LAMP2A regulates cisplatin resistance in colorectal cancer through mediating autophagy.

BACKGROUND: Drug resistance is an important constraint on clinical outcomes in advanced cancers. LAMP2A is a limiting protein in molecular chaperone-mediated autophagy. This study was aimed to explore LAMP2A function in cisplatin (cis-diamminedichloroplatinum, DDP) resistance colorectal cancer (CRC) to seek new ideas for CRC clinical treatment. METHODS: In this study, LAMP2A expression was analyzed by molecular experimental techniques,such as qRT-PCR and western blot. Then, LAMP2A in cells was interfered by cell transfection experiments. Subsequently, the function of LAMP2A on proliferation, migration, invasion, DDP sensitivity, and autophagy of CRC/DDP cells were further investigated by a series of experiments, such as CCK-8, transwell, and western blot. RESULTS: We revealed that LAMP2A was clearly augmented in DDP-resistant CRC and was related to poor patient prognosis. Functionally, LAMP2A insertion remarkably CRC/DDP proliferation, migration, invasion ability and DDP resistance by strengthen autophagy. In contrast, LAMP2A knockdown limited the proliferation, migration, and invasion while heightened cellular sensitivity to DDP by restraining autophagy in CRC/DDP cells. Furthermore, LAMP2A silencing was able to curb tumor formation and enhance sensitivity to DDP in vivo. CONCLUSION: In summary, LAMP2A boosted malignant progression and DDP resistance in CRC/DDP cells through mediating autophagy. Clarifying LAMP2A function in DDP resistance is promising to seek cancer therapies biomarkers targeting LAMP2A activity.

Enhanced bone regeneration by osteoinductive and angiogenic zein/whitlockite composite scaffolds loaded with levofloxacin.

Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method. Then, as a model antibiotic drug, the LEVO was loaded into zein/WH scaffolds. Moreover, the addition of WH enhanced the adhesion, differentiation, and mineralization of osteoblasts. The zein/WH/LEVO composite scaffolds not only had significant osteoinductivity but also showed excellent antibacterial properties. The prepared composite scaffolds were then implanted into a calvarial defect model to evaluate their osteogenic induction effects in vivo. Micro-CT observation and histological analysis indicate that the scaffolds can accelerate bone regeneration with the contribution of endogenous cytokines. Based on amounts of data in vitro and in vivo, the scaffolds present profound effects on improving bone regeneration, especially for the favorable osteogenic, intensive angiogenic, and alleviated inflammation abilities. The results showed that the synthesized scaffolds could be a potential material for bone tissue engineering.

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage.

BACKGROUND: Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown. METHODS: With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome. RESULTS: The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-ß which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome. CONCLUSIONS: UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.

SadNet: a novel multimodal fusion network for protein-ligand binding affinity prediction.

Protein-ligand binding affinity prediction plays an important role in the field of drug discovery. Existing deep learning-based approaches have significantly improved the efficiency of protein-ligand binding affinity prediction through their excellent inductive bias capability. However, these methods only focus on fragmented three-dimensional data, which truncates the integrity of pocket data, leading to the neglect of potential long-range interactions. In this paper, we propose a dual-stream framework, with amino acid sequence assisting the atomic data fusion for graph neural network (termed SadNet), to fuse both 3D atomic data and sequence data for more accurate prediction results. In detail, SadNet consists of a pocket module and a sequence module. The sequence module expands the "receptive field" of the pocket module through a mid-term virtual node fusion. To better integrate sequence-level information from the sequence module and 3D structural information from the pocket module, we incorporate structural information for each amino acid within the sequence module. Besides, to better understand the intrinsic relationship between sequences and 3D atomic information, our SadNet utilizes information stacking from both the early stage and later stage. Experimental results on publicly available benchmark datasets demonstrate the superiority of the proposed dual-stream approach over the state-of-the-art alternatives. The code of this work is available online at https://github.com/wardhong/SadNet.

Characterization of rotary valve control vibration system for vibration stress relief applications.

To enhance the vibration system characteristic distortion and pressure loss, we propose a novel rotary valve control vibration system. The paper presents the designed structural composition and generation mechanism of the rotary valve control vibration system. It also derives the mathematical model for the rotary valve distribution process and the overall system. The flow field inside the rotary valve is dynamically simulated using the multiple reference frame model, allowing for the determination of the change rule of the rotary valve's output characteristics. An AMESim model was developed to analyze the vibration characteristics of the rotary valve control system. The effects of parameters such as inlet pressure, motor speed, and oil supply pump displacement were investigated. A rotary valve control vibration system experimental bench was constructed to experimentally verify the output characteristics of the rotary valve and the vibration characteristics of the system. The results indicate that the characteristic curve of the designed vibration system closely resembles a sinusoidal wave. Additionally, the rotary valve exhibits low pressure loss, making it more suitable for vibration stress relief applications. By appropriately increasing the inlet pressure and decreasing the motor speed, the vibration characteristics of the system can be improved.

