse stimuli that regulate this process. These stimuli play a crucial role in shaping the phenotype and functions of macrophages. In addition, the advantages and limitations of current macrophage based clinical interventions are reviewed, including enhancing TAM phagocytosis, inducing TAM exhaustion, inhibiting TAM recruitment, and polarizing TAMs towards an M1-like phenotype. In conclusion, while the treatment strategies targeting macrophages in precision medicine show promise, overcoming several obstacles is still necessary to achieve an accessible and efficient immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The use of unicompartmental knee arthroplasty (UKA) in patients with preoperative synovitis is controversial. This study aimed to investigate the association between synovitis detected by magnetic resonance imaging (MRI) and prognosis after UKA. Methods: Synovitis was graded using the MRI Osteoarthritis Knee Score criteria based on preoperative MRI findings of 132 UKAs performed between June 2020 and August 2021. The Knee Society Knee Score (KS-KS) and the Knee Society Function Score were collected preoperatively and 1 year postoperatively. The relationship between synovitis and the changes in the Knee Society score was analyzed using logistic regression. Results: Univariate logistic regression showed that patients with higher preoperative synovitis scores (odds ratio (OR) = 1.925, 95% confidence interval (CI): 1.482–2.500, P < 0.001) had higher KS-KS changes. After adjusting for confounding variables, synovitis was proven to be an independent factor for KS-KS improvement after UKA in multivariate logistic regression (OR = 1.814, 95% CI: 1.354–2.430, P < 0.001). Before UKA, patients with synovitis had lower pain scores (PS) than patients without synovitis (95% CI: -17.159 – -11.160, t = -9.347, P < 0.001). There was no difference in PS between the two groups after UKA (95% CI: -6.559 – 0.345, t = -1.782, P = 0.077). Conclusions: Patients with synovitis can achieve good improvement of pain symptoms, and the efficacy is not inferior to that of non-synovitis patients after UKA. [ABSTRACT FROM AUTHOR]

Aptamers are short non-coding, single-stranded oligonucleotides (RNA or DNA) developed through Systematic Evolution of Ligands by Exponential enrichment (SELEX) in vitro. Similar to antibodies, aptamers can bind to specific targets with high affinity, and are considered promising therapeutic agents as they have several advantages over antibodies, including high specificity, stability, and non-immunogenicity. Furthermore, aptamers can be produced at a low cost and easily modified, and are, therefore, called "chemical antibodies". In the past years, a variety of aptamers specifically bound to both breast cancer biomarkers and cells had been selected. Besides, taking advantage of nanomaterials, there were a number of aptamer-nanomaterial conjugates been developed and widely investigated for diagnostics and targeted therapy of breast cancer. In this short review, we first present a systematical review of various aptamer selection methods. Then, various aptamer-based diagnostic and therapeutic strategies of breast cancer were provided. Finally, the current problems, challenges, and future perspectives in the field were thoroughly discussed. [ABSTRACT FROM AUTHOR]

Background: Autophagy is a cellular degradation process that is highly evolutionarily-conserved in yeast, plants, and animals. In plants, autophagy plays important roles in regulating intracellular degradation and recycling of amino acids in response to nutrient starvation, senescence, and other environmental stresses. Foxtail millet (Setaria italica) has strong resistance to stresses and has been proposed as an ideal material for use in the study of the physiological mechanisms of abiotic stress tolerance in plants. Although the genome sequence of foxtail millet (Setaria italica) is available, the characteristics and functions of abiotic stress-related genes remain largely unknown for this species. Results: A total of 37 putative ATG (autophagy-associated genes) genes in the foxtail millet genome were identified. Gene duplication analysis revealed that both segmental and tandem duplication events have played significant roles in the expansion of the ATG gene family in foxtail millet. Comparative synteny mapping between the genomes of foxtail millet and rice suggested that the ATG genes in both species have common ancestors, as their ATG genes were primarily located in similar syntenic regions. Gene expression analysis revealed the induced expression of 31 SiATG genes by one or more phytohormone treatments, 26 SiATG genes by drought, salt and cold, 24 SiATG genes by darkness and 25 SiATG genes by nitrogen starvation. Results of qRT-PCR showing that among 37 SiATG genes, the expression level of SiATG8a was the highest after nitrogen starvation treatment 24 h, suggesting its potential role in tolerance to nutrient starvation. Moreover, the heterologous expression of SiATG8a in rice improved nitrogen starvation tolerance. Compared to wild type rice, the transgenic rice performed better and had higher aboveground total nitrogen content when the plants were grown under nitrogen starvation conditions. Conclusions: Our results deepen understanding about the characteristics and functions of ATG genes in foxtail millet and also identify promising new genetic resources that should be of use in future efforts to develop varieties of foxtail millet and other crop species that have resistance to nitrogen deficiency stress. [ABSTRACT FROM AUTHOR]

