Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction.

Mutations in the gene encoding polycystin-1 (PC1) are the most common cause of autosomal dominant polycystic kidney disease (ADPKD). Cysts in ADPKD exhibit a Warburg-like metabolism characterized by dysfunctional mitochondria and aerobic glycolysis. PC1 is an integral membrane protein with a large extracellular domain, a short C-terminal cytoplasmic tail and shares structural and functional similarities with G protein-coupled receptors. Its exact function remains unclear. The C-terminal cytoplasmic tail of PC1 undergoes proteolytic cleavage, generating soluble fragments that are overexpressed in ADPKD kidneys. The regulation, localization, and function of these fragments is poorly understood. Here, we show that a ∼30 kDa cleavage fragment (PC1-p30), comprising the entire C-terminal tail, undergoes rapid proteasomal degradation by a mechanism involving the von Hippel-Lindau tumor suppressor protein. PC1-p30 is stabilized by reactive oxygen species, and the subcellular localization is regulated by reactive oxygen species in a dose-dependent manner. We found that a second, ∼15 kDa fragment (PC1-p15), is generated by caspase cleavage at a conserved site (Asp-4195) on the PC1 C-terminal tail. PC1-p15 is not subject to degradation and constitutively localizes to the mitochondrial matrix. Both cleavage fragments induce mitochondrial fragmentation, and PC1-p15 expression causes impaired fatty acid oxidation and increased lactate production, indicative of a Warburg-like phenotype. Endogenous PC1 tail fragments accumulate in renal cyst-lining cells in a mouse model of PKD. Collectively, these results identify novel mechanisms regarding the regulation and function of PC1 and suggest that C-terminal PC1 fragments may be involved in the mitochondrial and metabolic abnormalities observed in ADPKD.

Cell-cell communication inference and analysis in the tumour microenvironments from single-cell transcriptomics: data resources and computational strategies.

Carcinomas are complex ecosystems composed of cancer, stromal and immune cells. Communication between these cells and their microenvironments induces cancer progression and causes therapy resistance. In order to improve the treatment of cancers, it is essential to quantify crosstalk between and within various cell types in a tumour microenvironment. Focusing on the coordinated expression patterns of ligands and cognate receptors, cell-cell communication can be inferred through ligand-receptor interactions (LRIs). In this manuscript, we carry out the following work: (i) introduce pipeline for ligand-receptor-mediated intercellular communication estimation from single-cell transcriptomics and list a few available LRI-related databases and visualization tools; (ii) demonstrate seven classical intercellular communication scoring strategies, highlight four types of representative intercellular communication inference methods, including network-based approaches, machine learning-based approaches, spatial information-based approaches and other approaches; (iii) summarize the evaluation and validation avenues for intercellular communication inference and analyze the advantages and limitations for the above four types of cell-cell communication methods; (iv) comment several major challenges while provide further research directions for intercellular communication analysis in the tumour microenvironments. We anticipate that this work helps to better understand intercellular crosstalk and to further develop powerful cell-cell communication estimation tools for tumor-targeted therapy.

Wide field-of-view laser-based white light transmitter for visible light communications.

The advancement demands of high-speed wireless data link ask for higher requirements on visible light communication (VLC), where wide coverage stands as a critical criterion. Here, we present the design and implementation of a transmitter structure capable of emitting a high-power wide-coverage white light laser. This laser source exhibits excellent stability, with an irradiation range extending to a half-angle of 20°. Its high brightness satisfies the needs of indoor illumination while maintaining excellent communication performance. Utilizing bit-loading discrete multi-tone modulation, a peak data transmission rate of 3.24 Gbps has been achieved, spanning 1 to 5 m. Remarkably, the data rates exceed 2.5 Gbps within a 40° range at a distance of 5 m, enabling a long-distance, wide coverage, high-speed VLC link for future mobile network applications.

Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

Multistatic Integrated Sensing and Communication System Based on Macro-Micro Cooperation.

A novel multistatic integrated sensing and communication (ISAC) system based on macro-micro cooperation for the sixth-generation (6G) mobile network is proposed. Instead of using macrosites at both the transmitter and receiver sides, microsites are considered as receivers in cooperative sensing. This system is important since microsites can be deployed more flexibly to reduce their distances to the sensing objects, providing better coverage for sensing service. In this work, we first analyze the deployment problem of microsites, which can be deployed along the radius and azimuth angle to cover macrosite cells. The coverage area of each microsite is derived in terms of its position in the cell. Then, we describe an efficient estimating approach for obtaining the position and velocity of sensing objects in the macrosite cell. By choosing multiple microsites around the targeted sensing area, joint data processing with an efficient optimization method is also provided. Simulation results show that the multistatic ISAC system employing macro-micro cooperation can improve the position and velocity estimation accuracy of objects compared to systems employing macrosite cooperation alone, demonstrating the effectiveness and potential for implementing the proposed system in the 6G mobile network.