Harnessing HetHydrogel: A Universal Platform to Dropletize Single-Cell Multiomics.

A universal platform is developed for dropletizing single cell plate-based multiomic assays, consisting of three main pillars: a miniaturized open Heterogeneous Hydrogel reactor (abbreviated HetHydrogel) for multi-step biochemistry, its tunable permeability that allows Tn5 tagmentation, and single cell droplet barcoding. Through optimizing the HetHydrogel manufacturing procedure, the chemical composition, and cell permeation conditions, simultaneous high-throughput mitochondrial DNA genotyping and chromatin profiling at the single-cell level are demonstrated using a mixed-species experiment. This platform offers a powerful way to investigate the genotype-phenotype relationships of various mtDNA mutations in biological processes. The HetHydrogel platform is believed to have the potential to democratize droplet technologies, upgrading a whole range of plate-based single cell assays to high throughput format.

TREM1 facilitates the development of gastric cancer through regulating neutrophil extracellular traps-mediated macrophage polarization.

Triggering receptor expressed on myeloid cell 1 (TREM1) elevation is associated with the unfavorable prognosis of gastric cancer (GC) patients. This work uncovered the effects and mechanism of TREM1 in GC. IHC staining examined TREM1 expression in GC tissues. TREM1-knockout and TREM1 knock-in mice were generated prior to the construction of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GC mice model. H&E staining detected the pathological alternations of gastric tissues. IHC staining tested Ki67 expression. Wright-Giemsa staining performed neutrophil counting and flow cytometry analysis measured neutrophil infiltration. ELISA analyzed serum and tissue myeloperoxidase (MPO) levels and serum MPO-DNA levels. Immunofluorescence, Western blotting and related kits detected NETs formation. Immunofluorescence and IHC staining evaluated macrophage polarization. In MNNG-treated GES-1 cells and phorbal myristate acetate (PMA)-treated neutrophils, TREM1 expression was also examined. CCK-8 method and Western blotting assayed cell proliferation. Western blotting and immunofluorescence detected NETs formation. Flow cytometry analysis detected the changes of macrophage typing. TREM1 was overexpressed in tumor tissues, MNNG-treated GES-1 cells and PMA-treated neutrophils. TREM1 deficiency hindered tumor growth, reduced neutrophil infiltration, NETs formation and stimulated M1 macrophage polarization in MNNG-induced GC models. Neutrophil extracellular traps (NETs) degrader DNase-1 countervailed the impacts of TREM1 on MNNG-induced GC models in vivo. Collectively, TREM1 knockdown obstructed NETs-mediated M2 macrophage polarization to hamper GC progression.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.

Molecular identification of Bambusa changningensis is the natural bamboo hybrid of B. rigida × Dendrocalamus farinosus.

Bamboo is one of the fastest-growing plants commonly used in food, fibre, paper, biofuel, ornamental and medicinal industries. Natural hybridization in bamboo is rare due to its long vegetative period followed by gregarious flowering and death of the entire population. In the current study, a new bamboo species, Bambusa changningensis, shows intermediate characteristics of Dendrocalamus farinosus and B. rigida morphologically, but it is unknown whether B. changningensis is a natural hybrid. Moreover, B. changningensis has been identified as a superior variety of Sichuan Province with high pulping yield, fibre length and width. Therefore, we analyzed the morphological characteristics, DNA markers, DNA barcoding and chloroplast genomes to identify the hybrid origin of B. changningensis and possible maternal parent. We have developed the transcriptomic data for B. changningensis and mined the SSR loci. The putative parental lines and hybrid were screened for 64 SSR makers and identified that SSR14, SSR28, SSR31 and SSR34 markers showed both alleles of the parental species in B. changningensis, proving heterozygosity. Sequencing nuclear gene GBSSI partial regions and phylogenetic analysis also confirm the hybrid nature of B. changningensis. Further, we have generated the complete chloroplast genome sequence (139505 bp) of B. changningensis. By analyzing the cp genomes of both parents and B. changningensis, we identified that B. rigida might be the female parent. In conclusion, our study identified that B. changningensis is a natural hybrid, providing evidence for bamboo's natural hybridization. This is the first report on confirming a natural bamboo hybrid and its parents through SSR and chloroplast genome sequence.