Background: DNMT3A mutations are frequently discovered in acute myeloid leukemia (AML), associated with poor outcome. Recently, a relapse case report of AML extramedullary disease has showed that AML cells harboring DNMT3A variation were detected in the cerebral spinal fluid. However, whether a causal relationship exists between DNMT3A mutation (D3Amut) and extramedullary infiltration (EMI) is unclear. Methods: We took advantage of DNMT3A (R882C) mutation-carrying AML cell strain, that is, OCI-AML3, assessing its migration ability in vitro and in vivo. By RNA interfering technology and a xenograft mouse model, we evaluated the effect of DNMT3A mutation on cell mobility and explored the possible mechanism. Results: OCI-AML3 displayed extraordinary migration ability in vitro and infiltrated into meninges of NOD/SCID mice after intravenous transfusion. We found that this leukemic migration or infiltration capacity was significantly compromised by the knockdown of DNMT3A mutant. Notably, TWIST1, a critical inducer of epithelial–mesenchymal transition, which underlies the metastasis of carcinomas, was highly expressed in association with R882 mutations. Abrogation of TWIST1 in DNMT3A mutated cells considerably weakened their mobility or infiltration. Conclusions: Our results demonstrate that D3Amut in OCI-AML3 strain enhances leukemic aggressiveness by promoting EMI process, which is partially through upregulating TWIST1. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that palmitoylation is essential for NRAS leukemogenesis, suggesting that targeting RAS palmitoylation may be an effective therapy for NRAS-related cancers. For KRAS-driven cancer, although much research has been focused on the KRAS4B splice variant, which does not undergo palmitoylation, KRAS4A has recently been shown to play an essential role in the development of carcinogen-induced lung cancer in mice and to be widely expressed in human cancers. However, the role of palmitoylation in KRAS4A tumorigenesis is not clear. Methods: The expression of KRAS4A in KRAS-mutated leukemia cell lines and acute myeloid leukemia (AML) cells were checked using western blotting and reverse transcriptions-quantitative polymerase chain reaction (RT-qPCR) analysis, respectively. The leukemogenic potentials of oncogenic KRAS4A and its palmitoylation-defective mutants were examined by a mouse bone marrow transduction and transplantation model and the in vitro transformation assays. The activation of the RAS downstream signaling pathways and the membrane localizations of the KRAS4A and its mutants were analyzed via western blot analysis and confocal microscopy, respectively. Results: We show here that KRAS4A is expressed in human leukemia cell lines and in AML cells harboring KRAS mutations and that mutation at the palmitoylation site of oncogenic KRAS4A significantly abrogates its leukemogenic potential. However, unlike NRAS, palmitoylation-defective KRAS4A still induces leukemia in mice, albeit with a much longer latency. Using NRAS/KRAS4A chimeric constructs, we found that the KIKK motif of KRAS4A contributes to the transforming activity of KRAS4A. Mutations at both palmitoylation site and the KIKK motif abolish the ability of oncogenic KRAS4A to induce leukemia in mice. Conclusions: Our studies suggest that therapies targeting RAS palmitoylation may also be effective in treating KRAS4A associated malignancies and that interfering the KIKK membrane-targeting motif would enhance the therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Background: DNA methyltransferase 1 (Dnmt1) regulates expression of many critical genes through maintaining parental DNA methylation patterns on daughter DNA strands during mitosis. It is essential for embryonic development and diverse biological processes, including maintenance of hematopoietic stem and progenitor cells (HSPCs). However, the precise molecular mechanism of how Dnmt1 is involved in HSPC maintenance remains unexplored. Methods: An N-ethyl-N-nitrosourea (ENU)-based genetic screening was performed to identify putative mutants with defects in definitive HSPCs during hematopoiesis in zebrafish. The expression of hematopoietic markers was analyzed via whole mount in situ hybridization assay (WISH). Positional cloning approach was carried out to identify the gene responsible for the defective definitive hematopoiesis in the mutants. Analyses of the mechanism were conducted by morpholino-mediated gene knockdown, mRNA injection rescue assays, antiphosphorylated histone H3 (pH3) immunostaining and TUNEL assay, quantitative real-time PCR, and bisulfite sequencing analysis. Results: A heritable mutant line with impaired HSPCs of definitive hematopoiesis was identified. Positional cloning demonstrated that a stop codon mutation was introduced in dnmt1 which resulted in a predicted truncated Dnmt1 lacking the DNA methylation catalytic domain. Molecular analysis revealed that expression of CCAAT/enhancer-binding protein alpha (C/ebpa) was upregulated, which correlated with hypomethylation of CpG islands in the regulation regions of cebpa gene in Dnmt1 deficient HSPCs. Overexpression of a transcriptional repressive SUMO-C/ebpa fusion protein could rescue hematological defects in the dnmt1 mutants. Finally, dnmt1 and cebpa double null embryos exhibited no obvious abnormal hematopoiesis indicated that the HSPC defects triggered by dnmt1 mutation were C/ebpa dependent. Conclusions: Dnmt1 is required for HSPC maintenance via cebpa regulation during definitive hematopoiesis in zebrafish. [ABSTRACT FROM AUTHOR]

Background: To fully elucidate the roles and mechanisms of plant hormones in leaf senescence, we adopted an integrated analysis of both non-senescing and senescing leaves from red maple with transcriptome and metabolome data. Results: Transcription and metabolite profiles were generated through a combination of deep sequencing, third-generation sequencing data analysis, and ultrahigh-performance liquid chromatograph Q extractive mass spectrometry (UHPLC-QE-MS), respectively. We investigated the accumulation of compounds and the expression of biosynthesis and signaling genes for eight hormones. The results revealed that ethylene and abscisic acid concentrations increased during the leaf senescence process, while the contents of cytokinin, auxin, jasmonic acid, and salicylic acid continued to decrease. Correlation tests between the hormone content and transcriptional changes were analyzed, and in six pathways, genes closely linked with leaf senescence were identified. Conclusions: These results will enrich our understanding of the mechanisms of plant hormones that regulate leaf senescence in red maple, while establishing a foundation for the genetic modification of Acer in the future. [ABSTRACT FROM AUTHOR]

Aim: The transition from medical students to competent physicians requires comprehensive training during residency programs. In China, resident students typically undergo 2- or 3-year training programs. While they learn from patient interactions under the guidance of experienced doctors, integrating theoretical knowledge from textbooks into practical cases remains a challenge. This study aimed to explore the impact of medical interns acting as peer-students on the knowledge mastery of resident students., Method: The participants of this study consisted of resident students specializing in respiratory medicine at the Second Affiliated Hospital of Zhejiang University, School of Medicine. Resident students were given the opportunity to volunteer as peer-teachers for medical interns in the respiratory department. Those who chose to instruct interns were automatically placed into the test group, while those who opted not to partake in intern instruction formed the control group. In their role as peer-teachers, resident students assumed the responsibility of guiding interns in patient management throughout the entire continuum, spanning from initial engagement to discharge, a commitment that extended over a minimum period of 2 weeks. The resident students' academic performance was evaluated through a departmental examination consisting of 50 multiple-choice questions, which was administered upon completing their rotation. Statistical analysis was performed to assess the impact of peer-teaching on the resident students' performance., Results: Between January 2023 and June 2023, a total of 158 resident students completed their rotation in the respiratory department. Among them, 40 resident students willingly took on the responsibility of instructing medical interns, while 118 resident students did not participate in intern teaching. With a "one-to-one" teaching policy in place, the overall satisfaction rate of the interns was an impressive 95.35%. Pre-rotation test scores for the test group averaged 81.66 ± 8.325 (Mean ± SD) and the control group averaged 81.66 ± 8.002, without significance. The departmental examination scores of the test group averaged 85.60 ± 7.886, while the control group scored an average of 82.25 ± 8.292, with a statistically significant difference (p = 0.027)., Conclusion: In conclusion, our study underscores the positive influence of peer-teaching on the knowledge mastery of resident students., (© 2024. The Author(s).)

Background: Drought stress is one of the major natural challenges in the main tea-producing regions of China. The tea plant (Camellia sinensis) is a traditional beverage plant whose growth status directly affects tea quality. Recent studies have revealed that microRNAs (miRNAs) play key functions in plant growth and development. Although some miRNAs have been identified in C. sinensis, little is known about their roles in the drought stress response of tea plants., Results: Physiological characterization of Camellia sinensis 'Tieguanyin' under drought stress showed that the malondialdehyde concentration and electrical conductivity of leaves of drought-stressed plants increased when the chlorophyll concentration decreased under severe drought stress. We sequenced four small-RNA (sRNA) libraries constructed from leaves of plants subjected to four different treatments, normal water supply (CK); mild drought stress (T1); moderate drought stress (T2) and severe drought stress (T3). A total of 299 known mature miRNA sequences and 46 novel miRNAs were identified. Gene Ontology enrichment analysis revealed that most of the differentially expressed-miRNA target genes were related to regulation of transcription. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the most highly enriched pathways under drought stress were D-alanine metabolism, sulfur metabolism, and mineral absorption pathways. Real-time quantitative PCR (qPCR) was used to validate the expression patterns of 21 miRNAs (2 up-regulated and 19 down-regulated under drought stress). The observed co-regulation of the miR166 family and their targets ATHB-14-like and ATHB-15-like indicate the presence of negative feedback regulation in miRNA pathways., Conclusions: Analyses of drought-responsive miRNAs in tea plants showed that most of differentially expressed-miRNA target genes were related to regulation of transcription. The results of study revealed that the expressions of phase-specific miRNAs vary with morphological, physiological, and biochemical changes. These findings will be useful for research on drought resistance and provide insights into the mechanisms of drought adaptation and resistance in C. sinensis.

Background: Reconstructing gene regulatory networks (GRNs) from expression data plays an important role in understanding the fundamental cellular processes and revealing the underlying relations among genes. Although many algorithms have been proposed to reconstruct GRNs, more rapid and efficient methods which can handle large-scale problems still need to be developed. The process of reconstructing GRNs can be formulated as an optimization problem, which is actually reconstructing GRNs from time series data, and the reconstructed GRNs have good ability to simulate the observed time series. This is a typical big optimization problem, since the number of variables needs to be optimized increases quadratically with the scale of GRNs, resulting an exponential increase in the number of candidate solutions. Thus, there is a legitimate need to devise methods capable of automatically reconstructing large-scale GRNs., Results: In this paper, we use fuzzy cognitive maps (FCMs) to model GRNs, in which each node of FCMs represent a single gene. However, most of the current training algorithms for FCMs are only able to train FCMs with dozens of nodes. Here, a new evolutionary algorithm is proposed to train FCMs, which combines a dynamical multi-agent genetic algorithm (dMAGA) with the decomposition-based model, and termed as dMAGA-FCM D , which is able to deal with large-scale FCMs with up to 500 nodes. Both large-scale synthetic FCMs and the benchmark DREAM4 for reconstructing biological GRNs are used in the experiments to validate the performance of dMAGA-FCM D ., Conclusions: The dMAGA-FCM D is compared with the other four algorithms which are all state-of-the-art FCM training algorithms, and the results show that the dMAGA-FCM D performs the best. In addition, the experimental results on FCMs with 500 nodes and DREAM4 project demonstrate that dMAGA-FCM D is capable of effectively and computationally efficiently training large-scale FCMs and GRNs.