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ABSTRACTDirect ink writing of thermosetting materials, e.g. epoxy resin, is a promising technique for the rapid and low-cost fabrication of high-strength parts with complex geometry. In this study, a microwave-assisted 3D printer using rectangular waveguide (RWG) was developed to overcome the ink's low viscosity and slow curing speed. Microwave curing and ink extrusion are synchronous to improve shape retention of ink. The critical structure parameters of the RWG applicator were determined using the multiphysics simulation to achieve optimal microwave system matching and ink heating uniformity. Experiments were conducted to investigate the processing parameters and printability. At microwave radiation temperature 95°C, the extruded ink has a significantly increased storage modulus and presents a stable and continuous cylindrical gelatinous state. Filaments can be deposited with high-quality at screw rotary speed 70 rpm and printing speed 5 mm/s. The printed sample demonstrates the excellent printability of multiple layers of extruded ink.

Abstract Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of l-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.

The low ductility of titanium aluminide at room temperature has been one of the factors that severely limit its applications. In this study, Ti–6Al–4V (Ti64) alloys were combined with Ti–47Al–2Cr–2Nb (TiAl) alloys to make micro-laminated composites with optimal ply configurations to eliminate crack formation in TiAl and improve the ductility. A dual-material laser powder bed fusion (LPBF) system was used to fabricate the TiAl/Ti64 micro-laminate samples. The presence of cracks, elemental composition and mechanical properties were experimentally characterised and analysed to understand the effect of ply configuration and the mechanism of eliminating cracks. It was found that smaller TiAl ply thickness and lower TiAl volume fraction result in fewer cracks formed in the micro-laminates. Elemental composition analysis reveals that the Al content in the first two powder layers (i.e., 200 μm thick in total) of a TiAl ply is reduced to 10%–35% due to the partial mixture of the TiAl ply and the proceeding Ti64 ply in the LPBF. The reduced Al content leads to combined α-Ti, β-Ti and α2-Ti3Al phases instead of γ-TiAl phases, thus eliminating the formation of cracks within the first 200 μm thick region of the TiAl ply. This study demonstrates that crack-free and dense TiAl/Ti6 micro-laminated composites can be produced with the TiAl ply thickness reduced to 200 μm and the TiAl volume fraction reduced to 25% (Ti64 ply thickness 400 μm). Ductility of the crack-free micro-laminates at room temperature is comparable to or even exceeds the properties of TiAl/Ti64-type laminates made by other manufacturing processes, which may imply good machinability. Note that further research is required to investigate the properties and applications of the micro-laminates at elevated temperatures.

The DNA damage repair (DDR) pathway is a complex signaling cascade that can sense DNA damage and trigger cellular responses to DNA damage to maintain genome stability and integrity. A typical hallmark of cancer is genomic instability or nonintegrity, which is closely related to the accumulation of DNA damage within cancer cells. The treatment principles of radiotherapy and chemotherapy for cancer are based on their cytotoxic effects on DNA damage, which are accompanied by severe and unnecessary side effects on normal tissues, including dysregulation of the DDR and induced therapeutic tolerance. As a driving factor for oncogenes or tumor suppressor genes, noncoding RNA (ncRNA) have been shown to play an important role in cancer cell resistance to radiotherapy and chemotherapy. Recently, it has been found that ncRNA can regulate tumor treatment tolerance by altering the DDR induced by radiotherapy or chemotherapy in cancer cells, indicating that ncRNA are potential regulatory factors targeting the DDR to reverse tumor treatment tolerance. This review provides an overview of the basic information and functions of the DDR and ncRNAs in the tolerance or sensitivity of tumors to chemotherapy and radiation therapy. We focused on the impact of ncRNA (mainly microRNA [miRNA], long noncoding RNA [lncRNA], and circular RNA [circRNA]) on cancer treatment by regulating the DDR and the underlying molecular mechanisms of their effects. These findings provide a theoretical basis and new insights for tumor-targeted therapy and the development of novel drugs targeting the DDR or ncRNAs.

ObjectiveSchizonepeta tenuifolia -Saposhnikovia divaricata (Jingjie-Fangfeng, JF) has been used for years to treat allergic inflammatory skin diseases like atopic dermatitis, but the specific effects and mechanisms of JF are still unclear.PurposeWe aim to investigate the therapeutic effect and mechanism of JF in MC903-induced atopic dermatitis-like model.MethodsJF decoction was subjected to rigorous HPLC and GC analysis. The JF decoction was then freshly prepared and administered to MC903-induced atopic dermatitis -like mice models to investigate its therapeutic effects. Our evaluation focused on several markers of inflammation including the TEWL index, ear thickness, swelling, and specific inflammation indicators such as TSLP, IL33, IgE, and immune cell presence at the lesion sites. We measured Transient Receptor Potential Vanilloid 1 (TRPV1) expression levels through immunofluorescent staining in skin tissue from both atopic dermatitis patients and the MC903-treated mice. Furthermore, TRPV1 expression and macrophage activation markers were measured in LPS/IFN-γ-stimulated Raw264.7 and THP-1 cell models in vitro. Additionally, we developed cell lines that overexpress TRPV1 and investigated how JF treatment affects NF-κB p65 phosphorylation in these cells to understand better the role of TRPV1 in atopic dermatitis.ResultsThe JF decoction met the standards outlined in the Chinese pharmacopeia. The JF decoction significantly alleviated inflammatory skin symptoms and helped restore skin barrier function. Additionally, it reduced the levels of IgE and pro-inflammatory cytokines TSLP, IL-33, and IL-4. There was also a noticeable decrease in mast cell infiltration and degranulation. Notably, JF decoction reduced infiltrated macrophages with limited affection on T cell infiltration. It also decreased F4/80+/TRPV1+ cells in atopic dermatitis mice and TRPV1 expression in LPS/IFNγ-stimulated microphages. Additionally, we observed that CD68+/TRPV1+ cells increased in human atopic dermatitis tissue. Further studies showed that JF water extract (JF-WE) suppressed TRPV1 expression in macrophages, potentially by affecting NF-κB p65 phosphorylation rather than the JAK-STAT6 pathway.ConclusionThis study offers initial evidence of the effectiveness of JF-WE in suppressing inflammation in atopic dermatitis. The therapeutic effect might stems from its ability to downregulate TRPV1 expression and subsequent NF-κB p65 phosphorylation in macrophages.