YTHDF3as a prognostic predictive biomarker of thyroid cancer and its correlation with immune infiltration.

PURPOSE: Thyroid cancer (TC) is one of the most common endocrine malignancies, and its morbidity continues to rise. N6-methyladenosine (m6A) RNA methylation, an epigenetic modification, is an important regulator of gene expression in TC. Therefore, it's worth finding the characteristics and predictive value of the m6A RNA methylation regulators in thyroid cancer (TC). METHOD: RNA-seq data of TC was downloaded from the Cancer Genome Atlas (TCGA) database to screen out the differential expressed regulators. The absolute contraction selection operator (Lasso) Cox regression was used to construct the risk model of m6A methylation regulators. The predictive value of the risk scoring model was evaluated by Kaplan Meier (K-M) analysis and receiver operating characteristic (ROC) curves. The underlying mechanism of m6A methylation regulators in TC was predicted by gene set enrichment analysis (GSEA). Further validation was performed by using immunohistochemistry (IHC) and q-PCR. The correlation between risk-related gene and immune infiltration was evaluated by Tumour Immune Estimation Resource (TIMER). RESULTS: IGF2BP2, YTHDF1 and YTHDF3 were screened out as strong independent prognostic factors of TC. Then a risk score model was established to further screen the predictors. Finally, according to the results of overall survival (OS) and clinical characteristics of TC, YTHDF3 was screened out as a potential predictor. Meanwhile, IHC and qPCR confirmed that YTHDF3 was expressed differential in TC. The expression of YTHDF3 was positively associated with the infiltration level of CD4+ T cells and macrophages. It was strongly correlated with a variety of immune markers in TC. CONCLUSION: We confirmed that YTHDF3 can be used as a potential prognostic biomarker of TC. It not only plays a decisive role in the initiation and development of TC, but also provides a new perspective for understanding the modification of m6A RNA in TC.

A fluorescent probe based on modulation of ESIPT signaling for the highly selective detection of N2H4 and cell-imaging.

The broad occurrence of the hydrazine (N2H4) residues in aqueousenvironment is a potential threat to human health. Currently, the mainstream strategy for designing N2H4-specific probes is to functionalize a fluorophore with nucleophilic sites for the reductionreaction with N2H4. In this work, we designed and synthesized an excited-state intermolecular proton transfer (inter-ESPT) fluorescent dye(2-amino-4-(4-methoxyphenyl)-7,8-dihydro-5H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-carbonitrilem, DQN) and used it as a probe to sense N2H4. DQN exhibits blue fluorescence in conventional solvents, which is assigned to its normal emission. In the presence of N2H4, the probe DQN can anchor the N2H4 molecule via hydrogen binding, enabling DQN to undergo inter-ESPT process and light up its tautomeric fluorescence. From this basis, an inter-ESPT-based method for N2H4 detection was established, offering high selectivity and sensitivity (11.5 nM). Furthermore, we demonstrated that the probe DQN can recognize the proteins in living cells, affording cell-imaging. This research provides a promising sensing strategy for monitoring N2H4 in water environments and this inter-ESPT dye is a powerful tool for cell-imaging.

A polystyrene-based ESIPT fluorescent polymeric probe for highly sensitive detection of chromium(vi) ions and protein staining.

A "two-step" preparation method of an excited-state intermolecular proton transfer (ESIPT) fluorescent polymer (f-PP) is reported here. The synthesis of f-PP involves the acetylation of polystyrene and a "multicomponent one pot" reaction. The as-prepared polymer bears a group of ESIPT fluorescent units, enabling it to exhibit high brightness, moderate solubility and ESIPT fluorescence. F-PP gives off tautomeric bright green fluorescence under UV-tamp and the dual-emission could be specifically suppressed by Cr(vi). This phenomenon cannot be elicited by other competing species. On this basis, an ESIPT polymeric probe-based method for the determination of Cr(vi) was developed, offering high sensitivity (19.5 nM) and selectivity. The f-PP was successfully used to detect Cr(vi) in real water samples by standard adding methods, indicating its application feasibility.

Proteomics screening uncovers HMGA1 as a promising negative regulator for γ-globin expression in response to decreased ß-globin levels.