Laser-Based Mobile Visible Light Communication System.

Mobile visible light communication (VLC) is key for integrating lighting and communication applications in the 6G era, yet there exists a notable gap in experimental research on mobile VLC. In this study, we introduce a mobile VLC system and investigate the impact of mobility speed on communication performance. Leveraging a laser-based light transmitter with a wide coverage, we enable a light fidelity (LiFi) system with a mobile receiving end. The system is capable of supporting distances from 1 m to 4 m without a lens and could maintain a transmission rate of 500 Mbps. The transmission is stable at distances of 1 m and 2 m, but an increase in distance and speed introduces interference to the system, leading to a rise in the Bit Error Rate (BER). The mobile VLC experimental system provides a viable solution to the issue of mobile access in the integration of lighting and communication applications, establishing a solid practical foundation for future research.

A Highly Active and Durable Hierarchical Electrocatalyst for Large-Current-Density Water Splitting.

Designing bifunctional catalysts with high current densities under industrial circumstances is crucial to propelling hydrogen energy with a boost from fundamental to practical application. In this work, heterojunction nanowire arrays consisting of manganese oxide and cobalt phosphide (denoted as MnO-CoP/NF) are designed to meet the industrial demand by regulating the synergic mass transport and electronic structure coupling with numerous nano-heterogeneous interfaces. The optimal MnO-CoP/NF electrode exhibits remarkable bifunctional electrocatalytic performance with overpotentials of 259.5 mV for hydrogen evolution at a large current density of 1000 mA cm-2 and 392.2 mV for oxygen evolution at 1500 mA cm-2. Moreover, the MnO-CoP/NF electrode demonstrates superior durability and an ultralow voltage of 1.76 V at 500 mA cm-2, outperforming that of a commercial RuO2||Pt/C electrode. This work sheds light on the design of metallic heterostructures with optimized interfacial electronic structures and a high abundance of active sites for practical industrial water splitting applications.

New COVID-19 challenges and response strategies adopted by a national suicide prevention hotline: A qualitative study.

Crisis helplines provide important support for vulnerable individuals during the COVID-19 pandemic, which may also impact the helplines. We explored the challenges that the pandemic brought to Taiwan's national suicide prevention hotline and the hotline's responses. We interviewed 14 hotline workers and conducted data analysis using the framework method. The pandemic posed two new challenges to the hotline: potential service interruption and the adjustment of perceived role among hotline workers. The hotline's well-formulated response plan helped it sustain its services during the pandemic, although the workers also experienced stress and frustration resulted from role ambiguity. Our data highlighted the hotline workers' need for accurate COVID-19 information, relevant training, and timely support.

The GLI2/CDH6 axis enhances migration, invasion and mitochondrial fission of stomach adenocarcinoma cells.

It has been reported that cadherin 6 (CDH6) upregulation is associated with enhanced epithelial-to-mesenchymal transition (EMT) in several types of solid tumor cells. The current study aimed to explore the effect of CDH6 on the migration and invasion of stomach adenocarcinoma (STAD) cells, the transcription factors involved in CDH6 dysregulation and their effect on mitochondrial fission. Bioinformatics analysis was performed using data extracted from the Genotype-Tissue Expression Project, the Cancer Genome Atlas and Kaplan-Meier plotter. AGS and HGC27 cells were used to establish an in vitro STAD cell model. The results showed that higher CDH6 expression was associated with significantly shorter overall survival in patients with STAD. In addition, CDH6 overexpression promoted wound healing, enhanced the invasion ability of tumor cells and increased mitochondrial fission. Glioma-associated oncogene family zinc finger 2 (GLI2) could bind to the CDH6 promoter and activate its transcription. Fluorescent labeling also showed that GLI2 overexpression promoted mitochondrial fission. However, CDH6 silencing significantly reduced mitochondrial fragmentation. Besides, GLI2 overexpression notably upregulated phosphorylated-focal adhesion kinase and dynamin-related protein 1. However, the above effects were largely abrogated by CDH6 knockdown. In conclusion, the present study suggested that the novel GLI2/CDH6 axis could enhance the migration, invasion and mitochondrial fission of STAD cells.

Probing antiviral drugs against SARS-CoV-2 through virus-drug association prediction based on the KATZ method.

It is urgent to find an effective antiviral drug against SARS-CoV-2. In this study, 96 virus-drug associations (VDAs) from 12 viruses including SARS-CoV-2 and similar viruses and 78 small molecules are selected. Complete genomic sequence similarity of viruses and chemical structure similarity of drugs are then computed. A KATZ-based VDA prediction method (VDA-KATZ) is developed to infer possible drugs associated with SARS-CoV-2. VDA-KATZ obtained the best AUCs of 0.8803 when the walking length is 2. The predicted top 3 antiviral drugs against SARS-CoV-2 are remdesivir, oseltamivir, and zanamivir. Molecular docking is conducted between the predicted top 10 drugs and the virus spike protein/human ACE2. The results showed that the above 3 chemical agents have higher molecular binding energies with ACE2. For the first time, we found that zidovudine may be effective clues of treatment of COVID-19. We hope that our predicted drugs could help to prevent the spreading of COVID.

Maternal immune activation-induced PPARγ-dependent dysfunction of microglia associated with neurogenic impairment and aberrant postnatal behaviors in offspring.

Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.

Hetero-difunctional Reagent with Superior Flotation Performance to Chalcopyrite and the Associated Surface Interaction Mechanism.

Surface modification by chemical reagents is of profound importance to modulate the surface characteristic and functionality of materials, which has attracted tremendous interest in many research fields and industrial applications, such as froth flotation of minerals. In this work, a new reagent S-[(2-hydroxyamino)-2-oxoethyl]- O-octyl-dithiocarbonate ester (HAOODE) with heterodifunctional ligands was designed and synthesized to improve the flotability of chalcopyrite (CuFeS2). Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy results showed the co-adsorption of heterodifunctional ligands (i.e., dithiocarbonate and hydroxamate groups) of HAOODE on chalcopyrite via Cu(I)-S and Cu(II)-O covalent bonds. The bubble probe atomic force microscopy (AFM) technique was employed to quantitatively measure the air bubble-chalcopyrite interactions with and without the reagent adsorption. AFM force results revealed that the bubble could be more readily attached to flat chalcopyrite after HAOODE treatment under different hydrodynamic conditions because of the enhanced hydrophobic interaction, with the decay length D0 increasing from 0.65 to 1.20 nm. The calculated bubble-particle interaction forces also demonstrated the critical influence of HAOODE treatment, hydrodynamic conditions, and bubble size on the interaction behavior and thin-film drainage process in flotation. In froth flotation, HAOODE exhibited superior recovery for chalcopyrite over pH 3-12 and excellent selectivity for chalcopyrite against pyrite (FeS2) above pH 10.5, as compared to the conventional reagent sodium isobutyl xanthate. This work provides a useful approach to develop effective reagents that could selectively adsorb on desired mineral surfaces through heterodifunctional ligands and to quantitatively evaluate the role of reagent adsorption in the interactions between air bubbles and mineral surfaces at the nano- and microscale. Our results show implications on developing molecular design principles of novel reagents for surface modifications of materials in a wide range of engineering and biological applications.

A Practical Data-Gathering Algorithm for Lossy Wireless Sensor Networks Employing Distributed Data Storage and Compressive Sensing.

Reliability and energy efficiency are two key considerations when designing a compressive sensing (CS)-based data-gathering scheme. Most researchers assume there is no packets loss, thus, they focus only on reducing the energy consumption in wireless sensor networks (WSNs) while setting reliability concerns aside. To balance the performance⁻energy trade-off in lossy WSNs, a distributed data storage (DDS) and gathering scheme based on CS (CS-DDSG) is introduced, which combines CS and DDS. CS-DDSG utilizes broadcast properties to resist the impact of packet loss rates. Neighboring nodes receive packets with process constraints imposed to decrease the volume of both transmissions and receptions. The mobile sink randomly queries nodes and constructs a measurement matrix based on received data with the purpose of avoiding measuring the lossy nodes. Additionally, we demonstrate how this measurement matrix satisfies the restricted isometry property. To analyze the efficiency of the proposed scheme, an expression that reflects the total number of transmissions and receptions is formulated via random geometric graph theory. Simulation results indicate that our scheme achieves high precision for unreliable links and reduces the number of transmissions, receptions and fusions. Thus, our proposed CS-DDSG approach effectively balances energy consumption and reconstruction accuracy.

Generative Adversarial Networks-Based Semi-Supervised Automatic Modulation Recognition for Cognitive Radio Networks.

With the recently explosive growth of deep learning, automatic modulation recognition has undergone rapid development. Most of the newly proposed methods are dependent on large numbers of labeled samples. We are committed to using fewer labeled samples to perform automatic modulation recognition in the cognitive radio domain. Here, a semi-supervised learning method based on adversarial training is proposed which is called signal classifier generative adversarial network. Most of the prior methods based on this technology involve computer vision applications. However, we improve the existing network structure of a generative adversarial network by adding the encoder network and a signal spatial transform module, allowing our framework to address radio signal processing tasks more efficiently. These two technical improvements effectively avoid nonconvergence and mode collapse problems caused by the complexity of the radio signals. The results of simulations show that compared with well-known deep learning methods, our method improves the classification accuracy on a synthetic radio frequency dataset by 0.1% to 12%. In addition, we verify the advantages of our method in a semi-supervised scenario and obtain a significant increase in accuracy compared with traditional semi-supervised learning methods.

Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer.

BACKGROUND/AIMS: Human leukocyte antigen-G (HLA-G) plays an important role in inhibiting natural killer (NK) cell function and promoting immune escape. However, the specific mechanism of HLA-G on NK in gastric cancer (GC) remains not well understood. This study investigated the expression of HLA-G in GC and the role of HLA-G-effected NK cells in GC progression. METHODS: HLA-G expression in GC tissues obtained from 49 patients with GC was analyzed by immunohistochemistry and western blot. The number of tumor-infiltrating NK cells and the expression of their surface receptors were analyzed by immunohistochemistry and flow cytometry, respectively. The effect of HLA-G on NK cell proliferation was examined by Cell Counting Kit-8 (CCK8) assay. LDH release assay was used to evaluate the effect of HLA-G on the cytotoxic activity of NK cells, and the levels of IFN-γ and TNF-α in the co-cultured supernatant were detected by ELISA. Mice bearing a xenograft tumor model were used to examine the effect of HLA-G on the anti-tumor effect of NK cells. RESULTS: HLA-G positive expression was detected in most of the GC tissues, and was correlated with the adverse prognosis of the disease. The expression of HLA-G was negatively associated with the number of tumor-infiltrating NK cells. Furthermore, GC cell lines with overexpressed HLA-G revealed their ability to inhibit the cell proliferation and cytotoxic activity of NK-92MI cells, and reduce the secretion of IFN-γ and TNF-α through immunoglobulin-like transcript 2 (ILT2). Finally, this in vivo experiment was able to prove that HLA-G can inhibit the anti-tumor effect of NK cells through ILT2. CONCLUSION: The expression of HLA-G was strongly correlated with the adverse prognosis of GC. The reason may be that it inhibits the proliferation and cytotoxic activity of infiltrating NK cells through ILT2.

miR-155 Deficiency Ameliorates Autoimmune Inflammation of Systemic Lupus Erythematosus by Targeting S1pr1 in Faslpr/lpr Mice.

MicroRNA-155 (miR-155) was previously found involved in the development of systemic lupus erythematosus (SLE) and other autoimmune diseases and the inflammatory response; however, the detailed mechanism of miR-155 in SLE is not fully understood. To explore the in vivo role of miR-155 in the pathogenesis of SLE, miR-155-deficient Fas(lpr/lpr) (miR-155(-/-)Fas(lpr/lpr)) mice were obtained by crossing miR-155(-/-) and Fas(lpr/lpr) mice. Clinical SLE features such as glomerulonephritis, autoantibody levels, and immune system cell populations were compared between miR-155(-/-)Fas(lpr/lpr) and Fas(lpr/lpr) mice. Microarray analysis, RT-PCR, Western blot, and luciferase reporter gene assay were used to identify the target gene of miR-155. miR-155(-/-)Fas(lpr/lpr) mice showed milder SLE clinical features than did Fas(lpr/lpr)mice. As compared with Fas(lpr/lpr) mice, miR-155(-/-)Fas(lpr/lpr) mice showed less deposition of total IgA, IgM, and IgG and less infiltration of inflammatory cells in the kidney. Moreover, the serum levels of IL-4 and IL-17a, secreted by Th2 and Th17 cells, were lower in miR-155(-/-)Fas(lpr/lpr) than Fas(lpr/lpr) mice; the CD4(+)/CD8(+) T cell ratio was restored in miR-155(-/-)Fas(lpr/lpr) mice as well. Sphingosine-1-phosphate receptor 1 (S1PR1) was found as a new target gene of miR-155 by in vitro and in vivo studies; its expression was decreased in SLE patients and Fas(lpr/lpr) mice. miR-155(-/-)Fas(lpr/lpr) mice are resistant to the development of SLE by the regulation of the target gene S1pr1. miR-155 might be a new target for therapeutic intervention in SLE.

Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy.

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-ß (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.

Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study.