Helicobacter pylori (H. pylori) is a harmful bacterium that is difficult to conveniently diagnose and effectively eradicate. Chronic H. pylori infection increases the risk of gastrointestinal diseases, even cancers. Despite the known findings, more underlying mechanisms are to be deeply explored to facilitate the development of novel prevention and treatment strategies of H. pylori infection. Long noncoding RNAs (lncRNAs) are RNAs with more than 200 nucleotides. They may be implicated in cell proliferation, inflammation and many other signaling pathways of gastrointestinal cancer progression. The dynamic expression of lncRNAs indicates their potential to be diagnostic or prognostic biomarkers. In this paper, we comprehensively summarize the processes of H. pylori infection and the treatment methods, review the known findings of lncRNA classification and functional mechanisms, elucidate the roles of lncRNAs in H. pylori-related gastrointestinal cancer, and discuss the clinical perspectives of lncRNAs.

Background: Homer protein homolog 3 (HOMER3), a factor implicated in both physiological and pathological processes, has been studied extensively to determine the relationship between its expression level and the prognosis of various malignancies. However, the significance and clinicopathological role of HOMER3 in colorectal adenocarcinoma remain unclear. Methods: In this study, bioinformatics techniques were used to find the correlation between high HOMER3 expression levels and clinicopathological features of colorectal adenocarcinoma (COAD) patients. Results: Cellular experiments confirmed the differential expression of HOMER3 in tumor cells compared to normal cells. HOMER3 overexpression was significantly associated with COAD staging and carcinoembryonic antigen (CEA) levels. Patients with high HOMER3 expression levels have a poor prognosis. HOMER3 expression levels can be distinguished more accurately between tumor and non-tumor tissues (AUC = 0.634). The HOMER3 gene variation rate in COAD tissue was 0.7 %. Moreover, 16 of the 22 DNA methylation sites in HOMER3 were associated with COAD prognosis. Our findings confirmed that HOMER3 was positively correlated with immune cell infiltration and immune checkpoints (PD-1, CTLA-4, LMTK3, and LAG3) in COAD, Specifically, we will clearly state that while there is statistical significance, the actual strength of the correlations is weak. During KEGG enrichment analysis, HOMER3 was enriched along with DLG4 and SHANK1 in glutamatergic synapses. Additionally, upstream microRNAs that could bind to HOMER3 were predicted. These findings suggest that HOMER3 might be involved in COAD development and immune regulation. Conclusions: HOMER3 acts as a potential biomarker that can facilitate innovative developments in the diagnosis and prognostic assessment of COAD.

Abstract With the advancement of sequencing technologies and bioinformatics, over than 170 different RNA modifications have been identified. However, only a few of these modifications can lead to base pair changes, which are called RNA editing. RNA editing is a ubiquitous modification in mammalian transcriptomes and is an important co/posttranscriptional modification that plays a crucial role in various cellular processes. There are two main types of RNA editing events: adenosine to inosine (A-to-I) editing, catalyzed by ADARs on double-stranded RNA or ADATs on tRNA, and cytosine to uridine (C-to-U) editing catalyzed by APOBECs. This article provides an overview of the structure, function, and applications of RNA editing enzymes. We discuss the structural characteristics of three RNA editing enzyme families and their catalytic mechanisms in RNA editing. We also explain the biological role of RNA editing, particularly in innate immunity, cancer biogenesis, and antiviral activity. Additionally, this article describes RNA editing tools for manipulating RNA to correct disease-causing mutations, as well as the potential applications of RNA editing enzymes in the field of biotechnology and therapy.

The routine monitoring of eutrophication is an important measure for observing the variation in water quality and protecting the ecological health of lakes. However, in situ information reflects eutrophication levels within a limited distance and period. In this study, we retrieved the trophic level index (TLI) based on Landsat 8 remote sensing images and using a machine learning (ML) method in Liangzi Lake in Hubei Province, China. The results showed that random forest (RF) outperformed other ML algorithms in estimating the TLI, evaluated by its higher fitness through the Monte Carlo method (median values of R2, RMSE, and MAE are 0.54, 0.047, and 0.037, respectively). In general, 8% of the areas of Liangzi Lake presented an increasing eutrophication level from 2014 to 2022, and 20.1% of the areas reached a mild eutrophication level in 2022. In addition, we found that temperature and anthropogenic activities may impact the eutrophication conditions of the lake. This work uses remote sensing imagery and a ML method to monitor the dynamics of the lake’s eutrophication status, thereby providing a valuable reference for pollution control measures and enhancing the efficiency of water resource management.

The solute carrier family 12 (SLC12) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl− extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer 36Cl−, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, 22Na+ uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.

Self-lubricating aluminium matrix composites with enhanced tribological properties are sought for weight critical applications. In previous studies, the Al composites incorporating the solid lubricant WS2 have been shown to reduce both the coefficient of friction and wear rate, positioning them as promising candidates in various tribological applications (e.g. automotive industry). However, the impact of interfacial reactions between Al and WS2 during composite production on tribological performance has still not yet been explored. This study highlights the hardening effect of the reaction products. Despite some literature assuming a negative impact of these reactions as they consume WS2 in the composites, this study presents evidence that this cannot be generalised for the overall outcome. Interestingly, a controlled amount is shown to be beneficial for tribological properties. In this work, the tribological influence of the Al–W intermetallic structure forming during spark plasma sintering of the Al–WS2 composites was investigated. The microstructure was tailored by adjusting the manufacturing temperature between 500 and 600 °C. The Al–WS2 fabricated at 580 °C exhibited the lowest coefficient of friction and specific wear rate (reduced by 20 % and 97 %, respectively, compared to the one fabricated at 500 °C. Furthermore, the worn surface morphology in different stages during friction was evaluated by a novel wear track evolution analysis. This study confirmed that offering a balance between the fraction of solid lubricants and in-situ formed hard intermetallic structure is crucial to the effective formation a protective layer on the worn surface.

Three-dimensional interconnected mesoporous nanoflakes of amorphous Ni-Mo-Co trimetallic hydroxides were successfully deposited on a Ni foam (NF) using a facile, environmentally friendly, and scalable electrochemical deposition method. The elemental composition of the nanoflakes, including Ni2+, Mo6+, and Co2+, was characterized by X-ray photoelectron spectroscopy (XPS), while the morphology and particle size of the synthesized nanomaterials were examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The Ni-Mo-Co trimetallic hydroxides on NF were employed as binder-free electrodes for supercapacitors. The Ni-Mo-Co trimetallic hydroxides with a Ni/Mo/Co ratio of 1/1/0.4 exhibited outstanding long-term cyclability over 5000 cycles, with a high reversible specific capacitance of 2700 F g−1 and a high capacitance retention of 96.63% at 10 A g−1. Furthermore, they demonstrated excellent rate performance, maintaining a capacitance of 2429 F g−1 at a current of 50 A g−1, which corresponds to approximately 80% capacitance retention compared to the capacitance at 2 A g−1. The superior performance of these Ni-Mo-Co trimetallic hydroxides can be attributed to their mesoporous hierarchical architecture, which provides large open spaces between the interconnected nanoflakes, numerous electroactive surface sites, facile electron transmission paths, and the synergistic effects of the trimetallic components. These findings demonstrate that Ni-Mo-Co trimetallic hydroxides are promising electrode materials, offering both high capacitance and long-term cyclability for supercapacitors.

The hypothalamic–pituitary–ovarian (HPO) axis plays a pivotal role in the regulation of egg production in chickens. In addition to the traditional understanding of the HPO axis, emerging research highlights the significant role of circRNAs in modulating the functions of this axis. In the study, we collected hypothalamus, pituitary, and ovarian tissues from low-yielding and high-yielding Bian chickens for transcriptome sequencing. We identified 339, 339, and 287 differentially expressed (DE) circRNAs with p_value < 0.05 and |log2 (fold change)| ≥ 1 in hypothalamus, pituitary, and ovarian tissues. The Gene Ontology (GO) enrichment analysis for the source genes of DE circRNAs has yielded multiple biological process (BP) entries related to cell development, the nervous system, and proteins, including cellular component morphogenesis, cell morphogenesis, nervous system development, neurogenesis, protein modification process, and protein metabolic process. In the top 30 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we observed the enrichment of the GnRH signaling pathway in both the hypothalamus and the pituitary, solely identified the GnRH secretion pathway in the pituitary, and discovered the pathway of oocyte meiosis in the ovary. Furthermore, given that circRNA primarily functions through the ceRNA mechanism, we constructed ceRNA regulatory networks with DE circRNAs originating from the GnRH signaling pathway, GnRH secretion, ovarian steroidogenesis, steroid hormone biosynthesis, and the estrogen signaling pathway. Finally, several important ceRNA regulatory networks related to reproduction were discovered, such as novel_circ_003662-gga-let-7b/miR-148a-3p/miR-146a-5p/miR-146b-5p and novel_circ_003538-gga-miR-7464-3p-SLC19A1. This study will contribute to advancements in understanding the involvement of circRNAs in the HPO axis, potentially leading to innovations in improving egg production and poultry health.

Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.

Crop diseases significantly impact crop yields, and promoting specialized control of crop diseases is crucial for ensuring agricultural production stability. Disease identification primarily relies on human visual inspection, which is inefficient, inaccurate, and subjective. This study focused on the plum red spot (Polystigma rubrum), proposing a two-stage detection algorithm based on deep learning and assessing the severity of the disease through lesion coverage rate. The specific contributions are as follows: We utilized the object detection model YOLOv8 to strip leaves to eliminate the influence of complex backgrounds. We used an improved U-Net network to segment leaves and lesions. We combined Dice Loss with Focal Loss to address the poor training performance due to the pixel ratio imbalance between leaves and disease spots. For inconsistencies in the size and shape of leaves and lesions, we utilized ODConv and MSCA so that the model could focus on features at different scales. After verification, the accuracy rate of leaf recognition is 95.3%, and the mIoU, mPA, mPrecision, and mRecall of the leaf disease segmentation model are 90.93%, 95.21%, 95.17%, and 95.21%, respectively. This research provides an effective solution for the detection and severity assessment of plum leaf red spot disease under complex backgrounds.

Laser cladding with coaxial shroud protection offers the possibility to process reactive metals in an open environment. The numerical analysis was performed on the thermal field and dynamics of molten pool with the aim of clarifying the mechanism of the complex effects of the applied extra shielding gas on the resultant microstructure and surface quality of cladding layers of Ti6Al4V. A three-dimensional (3D) computational fluid dynamics (CFD) model was first developed to investigate the extra shielding gas effect on the molten pool. The simulation shows that the extra shielding gas influences both the surface and internal flow field characteristics of the molten pool. The predicted solidification parameters imply fully columnar microstructure in the entire cladding layer. Comparative analysis was then carried out between the numerical simulation and experiments. The electron backscattering diffraction (EBSD) examination reveals that the high cooling rate due to the extra shielding gas inhibits the formation of grain boundary α phase and simultaneously refines the microstructure. The extra shielding gas reduces the surface roughness of cladding layers, and its bunching effect improves the powder utilization. The multi-track cladding experiments reveal that the extra shielding gas can effectively suppress crack formation with a large overlap ratio. This study provides a better understanding of the effect of extra shielding gas flow on molten pool, which helps control and improve the quality of cladding layers.

Autophagy is a conserved, cellular self-degradation system that is essential for maintaining intracellular homeostasis. Increasing evidence suggests that autophagy plays an important dual regulatory role in the development of many human diseases, such as cancer. Recent studies have shown that the autophagy process in tumor cells can be regulated by various stimuli from both intracellular and extracellular environments, including the effects of anesthesia. Anesthetics have been shown to not only have clinical anesthetic and sedative effects but also play important roles in the progression of tumors. The effects of different types of anesthetics on tumors differ. In this review, we summarize the basic information on autophagy, the regulatory function of autophagy in cancer, currently used autophagy-targeted tumor therapy, and the effects of different types of anesthetics on tumor progression. We focus on the molecular mechanisms by which anesthetics exert tumor-inhibiting effects by activating or inhibiting autophagy. Herein, we also explore the potential application of the anesthetic/autophagy system in clinical tumor treatment. These findings provide a theoretical basis for the use of anesthetics during the perioperative period to suppress tumor development and provide insights for autophagy-targeted cancer treatment and drug development.

Notch signaling pathway is a highly conserved system of cell-to-cell communication that participates in various biological processes, such as stem cell maintenance, cell fate decision, cell proliferation and death during homeostasis and development. Dysregulation of Notch signaling has been associated with many aspects of cancer biology, such as maintenance of cancer stem-like cells (CSCs), cancer cell metabolism, angiogenesis and tumor immunity. Particularly, Notch signaling can regulate antitumor or pro-tumor immune cells within the tumor microenvironment (TME). Currently, Notch signaling has drawn significant attention in the therapeutic development of cancer treatment. In this review, we focus on the role of Notch signaling pathway in remodeling tumor immune microenvironment. We describe the impact of Notch signaling on the efficacy of cancer immunotherapies. Furthermore, we summarize the results of relevant preclinical and clinical trials of Notch-targeted therapeutics and discuss the challenges in their clinical application in cancer therapy. An improved understanding of the involvement of Notch signaling in tumor immunity will open the door to new options in cancer immunotherapy treatment.

Drug-resistant bacteria arising from antibiotic abuse infections have always been a serious threat to human health. Killing bacteria with toxic reactive oxygen species (ROS) is an ideal antibacterial method for treating drug-resistant bacterial infections. Here, we prepared Pt-Ru bimetallic nanoclusters (Pt-Ru NCs) with higher peroxidase (POD)-like activity than Pt monometallic nanoclusters. Pt-Ru can easily catalyze the decomposition of H2O2 to produce ·OH, thereby catalyzing the transformation of 3,3',5,5'-tetramethylbiphenylamine (TMB) to blue oxidized TMB (oxTMB). We utilized the POD-like activity of the Pt-Ru NCs for antibacterial therapy. The results showed that at doses of 40 μg/mL and 16 μg/mL, the Pt-Ru NCs exhibited extraordinary antibacterial activity against E. coli and S. aureus, demonstrating the enormous potential of Pt-Ru NCs as antibacterial agents.

Programmed cell death (PCD) is an evolutionarily conserved mechanism of cell suicide that is controlled by various signaling pathways. PCD plays an important role in a multitude of biological processes, such as cell turnover, development, tissue homeostasis and immunity. Some forms of PCD, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis and necroptosis, contribute to carcinogenesis and cancer development, and thus have attracted increasing attention in the field of oncology. Recently, increasing research-based evidence has demonstrated that PCD acts as a critical modulator of tumor immunity. PCD can affect the function of innate and adaptive immune cells, which leads to distinct immunological consequences, such as the priming of tumor-specific T cells, immunosuppression and immune evasion. Targeting PCD alone or in combination with conventional immunotherapy may provide new options to enhance the clinical efficacy of anticancer therapeutics. In this review, we introduce the characteristics and mechanisms of ubiquitous PCD pathways (e.g., apoptosis, autophagy-dependent cell death, pyroptosis and ferroptosis) and explore the complex interaction between these cell death mechanisms and tumor immunity based on currently available evidence. We also discuss the therapeutic potential of PCD-based approaches by outlining clinical trials targeting PCD in cancer treatment. Elucidating the immune-related effects of PCD on cancer pathogenesis will likely contribute to an improved understanding of oncoimmunology and allow PCD to be exploited for cancer treatment.

The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR associated) system has proven to be a powerful tool for nucleic acid detection due to its inherent advantages of effective nucleic acid identification and editing capabilities, and is therefore known as the next-generation of molecular diagnostic technology. However, the detection technologies based on CRISPR/Cas systems require preamplification of target analytes; that is, target gene amplification steps through isothermal amplification or PCR before detection to increase target analyte concentrations. This creates a number of testing limitations, such as extended testing time and the need for more sophisticated testing instruments. To overcome the above limitations, various amplification-free assay strategies based on CRISPR/Cas systems have been explored as alternatives, which omit the preamplification step to increase the concentrations of the target analytes. Nanozymes play a pivotal role in enhancing the sensitivity of CRISPR-based detection, enabling visual and rapid CRISPR assays. The utilization of nanozyme exceptional enzyme-like catalytic activity holds great promise for signal amplification in both electrochemical and optical domains, encompassing strategies for electrochemical signal sensors and colorimetric signal sensors. Rather than relying on converting a single detection target analyte into multiple analytes, these methods focus on signal amplification, the main mechanism of which involves the ability to form a large number of reporter molecules or to improve the performance of the sensor. This exploitation of nanozymes for signal amplification results in the heightened sensitivity and accuracy of detection outcomes. In addition to the strategies that improve sensor performance through the application of nanozymes, additional methods are needed to achieve visual signal amplification strategies without preamplification processes. Herein, we review the strategies for improving CRISPR/Cas systems that do not require preamplification, providing a simple, intuitive and preamplification-free CRISPR/Cas system detection platform by improving in-system one-step amplification programs, or enhancing nanozyme-mediated signal amplification strategies.

BiFeO3–BaTiO3 is a promising lead-free piezoelectric ceramic, exhibiting high Curie temperature and superior electrochemical characteristics. In this work, [Formula: see text]BiFeO3–xBaTiO3 (BF–xBT, [Formula: see text], 0.28, 0.30, 0.32, 0.34, 0.36) ceramics were fabricated using the conventional solid-state reaction method through precise composition control. Multiple characterization techniques, including X-ray powder diffraction (XRD), scanning electron microscope (SEM), and electrical property testing systems, were applied to systematically examine the crystallographic structure, microstructure, as well as the dielectric, ferroelectric and piezoelectric properties of the BF–xBT ceramics. The XRD results confirm that all compositions exhibit a typical perovskite structure, transitioning from a single rhombohedral phase to a rhombohedral–cubic phase mixture as the BT content increases. SEM shows apparent core–shell microstructures in the ceramics. Notably, the results demonstrated that the BF–0.30BT ceramic exhibits the maximum piezoelectric constant ([Formula: see text]) [Formula: see text][Formula: see text]pC/N, while the BF–0.34BT ceramic displays the maximum converse piezoelectric constant [Formula: see text][Formula: see text]pm/V, which highlights the suitability of BF–BT ceramics for high-performance piezoelectric applications.

Microlattice structures produced by laser powder bed fusion (LPBF) have been tested in compression extensively. Yet, their failure modes remain unexplained. This study bridges this research gap by accurately predicting the crack initiation process in LPBF body centred cubic (BCC) microlattices and their failure mode. In this study, LPBF AlSi10Mg BCC microlattice structures were tested in uniaxial compression and their detailed response modelled using a finite element (FE) modelling methodology on microlattices with idealised struts which was validated experimentally. Crack initiation in BCC microlattices with 2 × 1 × 2 unit cells loaded in compression was observed in situ via a scanning electron microscope (SEM). The force–displacement response of the microlattice was studied with respect to crack initiation and propagation. It was found that the locations of crack initiation could be predicted by considering the equivalent plastic strain and stress triaxiality fields obtained by an FE analysis and assuming a monotonically decreasing fracture locus. Subsequently, microlattices with 4 × 4 × 4.5 unit cells were similarly subjected to compression. Using a monotonically decreasing fracture locus extrapolated from uniaxial tension testing of the bulk LPBF AlSi10Mg, an FE simulation successfully predicted the commonly reported diagonal shear band failure mode of the microlattice on a model with idealised struts.

Laser beam powder bed fusion (PBF-LB) of AlSi10Mg has attained technology maturity in various industries. Nevertheless, the manufactured components often require thermal treatments to tailor their microstructures and mechanical properties. Experimental development of suitable thermal cycles for the printed parts is time and energy intensive. However, the characteristic microstructure of parts produced by PBF-LB resembles that of gas-atomised powder. Therefore, this study presents an in-depth investigation on the correlation between the properties of the powder and PBF-LB samples. In-situ heat treatment methodology was deployed to consistently heat-treat the powder and PBF-LB samples using elevated build-plate temperatures (220 - 500 ºC). Scanning electron microscopy revealed Si atoms’ diffusion, followed by eutectic network's disruption and Si particles’ coarsening, with increased build plate temperatures, in both parts and powder. X-ray diffraction and differential scanning calorimetry showed a strong correlation between the powder and parts treated at the same build-plate temperatures. A 500 ºC in-situ heat-treatment temperature reduced the hardness by ∼43% (powder) and ∼52% (printed samples). Nano- and micro-hardness values on the powder and printed samples also exhibited high correlation. Similarities between the powder and part's microstructural changes with temperature were attributed to the similar scale of cooling rates in gas-atomisation and PBF-LB, respectively. The findings in this study pave a clear pathway that experimentation on small batches of powder via ex-situ heat treatments could be efficiently used as a high-throughput method to predict the effect of thermal treatments on printed parts and to design new heat treatment protocols, specifically for PBF-LB materials.

Type 2 diabetes (T2D) is a metabolic disease with complex etiology and mechanisms. Long non-coding ribonucleic acid (LncRNA) is a novel class of functional long RNA molecules that regulate multiple biological functions through various mechanisms. Studies in the past decade have shown that lncRNAs may play an important role in regulating insulin resistance and the progression of T2D. As a widely used biguanide drug, metformin has been used for glucose lowering effects in clinical practice for more than 60 years. For diabetic therapy, metformin reduces glucose absorption from the intestines, lowers hepatic gluconeogenesis, reduces inflammation, and improves insulin sensitivity. However, despite being widely used as the first-line oral antidiabetic drug, its mechanism of action remains largely elusive. Currently, an increasing number of studies have demonstrated that the anti-diabetic effects of metformin were mediated by the regulation of lncRNAs. Metformin-regulated lncRNAs have been shown to participate in the inhibition of gluconeogenesis, regulation of lipid metabolism, and be anti-inflammatory. Thus, this review focuses on the mechanisms of action of metformin in regulating lncRNAs in diabetes, including pathways altered by metformin via targeting lncRNAs, and the potential targets of metformin through modulation of lncRNAs. Knowledge of the mechanisms of lncRNA modulation by metformin in diabetes will aid the development of new therapeutic drugs for T2D in the future.

Biaxial compression is a typical stress state experienced by the surrounding rock near the excavation boundaries under deep underground engineering, frequently resulting in engineering geological disasters (spalling and rockburst). The motivation to mitigate the risk and damage of these disasters has led us to compressively examine the evolutionary characteristics of acoustic signals [microseismic (MS) events, sound and acoustic emission (AEs)] produced by granite under biaxial compression with different intermediate principal stresses. These characteristics include time (activeness and b value) and frequency (main frequency and proportion of the advantage frequency bands) domains. The results suggest that: 1) the signal properties-driven order of activeness under low and high intermediate principal stresses for the initial stresses were as follows: AE accounted for 37.4% and 43.5% of σpeak, MS for 61.1% and 66% of σpeak, and sound for 81.8% and 85.5% of σpeak. 2) The notable distinction in precursors of different acoustic signals before granite failure was confirmed: the sequential relationship in the continuous decrease rate of the b value (AE < MS < sound), the occurrence (only existing in AE signals) of a few signals with extremely high amplitude (the “quiescent period”) and the different frequency-change rule in the proportion of the advantage frequency bands. 3) The strong influences of intermediate principal stress on the signal precursors were determined; these precursors in the activeness, b value, and proportion are negative to intermediate principal stress, whereas that of the main frequency shows a positive correlation. Consequently, these findings can contribute integrated usage of the multifrequency signals in the prediction and warning of geological disasters under deep underground engineering.

Microbial species that dwell human bodies have profound effects on overall health and multiple pathological conditions. The tumor microenvironment (TME) is characterized by disordered vasculature, hypoxia, excessive nutrition and immunosuppression. Thus, it is a favorable niche for microbial survival and growth. Multiple lines of evidence support the existence of microorganisms within diverse types of cancers. Like gut microbiota, intratumoral microbes have been tightly associated with cancer pathogenesis. Intratumoral microbiota can affect cancer development through various mechanisms, including induction of host genetic mutation, remodeling of the immune landscape and regulation of cancer metabolism and oncogenic pathways. Tumor-associated microbes modulate the efficacy of anticancer therapies, suggesting their potential utility as novel targets for future intervention. In addition, a growing body of evidence has manifested the diagnostic, prognostic, and therapeutic potential of intratumoral microorganisms in cancer. Nevertheless, our knowledge of the diversity and biological function of intratumoral microbiota is still incomplete. A deeper appreciation of tumor microbiome will be crucial to delineate the key pathological mechanisms underlying cancer progression and hasten the development of personalized treatment approaches. Herein, we summarize the most recent progress of the research into the emerging roles of intratumoral microbiota in cancer and towards clarifying the sophisticated mechanisms involved. Moreover, we discuss the effect of intratumoral microbiota on cancer treatment response and highlight its potential clinical implications in cancer.

Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), yet the underlying mechanisms are still elusive. Here, we demonstrate that phosphoribosyl pyrophosphate synthetase 2 (PRPS2) mutations drive ALL relapse through influencing PRPS1/2 hexamer stability. Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples. The effects of PRPS2 mutations on cell survival, cell apoptosis, and drug resistance were evaluated. In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed. Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry (UPLC–MS/MS). Integrating sequencing data with clinical information, we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy. Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability, leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance. The 3-amino acid V103-G104-E105, the key difference between PRPS1 and PRPS2, insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer, leading to its low enzyme activity. In addition, we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models. Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.

Abstract As a typical two‐dimensional (2D) transition metal dichalcogenides (TMDCs) material with nonzero band gap, MoS2 has a wide range of potential applications as building blocks in the field of nanoelectronics. The stability and reliability of the corresponding nanoelectronic devices depend critically on the mechanical performance and cyclic reliability of 2D MoS2. Although an in situ technique has been used to analyze the mechanical properties of 2D materials, the cyclic mechanical behavior, that is, fatigue, remains a major challenge in the practical application of the devices. This study was aimed at analyzing the planar cyclic performance and deformation behavior of three‐layer MoS2 nanosheets (NSs) using an in situ transmission electron microscopy (TEM) variable‐amplitude uniaxial low‐frequency and cyclic loading–unloading tensile acceleration test. We also elucidated the strengthening effect of the natural overlaying affix fragments (other external NSs) or wrinkle folds (internal folds from the NS itself) on cycling performances and service life of MoS2 NSs by delaying the whole process of fatigue crack initiation, propagation, and fracture. The results have been confirmed by molecular dynamics (MDs) simulations. The overlaying enhancement effect effectively ensures the long‐term reliability and stability of nanoelectronic devices made of few‐layer 2D materials.

The increasing knowledge in the field of oncoimmunology has led to extensive research into tumor immune landscape and a plethora of clinical immunotherapy trials in cancer patients. Immunotherapy has become a clinically beneficial alternative to traditional treatments by enhancing the power of the host immune system against cancer. However, it only works for a minority of cancers. Drug resistance continues to be a major obstacle to the success of immunotherapy in cancer. A fundamental understanding of the detailed mechanisms underlying immunotherapy resistance in cancer patients will provide new potential directions for further investigations of cancer treatment. Noncoding RNAs (ncRNAs) are tightly linked with cancer initiation and development due to their critical roles in gene expression and epigenetic modulation. The clear appreciation of the role of ncRNAs in tumor immunity has opened new frontiers in cancer research and therapy. Furthermore, ncRNAs are increasingly acknowledged as a key factor influencing immunotherapeutic treatment outcomes. Here, we review the available evidence on the roles of ncRNAs in immunotherapy resistance, with an emphasis on the associated mechanisms behind ncRNA-mediated immune resistance. The clinical implications of immune-related ncRNAs are also discussed, shedding light on the potential ncRNA-based therapies to overcome the resistance to immunotherapy.

Comparisons of genomic and methylomic changes during the conservation of indigenous chicken breeds in China provide insight into conservation programmes for these breeds and their adaptations to unique environments.

Background: Previous studies have found that blueberry anthocyanin extract (BAE) could prevent diabetic retinopathy (DR) development, but the underlying molecular mechanism is still a mystery. Methods: Human retinal pigment epithelium cell line ARPE-19 cells were exposed to high concentration glucose (H-Glu) with 25 mM for 24 h, and the cell viability and apoptosis were analyzed by MTT assay and flow cytometry, respectively. The endoplasmic reticulum stress (ERS) markers were determined by western blotting. Dual luciferase assay was applied to investigate the relationship between miR-182 and 8-oxoguanine-DNA glycosylase (OGG1). Furthermore, experiments in vivo were also performed to confirm the function of BAE in DR. Results: The increase of apoptosis, reactive oxygen species (ROS) level and ERS in ARPE-19 cells induced by H-Glu was notably restored by BAE. Meanwhile, BAE greatly inhibited H-Glu-induced miR-182 expression in ARPE-19 cells, and OGG1 was identified to be one of the downstream target moleculars of miR-182. Furthermore, miR-182 overexpression or OGG1 knockdown restored the impact of BAE on H-Glu-treated APRE-19 cells. Even more important, BAE was further confirmed to alleviated the development of DR in diabetes rat models. Conclusions: BAE significantly inhibited the progression of DR via molecular regulation function between miR-182/OGG1 axis and ROS/ERS.

Abstract Doxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.

Cancers, especially malignant tumors, contribute to high global mortality rates, resulting in great economic burden to society. Many factors are associated with cancer pathogenesis, including vascular endothelial growth factor-A (VEGFA) and circular RNAs (circRNA). VEGFA is a pivotal regulator of vascular development such as angiogenesis, which is an important process in cancer development. CircRNAs have covalently closed structures, making them highly stable. CircRNAs are widely distributed and participate in many physiological and pathological processes, including modulating cancer pathogenesis. CircRNAs act as transcriptional regulators of parental genes, microRNA (miRNA)/RNA binding protein (RBP) sponges, protein templates. CircRNAs mainly function via binding to miRNAs. CircRNAs have been shown to influence different diseases such as coronary artery diseases and cancers by regulating VEGFA levels via binding to miRNAs. In this paper, we explored the origin and functional pathways of VEGFA, reviewed the current understanding of circRNA properties and action mechanisms, and summarized the role of circRNAs in regulating VEGFA during cancer pathogenesis.

The tumor microenvironment (TME) is a well-recognized system that plays an essential role in tumor initiation, development, and progression. Intense intercellular communication between tumor cells and other cells (especially macrophages) occurs in the TME and is mediated by cell-to-cell contact and/or soluble messengers. Emerging evidence indicates that noncoding RNAs (ncRNAs) are critical regulators of the relationship between cells within the TME. In this review, we provide an update on the regulation of ncRNAs (primarily micro RNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) in the crosstalk between macrophages and tumor cells in hepatocellular carcinoma (HCC). These ncRNAs are derived from macrophages or tumor cells and act as oncogenes or tumor suppressors, contributing to tumor progression not only by regulating the physiological and pathological processes of tumor cells but also by controlling macrophage infiltration, activation, polarization, and function. Herein, we also explore the options available for clinical therapeutic strategies targeting crosstalk-related ncRNAs to treat HCC. A better understanding of the relationship between macrophages and tumor cells mediated by ncRNAs will uncover new diagnostic biomarkers and pharmacological targets in cancer.

Abstract Background The aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS). Methods A total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell’s concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan–Meier curves and log-rank tests. Results The twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts. Conclusions In this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.

Abstract Background Chicken provides humans with a large amount of animal protein every year, in which skeletal muscle plays a leading role. The embryonic skeletal muscle development determines the number of muscle fibers and will affect the muscle production of chickens. CircRNAs are involved in a variety of important biological processes, including muscle development. However, studies on circRNAs in the chicken embryo muscle development are still lacking. Results In the study, we collected chicken leg muscles at 14 and 20-day embryo ages both in the fast- and slow-growing groups for RNA-seq. We identified 245 and 440 differentially expressed (DE) circRNAs in the comparison group F14vsF20 and S14vsS20 respectively. GO enrichment analysis for the host genes of DE circRNAs showed that biological process (BP) terms in the top 20 related to growth in F14vsF20 were found such as positive regulation of transcription involved in G1/S phase of mitotic cell cycle, multicellular organismal macromolecule metabolic process, and multicellular organismal metabolic process. In group S14vsS20, we also found some BP terms associated with growth in the top 20 including actomyosin structure organization, actin cytoskeleton organization and myofibril assembly. A total of 7 significantly enriched pathways were obtained, containing Adherens junction and Tight junction. Further analysis of those pathways found three crucial host genes MYH9, YBX3, IGF1R in both fast- and slow-growing groups, three important host genes CTNNA3, AFDN and CREBBP only in the fast-growing group, and six host genes FGFR2, ACTN2, COL1A2, CDC42, DOCK1 and MYL3 only in the slow-growing group. In addition, circRNA-miRNA network also revealed some key regulation pairs such as novel_circ_0007646-miR-1625-5p, novel_circ_0007646-miR-1680-5p, novel_circ_0008913-miR-148b-5p, novel_circ_0008906-miR-148b-5p and novel_circ_0001640-miR-1759-3p. Conclusions Comprehensive analysis of circRNAs and their targets would contribute to a better understanding of the molecular mechanisms in poultry skeletal muscle and it also plays an important guiding role in the next research.

To give consideration to both chip density and device performance, an In0.53Ga0.47As vertical electron–hole bilayer tunnel field effect transistor (EHBTFET) with a P+-pocket and an In0.52Al0.48As-block (VPB-EHBTFET) is introduced and systematically studied by TCAD simulation. The introduction of the P+-pocket can reduce the line tunneling distance, thereby enhancing the on-state current. This can also effectively address the challenge of forming a hole inversion layer in an undoped InGaAs channel during device fabrication. Moreover, the point tunneling can be significantly suppressed by the In0.52Al0.48As-block, resulting in a substantial decrease in the off-state current. By optimizing the width and doping concentration of the P+-pocket as well as the length and width of the In0.52Al0.48As-block, VPB-EHBTFET can obtain an off-state current of 1.83 × 10−19 A/μm, on-state current of 1.04 × 10−4 A/μm, and an average subthreshold swing of 5.5 mV/dec. Compared with traditional InGaAs vertical EHBTFET, the proposed VPB-EHBTFET has a three orders of magnitude decrease in the off-state current, about six times increase in the on-state current, 81.8% reduction in the average subthreshold swing, and stronger inhibitory ability on the drain-induced barrier-lowering effect (7.5 mV/V); these benefits enhance the practical application of EHBTFETs.

Malignant phyllodes tumor is a rare breast tumor, with distant metastases and heterologous differentiation in a few cases. We report a case of malignant phyllodes tumor with liposarcomatous differentiation in the primary tumor and osteosarcomatous differentiation in the lung metastatic tumor. A middle-aged female presented with a well-defined mass in the upper lobe of the right lung measuring 5.0 × 5.0 × 3.0 cm. The patient had a history of malignant phyllodes tumor in the breast. The patient underwent a right superior lobectomy. Histologically, the primary tumor was a typical malignant phyllodes tumor with pleomorphic liposarcomatous differentiation, while the lung metastasis showed osteosarcomatous differentiation without original biphasic features. The phyllodes tumor and heterologous components showed CD10 and p53 expression, and were negative for ER, PR, and CD34. Exome sequencing revealed TP53, TERT, EGFR, RARA, RB1, and GNAS mutations in all three components. Although the lung metastasis were morphologically different from the primary breast tumor, their common origin was demonstrated through immunohistochemical and molecular characterization. Cancer stem cells give rise to tumor heterogeneous cells, and heterologous components in malignant phyllodes tumors may indicate unfavorable prognosis and a greater risk of early recurrence and metastasis.

Research over the past two decades has confirmed that noncoding RNAs (ncRNAs), which are abundant in cells from yeast to vertebrates, are no longer “junk” transcripts but functional regulators that can mediate various cellular and physiological processes. The dysregulation of ncRNAs is closely related to the imbalance of cellular homeostasis and the occurrence and development of various diseases. In mammals, ncRNAs, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to serve as biomarkers and intervention targets in growth, development, immunity, and disease progression. The regulatory functions of lncRNAs on gene expression are usually mediated by crosstalk with miRNAs. The most predominant mode of lncRNA-miRNA crosstalk is the lncRNA-miRNA-mRNA axis, in which lncRNAs act as competing endogenous RNAs (ceRNAs). Compared to mammals, little attention has been given to the role and mechanism of the lncRNA-miRNA-mRNA axis in teleost species. In this review, we provide current knowledge about the teleost lncRNA-miRNA-mRNA axis, focusing on its physiological and pathological regulation in growth and development, reproduction, skeletal muscle, immunity to bacterial and viral infections, and other stress-related immune responses. Herein, we also explored the potential application of the lncRNA-miRNA-mRNA axis in the aquaculture industry. These findings contribute to an enhanced understanding of ncRNA and ncRNA-ncRNA crosstalk in fish biology to improve aquaculture productivity, fish health and quality.

Gastric cancer (GC) is a malignant cancer that reduces life expectancy worldwide. Although treatment strategies have improved, patients with GC still have poor prognoses. Hence, it is necessary to understand the molecular mechanisms of GC and to find new therapeutic targets. Mitochondrial dynamics and mitochondrial dysfunction are associated with cancer cell growth and progression. Numerous studies have reported that non-coding RNAs (ncRNAs) can participate in the occurrence and development of GC by regulating mitochondrial dynamics. Elucidating the crosstalk between ncRNAs and mitochondria would be helpful in preventing and treating GC. Herein, we review and summarize the functions of oncogenes and tumor suppressors in suppressing ncRNAs and regulating mitochondrial dynamics in GC tumor growth, proliferation, invasion and metastasis. This review provides new insights into the pathogenesis of and intervention for GC.

Myocardial injury is a major pathological factor that causes death in patients with heart diseases. In recent years, mesenchymal stromal cells (MSCs) have been generally used in treating many diseases in animal models and clinical trials. mesenchymal stromal cells have the ability to differentiate into osteocytes, adipocytes and chondrocytes. Thus, these cells are considered suitable for cardiac injury repair. However, mechanistic studies have shown that the secretomes of mesenchymal stromal cells, mainly small extracellular vesicles (sEVs), have better therapeutic effects than mesenchymal stromal cells themselves. In addition, small extracellular vesicles have easier quality control characteristics and better safety profiles. Therefore, mesenchymal stromal cell-small extracellular vesicles are emerging as novel therapeutic agents for damaged myocardial treatment. To date, many clinical trials and preclinical experimental results have demonstrated the beneficial effects of bone marrow-derived mesenchymal stromal cells (BMMSCs) and bone marrow-derived mesenchymal stromal cells-small extracellular vesicles on ischemic heart disease. However, the validation of therapeutic efficacy and the use of tissue engineering methods require an exacting scientific rigor and robustness. This review summarizes the current knowledge of bone marrow-derived mesenchymal stromal cells- or bone marrow-derived mesenchymal stromal cells-small extracellular vesicle-based therapy for cardiac injury and discusses critical scientific issues in the development of these therapeutic strategies.

Abstract Background The detection and identification of single nucleotide polymorphism (SNP) is essential for determining patient disease susceptibility and the delivery of medicines targeted to the individual. At present, SNP genotyping technology includes Sanger sequencing, TaqMan-probe quantitative polymerase chain reaction (qPCR), amplification-refractory mutation system (ARMS)-PCR, and Kompetitive Allele-Specific PCR (KASP). However, these technologies have some disadvantages: the high cost of development and detection, long and time consuming protocols, and high false positive rates. Focusing on these limitations, we proposed a new SNP detection method named universal probe-based intermediate primer-triggered qPCR (UPIP-qPCR). In this method, only two types of fluorescence-labeled probes were used for SNP genotyping, thus greatly reducing the cost of development and detection for SNP genotyping. Results In the amplification process of UPIP-qPCR, unlabeled intermediate primers with template-specific recognition functions could trigger probe hydrolysis and specific signal release. UPIP-qPCR can be used successfully and widely for SNP genotyping. The sensitivity of UPIP-qPCR in SNP genotyping was 0.01 ng, the call rate was more than 99.1%, and the accuracy was more than 99.9%. High-throughput DNA microarrays based on intermediate primers can be used for SNP genotyping. Conclusion This novel approach is both cost effective and highly accurate; it is a reliable SNP genotyping method that would serve the needs of the clinician in the provision of targeted medicine.

Abstract Vascularization is fundamental for large‐scale tissue engineering. Most of the current vascularization strategies including microfluidics and three‐dimensional (3D) printing aim to precisely fabricate microchannels for individual microvessels. However, few studies have examined the remodeling capacity of the microvessels in the engineered constructs, which is important for transplantation in vivo. Here we present a method for patterning microvessels in a directional ice‐templated scaffold of decellularized porcine kidney extracellular matrix. The aligned microchannels made by directional ice templating allowed for fast and efficient cell seeding. The pure decellularized matrix without any fixatives or cross‐linkers maximized the potential of tissue remodeling. Dramatical microvascular remodeling happened in the scaffold in 2 weeks, from small primary microvessel segments to long patterned microvessels. The majority of the microvessels were aligned in parallel and interconnected with each other to form a network. This method is compatible with other engineering techniques, such as microfluidics and 3D printing, and multiple cell types can be co‐cultured to make complex vascularized tissue and organ models.

In the last two decades, natural active substances have attracted great attention in developing new antitumor drugs, especially in the marine environment. A series of marine-derived compounds or derivatives with potential antitumor effects have been discovered and developed, but their mechanisms of action are not well understood. Emerging studies have found that several tumor-related signaling pathways and molecules are involved in the antitumor mechanisms of marine-derived agents, including noncoding RNAs (ncRNAs). In this review, we provide an update on the regulation of marine-derived agents associated with ncRNAs on tumor cell proliferation, apoptosis, cell cycle, invasion, migration, drug sensitivity and resistance. Herein, we also describe recent advances in marine food-derived ncRNAs as antitumor agents that modulate cross-species gene expression. A better understanding of the antitumor mechanisms of marine-derived agents mediated, regulated, or sourced by ncRNAs will provide new biomarkers or targets for potential antitumor drugs from preclinical discovery and development to clinical application.

Pyroptosis is a newly discovered form of programmed cell death, which is manifested by DNA fragmentation, cell swelling, cell membrane rupture and leakage of cell contents. Previous studies have demonstrated that pyroptosis is tightly associated with the initiation and development of various cancers, whereas the molecular mechanisms underlying pyroptosis remain obscure. Noncoding RNAs (ncRNAs) are a type of heterogeneous transcripts that are broadly expressed in mammalian cells. Owing to their potency of regulating gene expression, ncRNAs play essential roles in physiological and pathological processes. NcRNAs are increasingly acknowledged as important regulators of the pyroptosis process. Importantly, the crosstalk between ncRNAs and pyroptosis affects various hallmarks of cancer, including cell growth, survival, metastasis and therapeutic resistance. The study of the involvement of pyroptosis-associated ncRNAs in cancer pathobiology has become a hot area in recent years, while there are limited reviews on this topic. Herein, we provide an overview of the complicated roles of ncRNAs, mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in modulating pyroptosis, with a focus on the underlying mechanisms of the ncRNA-pyroptosis axis in cancer pathogenesis. Finally, we discuss the potential applications and challenges of exploiting pyroptosis-regulating ncRNAs as molecular biomarkers and therapeutic targets in cancer.

Cardiovascular disease (CVD) is one of the most important diseases endangering human life. The pathogenesis of CVDs is complex. Pyroptosis, which differs from traditional apoptosis and necrosis, is characterized by cell swelling until membrane rupture, resulting in the release of cell contents and activation of a strong inflammatory response. Recent studies have revealed that inflammation and pyroptosis play important roles in the progression of CVDs. Noncoding RNAs (ncRNAs) are considered promising biomarkers and potential therapeutic targets for the diagnosis and treatment of various diseases, including CVDs. Growing evidence has revealed that ncRNAs can mediate the transcriptional or posttranscriptional regulation of pyroptosis-related genes by participating in the pyroptosis regulatory network. The role and molecular mechanism of pyroptosis-regulating ncRNAs in cardiovascular pathologies are attracting increasing attention. Here, we summarize research progress on pyroptosis and the role of ncRNAs, particularly microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the regulation of pyroptosis in CVD pathologies. Identifying these disease-related ncRNAs is important for understanding the pathogenesis of CVDs and providing new targets and ideas for their prevention and treatment.

Pathological cardiac hypertrophy begins as an adaptive response to increased workload; however, sustained hemodynamic stress will lead it to maladaptation and eventually cardiac failure. Mitochondria, being the powerhouse of the cells, can regulate cardiac hypertrophy in both adaptive and maladaptive phases; they are dynamic organelles that can adjust their number, size, and shape through a process called mitochondrial dynamics. Recently, several studies indicate that promoting mitochondrial fusion along with preventing mitochondrial fission could improve cardiac function during cardiac hypertrophy and avert its progression toward heart failure. However, some studies also indicate that either hyperfusion or hypo-fission could induce apoptosis and cardiac dysfunction. In this review, we summarize the recent knowledge regarding the effects of mitochondrial dynamics on the development and progression of cardiac hypertrophy with particular emphasis on the regulatory role of mitochondrial dynamics proteins through the genetic, epigenetic, and post-translational mechanisms, followed by discussing the novel therapeutic strategies targeting mitochondrial dynamic pathways.

Doxorubicin (DOX)-induced cardiotoxicity has been one of the major limitations for its clinical use. Although extensive studies have been conducted to decipher the molecular mechanisms underlying DOX cardiotoxicity, no effective preventive or therapeutic measures have yet been identified. Microarray analysis showed that multiple long non-coding RNAs (lncRNAs) are differentially expressed between control- and DOX-treated cardiomyocytes. Functional enrichment analysis indicated that the differentially expressed genes are annotated to cardiac hypertrophic pathways. Among differentially expressed lncRNAs, cardiomyocyte mitochondrial dynamic-related lncRNA 1 (CMDL-1) is the most significantly downregulated lncRNA in cardiomyocytes after DOX exposure. The protein-RNA interaction analysis showed that CMDL-1 may target dynamin-related protein 1 (Drp1). Mechanistic analysis shows that lentiviral overexpression of CMDL-1 prevents DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. However, overexpression of CMDL-1 cannot effectively reduce mitochondrial fission when Drp1 is minimally expressed by small interfering RNA Drp1 (siDrp1). Overexpression of CMDL-1 promotes the association between CMDL-1 and Drp1, as well as with phosphorylated (p-)Drp1, as evidenced by RNA immunoprecipitation analysis. These data indicate the role of CMDL-1 in posttranslational modification of a target protein via regulating its phosphorylation. Collectively, our data indicate that CMDL-1 may play an anti-apoptotic role in DOX cardiotoxicity by regulating Drp1 S637 phosphorylation. Thus, CMDL-1 may serve as a potential therapeutic target in DOX cardiotoxicity.