Reactivation of fetal hemoglobin (HbF) is a critical goal for the treatment of patients with hemoglobinopathies. ß-globin disorders can trigger stress erythropoiesis in red blood cells (RBCs). Cell-intrinsic erythroid stress signals promote erythroid precursors to express high levels of fetal hemoglobin, which is also known as γ-globin. However, the molecular mechanism underlying γ-globin production during cell-intrinsic erythroid stress remains to be elucidated. Here, we utilized CRISPR-Cas9 to model a stressed state caused by reduced levels of adult ß-globin in HUDEP2 human erythroid progenitor cells. We found that a decrease in ß-globin expression correlates with the upregulation of γ-globin expression. We also identified transcription factor high-mobility group A1 (HMGA1; formerly HMG-I/Y) as a potential γ-globin regulator that responds to reduced ß-globin levels. Upon erythroid stress, there is a downregulation of HMGA1, which normally binds -626 to -610 base pairs upstream from the STAT3 promoter, to downregulate STAT3 expression. STAT3 is a known γ-globin repressor, so the downregulation of HMGA1 ultimately upregulates γ-globin expression. SIGNIFICANCE: This study demonstrated HMGA1 as a potential regulator in the poorly understood phenomenon of stress-induced globin compensation, and after further validation these results might inform new strategies to treat patients with sickle cell disease and ß-thalassemia.

Multi-walled carbon nanotubes reversing the bone formation of bone marrow stromal cells by activating M2 macrophage polarization.

Multi-walled carbon nanotubes (MWCNTs) are an excellent bone tissue repair material both in vitro and in vivo. The interactions between MWCNTs and single type of cells of bone tissue, including osteoblasts, bone marrow stromal cells (BMSCs) or osteoclasts, have been extensively studied. However, the interactions between MWCNTs with different types of cells in the bone microenvironment remain elusive. Bone microenvironment is a complex system composed of different types of cells, which have interactions between each other. In this work, the effects of MWCNTs on bone microenvironment were firstly studied by culture of MWCNTs with BMSCs, osteoblasts, osteoclasts, macrophages and vascular endothelial cells, respectively. Then, co-culture systems of macrophages-BMSCs, macrophages-calvaria and macrophages-BMSCs-vascular endothelial cells were treated with MWCNTs, respectively. The osteogenic differentiation of BMSCs and osteoblasts was inhibited when these two types of cells were cultured with MWCNTs, respectively. Strikingly, when co-culture MWCNTs with BMSCs and macrophages, the osteogenesis of BMSCs was promoted by inducing the M2 polymerization of macrophages. Meanwhile, MWCNTs promoted the bone formation in the osteolysis model of calvaria ex vivo. In addition, the formation of osteoclasts was inhibited, and angiogenesis was increased when treated with MWCNTs. This study revealed the inconsistent effects of MWCNTs on single type of bone cells and on the bone microenvironment. The results provided basic research data for the application of MWCNTs in bone tissue repair.

Tooth-Implant digital guide improves implantation accuracy in patients with periodontitis.

OBJECTIVE: To investigate the accuracy of Tooth-Implant digital guide-assisted implantation, explore the influence of periodontitis on the accuracy of the digital guide, and evaluate the effect of the residual abutment looseness after periodontitis treatment on the implant accuracy of the digital guide. METHODS: In this retrospective clinical study, 45 patients who received dental implantation at the Department of Periodontology, Beijing Stomatological Hospital affiliated with Capital Medical University, were selected and grouped. Group A consisted of non-periodontitis patients (n=15) who underwent Tooth-Implant digital guide-assisted implantation surgery. Group B was composed of periodontitis patients (n=15) who received Tooth-Implant digital guide-assisted implantation surgery. Group C included periodontitis patients (n=15) with freehand implantation. Three dental landmarks were identified to compare the planned implant position generated by the Tooth-Implant digital guide before implantation and the actual implant position in the same patient. Differences in implant depth, angle, shoulder and apex were analyzed before and after the implantation. RESULTS: There were statistical differences in implant depth, angle, shoulder, and apex between group B and group C. While statistical significance was found only in the implant angle and depth between group A and group B, not in the implant shoulder or apex. In periodontitis patients treated by Tooth-Implant digital guide-assisted implantation, significant differences were identified in implant depth and shoulder between non-abutment looseness and abutment looseness subgroups, but not in implant angle and apex. Under the digital guide-assisted implantation, no significant differences were found in implant depth, angle, shoulder and apex at different jaw positions, but at different tooth positions, significant differences were identified in implant angle and apex, not in implant depth and shoulder. The accuracy of Tooth-Implant digital guide-assisted implantation was consistent with previous data. CONCLUSIONS: The Tooth-Implant digital guide-assisted implantation has reliable implant accuracy that outperforms freehand implantation. Periodontitis is a factor affecting the accuracy of digital guide in dental implant placement, and this could be due to the looseness of residual abutments after systematic periodontal treatment. Different jaw positions have no impact on the accuracy of digital guide-assisted implantation, but different tooth positions have an impact on the accuracy of implant placement using a digital guide.