BACKGROUND: Acute rejection (AR) and acute tubular necrosis (ATN) are main causes of early renal allograft dysfunction. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) and Diffusion weighted (DW) MRI can provide valuable information about changes of oxygen bioavailability and water diffusion by measuring R2* or apparent diffusion coefficient (ADC) respectively. We aimed to determine the value of BOLD MRI and DW MRI in detecting causes for early allograft dysfunction in renal allograft recipients. METHODS: Fifty patients received renal allografts from deceased donors were analyzed, including 35 patients with normal renal function (control group), 10 AR patients and 5 ATN patients. Cortical R2* (CR2*) and medullary R2* (MR2*) were measured by BOLD MRI. Ten diffusion gradient b values (0, 5, 10, 20, 50, 100, 200, 400, 800, 1200s/mm2) were used in DW MRI. ADC values were measured in renal cortex (CADC) and medulla (MADC). CADCl and MADCl were measured under low b values (b ≤ 200 s/mm2), while CADCh and MADCh were measured under high b values (b > 200 s/mm2). RESULTS: MR2* was significantly lower in AR group (18.2 ± 1.5/s) than control group (23.8 ± 5.0/s, p = 0.001) and ATN group (25.8 ± 5.0/s, p = 0.004). There was a tendency of lower levels on CADCl, MADCl, CADCh or MADCh in AR group than in control group. There were no differences on ADC values between AR group and ATN group. CONCLUSIONS: BOLD MRI was a valuable method in detection of renal allografts with acute rejection.

TRIP13 Activates Glycolysis to Promote Cell Stemness and Strengthen Doxorubicin Resistance of Colorectal Cancer Cells.

BACKGROUND: Chemotherapy resistance is one of the main causes of clinical chemotherapy failure. Current cancer research explores the drug resistance mechanism and new therapeutic targets. This work aims to elucidate the mechanism of thyroid hormone receptor interactor 13 (TRIP13) affecting doxorubicin (DOX) resistance in colorectal cancer (CRC). METHODS: Bioinformatics analyses were employed to clarify TRIP13 expression in CRC tissues and predict the correlation of the TRIP13 enrichment pathway with glycolysis-related genes and stemness index mRNAsi. Quantitative real-time polymerase chain reaction and western blot were adopted to analyze the expression of TRIP13 and glycolysis- related genes. Cell Counting Kit-8 was utilized to determine the cell viability and IC50 value. Western blot was employed to measure the expression of stemness-related factors. Cell function assays were performed to detect cells' sphere-forming ability and glycolysis level. Animal models were constructed to determine the effects of TRIP13 expression on CRC tumor growth. RESULTS: TRIP13 was significantly overexpressed in CRC, concentrated in the glycolysis signaling pathway, and positively correlated with stemness index mRNAsi. High expression of TRIP13 facilitated DOX resistance in CRC. Further mechanistic studies revealed that overexpression of TRIP13 could promote cell stemness through glycolysis, which was also confirmed in animal experiments. CONCLUSION: TRIP13 was highly expressed in CRC, which enhanced the DOX resistance of CRC cells by activating glycolysis to promote cell stemness. These findings offer new insights into the pathogenesis of DOX resistance in CRC and suggest that TRIP13 may be a new target for reversing DOX resistance in CRC.

Double domain fusion improves the reverse transcriptase activity and inhibitor tolerance of Bst DNA polymerase.

To enhance the DNA/RNA amplification efficiency and inhibitor tolerance of Bst DNA polymerase, four chimeric Bst DNA polymerase by fusing with a DNA-binding protein Sto7d and/or a highly hydrophobic protein Hp47 to Bst DNA polymerase large fragment. One of chimeric protein HpStBL exhibited highest inhibitor tolerance, which retained high active under 0.1 U/µL sodium heparin, 0.8 ng/µL humic acid, 2.5× SYBR Green I, 8 % (v/v) whole blood, 20 % (v/v) tissue, and 2.5 % (v/v) stool. Meanwhile, HpStBL showed highest sensitivity (93.75 %) to crude whole blood infected with the African swine fever virus. Moreover, HpStBL showed excellent reverse transcriptase activity in reverse transcription loop-mediated isothermal amplification, which could successfully detect 0.5 pg/µL severe acute respiratory syndrome coronavirus 2 RNA in the presence of 1 % (v/v) stools. The fusion of two domains with different functions to Bst DNA polymerase would be an effective strategy to improve Bst DNA polymerase performance in direct loop-mediated isothermal amplification and reverse transcription loop-mediated isothermal amplification detection, and HpStBL would be a promising DNA polymerase for direct African swine fever virus/severe acute respiratory syndrome coronavirus 2 detection due to simultaneously increased inhibitor tolerance and reverse transcriptase activity.