Laparoscopic-Assisted Colorectal Resection Can Reduce the Inhibition of Immune Function Compared with Conventional Open Surgery: A Retrospective Clinical Study.

BACKGROUND: Immune function is an important indicator for assessing postoperative recovery and long-term survival in patients with malignancy, and laparoscopic surgery is thought to have a less suppressive effect on the immune response than open surgery. This study aimed to investigate this effect in a retrospective clinical study. METHODS: In this retrospective clinical study, we enrolled 63 patients with colorectal cancer in the Department of General Surgery of the First Affiliated Hospital of Soochow University and assessed the changes in their postoperative immune function by measuring CD3+T, CD4+T, CD8+T lymphocytes, and CD4+/CD8+ ratio. RESULTS: Compared with open surgery, laparoscopic colorectal surgery was effective in improving the postoperative decline in immune function. We determined that the number of CD4+, CD8+T lymphocytes, and the CD4+/CD8+ ratio was not significantly reduced in the laparoscopic group. CONCLUSION: Laparoscopic-assisted colorectal resection can reduce the inhibition of immune functions compared with conventional open surgery.

RFC5, regulated by circ_0038985/miR-3614-5p, functions as an oncogene in the progression of colorectal cancer.

Replication factor C 5 (RFC5) is involved in a variety of biological functions of cancer. However, the expression pattern of RFC5 and the underlying mechanisms in colorectal cancer (CRC) remain elusive. Here, we show that RFC5 is significantly upregulated in CRC tissues and cells. Patients with CRC and increased RFC5 levels have an unfavorable prognosis. RFC5 can promote the proliferation, migration, and invasion of CRC cells and inhibit the apoptosis of CRC cells. Additionally, upstream of RFC5, we constructed the competing endogenous RNA network and confirmed that RFC5 in this network was inhibited by miR-3614-5p by directly targeting its 3'-untranslated regions. We verified that circ_0038985, which is positively correlated with RFC5, directly targeted miR-3614-5p. Overexpression of circ_0038985 promoted CRC cell migration and invasion, and these effects were partially reversed by the reintroduction of miR-3614-5p. Moreover, we found that RFC5 may promote the vascular endothelial growth factor A (VEGFa)/vascular endothelial growth factor receptor 2 (VEGFR2)/extracellular signal-regulated protein kinase (ERK) pathway. The knockdown of RFC5 reduced CRC tumorigenesis in vivo. Collectively, these data demonstrate that the circ_0038985/miR-3614-5p/RFC5 axis plays a critical role in the progression of CRC, and RFC5 may promote CRC progression by affecting the VEGFa/VEGFR2/ERK pathway.

3D Printed Nitrogen-Doped Thick Carbon Architectures for Supercapacitor: Ink Rheology and Electrochemical Performance.

The 3D printing technique offers huge opportunities for customized thick-electrode designs with high loading densities to enhance the area capacity in a limited space. However, key challenges remain in formulating 3D printable inks with exceptional rheological performance and facilitating electronic/ion transport in thick bulk electrodes. Herein, a hybrid ink consisting of woody-derived cellulose nanofibers (CNFs), multiwalled carbon nanotubes (MWCNTs), and urea is formulated for the 3D printing nitrogen-doped thick electrodes, in which CNFs serve as both dispersing and thickening agents for MWCNTs, whereas urea acts as a doping agent. By systematically tailoring the concentration-dependent rheological performance and 3D printing process of the ink, a variety of gel architectures with high geometric accuracy and superior shape fidelity are successfully printed. The as-printed gel architecture is then transformed into a nitrogen-doped carbon block with a hierarchical porous structure and superior electrochemical performance after freeze-drying and annealing treatments. Furthermore, a quasi-solid-state symmetric supercapacitor assembled with two interdigitated carbon blocks obtained by a 3D printing technique combined with a nitrogen-doping strategy delivers an energy density of 0.10 mWh cm-2 at 0.56 mW cm-2 . This work provides guidance for the formulation of the printable ink used for 3D printing of high-performance thick carbon electrodes.

Flavivirus prM interacts with MDA5 and MAVS to inhibit RLR antiviral signaling.

BACKGROUND: Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. RESULTS: We showed that TBEV structural protein, pre-membrane (prM) protein, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeding the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKV and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKV prM significantly promoted the replication of TBEV and Sendai virus. CONCLUSION: Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.

Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction.

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes. It is also a prominent target for pharmacological inhibition in diseases such as cancer, aging, and neurodegenerative disorders. Interactions between WDR5 and various partners are essential for sustaining its function. Most drug discovery efforts center on the WIN (WDR5 interaction motif) site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM (WDR5 binding motif) pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization, and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy.