Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I.

Senecavirus A (SVA)-induced porcine idiopathic vesicular disease has caused huge economic losses worldwide. Glucose metabolism in the host cell is essential for SVA proliferation; however, the impact of the virus on glucose metabolism in host cells and the subsequent effects are still unknown. Here, glycolysis induced by SVA is shown to facilitate virus replication by promoting lactate production, which then attenuates the interaction between the mitochondrial antiviral-signaling protein (MAVS) and retinoic acid-inducible gene I (RIG-I). SVA induces glycolysis in PK-15 cells, as indicated by significantly increased expression of hexokinase 2 (HK2), 6-phosphofructokinase (PFKM), pyruvate kinase M (PKM), phosphoglycerate kinase 1 (PGK1), hypoxia-inducible factor-1 alpha (HIF-1α), and superoxide dismutase-2 (SOD2) in a dose-and replication-dependent manner, and enhanced lactate production, while reducing ATP generation. Overexpression of PKM, PGK1, HIF-1α, and PDK3 in PK-15 cells and high glucose concentrations promote SVA replication, while glycolytic inhibitors decrease it. Inhibition of RLR signaling allowed better replication of SVA by promoting lactate production to attenuate the interaction between MAVS and RIG-I, and regulatory effect of glycolysis on replication of SVA was mainly via RIG-I signaling. SVA infection in mice increased expression of PKM and PGK1 in tissues and serum yields of lactate. Mice treated with high glucose and administered sodium lactate showed elevated lactate levels and better SVA replication, as well as suppressed induction of RIG-I, interferon beta (IFNß), IFNα, interferon-stimulated gene 15 (ISG15), and interleukin 6 (IL-6). The inhibitory effect on interferons was lower in mice administered sodium oxamate and low glucose compared to the high glucose, indicating that RLR signaling was inhibited by SVA infection through lactate in vitro and in vivo. These results provide a new perspective on the relationship between metabolism and innate immunity of the host in SVA infection, suggesting that glycolysis or lactate may be new targets against the virus.

The circRNA circVAMP3 restricts influenza A virus replication by interfering with NP and NS1 proteins.

Circular RNAs (circRNAs) are involved in various biological roles, including viral infection and antiviral immune responses. To identify influenza A virus (IAV) infection-related circRNAs, we compared the circRNA profiles of A549 cells upon IAV infection. We found that circVAMP3 is substantially upregulated after IAV infection or interferon (IFN) stimulation. Furthermore, IAV and IFN-ß induced the expression of QKI-5, which promoted the biogenesis of circVAMP3. Overexpression of circVAMP3 inhibited IAV replication, while circVAMP3 knockdown promoted viral replication, suggesting that circVAMP3 restricts IAV replication. We verified the effect of circVAMP3 on viral infection in mice and found that circVAMP3 restricted IAV replication and pathogenesis in vivo. We also found that circVAMP3 functions as a decoy to the viral proteins nucleoprotein (NP) and nonstructural protein 1 (NS1). Mechanistically, circVAMP3 interfered with viral ribonucleoprotein complex activity by reducing the interaction of NP with polymerase basic 1, polymerase basic 2, or vRNA and restored the activation of IFN-ß by alleviating the inhibitory effect of NS1 to RIG-I or TRIM25. Our study provides new insights into the roles of circRNAs, both in directly inhibiting virus replication and in restoring innate immunity against IAV infection.

The extracellular cyclophilin A-integrin ß2 complex as a therapeutic target of viral pneumonia.

The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin ß2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin ß2 interaction. Overall, our findings reveal that eCypA-integrin ß2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.

Unraveling a novel hippo-associated immunological prognostic signature: The contribution of SERPINE1 in facilitating colorectal cancer progression via the notch signaling pathway.

BACKGROUND: Accumulating evidence demonstrated that Hippo signaling pathway is implicated in tumor initiation and progression. However, there have been limited studies on establishing signatures utilizing genes related to the Hippo pathway to evaluate prognosis and clinical efficacy in colorectal cancer (CRC) patients. METHODS: Hippo pathway-associated genes with prognostic significance were identified in the TCGA database. Subsequently, a prognostic signature associated with the Hippo pathway was constructed using Cox and LASSO regression analyses. Survival analysis, ROC analysis, and stratified analyses were conducted to appraise the performance effect of our prognostic model. We also explored the relationship between the risk score and tumor immune microenvironment. Furthermore, GO analyses and GSEA were performed for SERPINE1. Additional experiments were conducted to illuminate the underlying function and possible mechanism of SERPINE1 in CRC cell proliferation and migration. RESULTS: We identified 58 differentially expressed genes associated with Hippo pathway that have prognostic significance in CRC. Among them, five genes (PPP2CB, SERPINE1, WNT5A, TCF7L1, and LEF1) were selected to establish a prognostic signature for CRC. Multivariate analysis demonstrated that this signature exhibited excellent diagnostic and prognostic performance, providing maximum benefits for CRC patients. In accordance with the prognostic signatures, the cases were divided into low-risk and high-risk groups. Remarkably, the high-risk group displayed lower immune scores, reduced immune cell infiltration, and decreased expression of immune checkpoints. Low-risk group could more possibly benefit from conventional chemotherapeutic and targeted therapies. CRC exhibited significantly elevated expression of SERPINE1, which was linked to worst overall survival. Moreover, inhibition of SERPINE1 suppressed proliferation, invasion, and migration of CRC cells via Notch pathway. CONCLUSIONS: To sum up, we established a novel immunological prognostic signature utilizing genes associated with the Hippo pathway. This signature offers accurate prognostic prediction and can guide individualized therapy for patients with CRC.

The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC.

Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.

The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation.

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.

TRIM5 inhibits the replication of Senecavirus A by promoting the RIG-I-mediated type I interferon antiviral response.

Senecavirus A (SVA) is an emerging virus that poses a threat to swine herds worldwide. To date, the role of tripartite motif 5 (TRIM5) in the replication of viruses has not been evaluated. Here, TRIM5 was reported to inhibit SVA replication by promoting the type I interferon (IFN) antiviral response mediated by retinoic acid-inducible gene I (RIG-I). TRIM5 expression was significantly upregulated in SVA-infected cells, and TRIM5 overexpression inhibited viral replication and promoted IFN-α, IFN-ß, interleukin-1beta (IL-1ß), IL-6, and IL-18 expression. Conversely, interfering with the expression of TRIM5 had the opposite effect. Viral adsorption and entry assays showed that TRIM5 did not affect the adsorption of SVA but inhibited its entry. In addition, TRIM5 promoted the expression of RIG-I and RIG-I-mediated IFNs and proinflammatory cytokines, and this effect was also proven by inhibiting the expression of TRIM5. These findings expand the scope of knowledge on host factors inhibiting the replication of SVA and indicate that targeting TRIM5 may aid in the development of new agents against SVA.

Lymph node metastasis detection using artificial intelligence in T1 colorectal cancer: A comprehensive systematic review.

We systematically reviewed the application of artificial intelligence (AI) in predicting lymph node metastasis (LNM) in T1 colorectal cancer (CRC). Thirteen studies with 8417 patients were included. AI demonstrated high potential in predicting LNM with sensitivity, specificity, and AUC ranging from 0.561 to 1.0, 0.45 to 1.0, and 0.717 to 1.0, respectively, reducing unnecessary surgeries by approximately 70%.

Attenuated neural activity in processing decision-making feedback in uncertain conditions in patients with mild cognitive impairment.

The present study aimed to explore the potential neural correlates during feedback evaluation during decision-making under risk and ambiguity in MCI. Nineteen individuals with MCI and twenty age-matched HCs were enrolled. Decision-making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task-related EEG data, reward positivity (RewP) and feedback P3 (fb-P3) were used to characterize participants' motivation and allocation of cognitive resources. Also, response time and event-related oscillation (ERO) were used to evaluate information processing speed, and the potent of post-feedback information integration and behavioral modulation. MCI patients had lower RewP (p = 0.022) and fb-P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb-P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb-P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011). The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.

Incongruent gray matter atrophy and functional connectivity of striatal subregions in behavioral variant frontotemporal dementia.

Previous studies on the striatum demonstrated that it is involved in the regulation of cognitive function and psychiatric symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). Multiple lines of evidence have shown that striatal subregions have their own functions. However, the results of the existing studies on striatal subregions are inconsistent and unclear. In this study, we found that structural imaging analysis revealed that the bvFTD patients had smaller volumes of striatal subregions than the controls. We found that the degree of atrophy varied across the striatal subregions. Additionally, the right striatal subregions were significantly more atrophic than the left in bvFTD. Functional imaging analysis revealed that bvFTD patients exhibited different changed patterns of resting-state functional connectivity (RSFC) when striatal subregions were selected as regions of interest (ROI). The RSFC extending range on the right ROIs was more significant than on the left in the same subregion. Interestingly, the RSFC of the subregions extending to the insula were consistent. In addition, the left dorsolateral putamen may be involved in executive function regulation. This suggests that incongruence in striatal subregions may be critical to the bvFTD characteristics.

ZBP1 inhibits the replication of Senecavirus A by enhancing NF-κB signaling pathway mediated antiviral response in porcine alveolar macrophage 3D4/21 cells.

BACKGROUND: Senecavirus A (SVA) caused porcine idiopathic vesicular disease (PIVD) showing worldwide spread with economic losses in swine industry. Although some progress has been made on host factors regulating the replication of SVA, the role of Z-DNA binding protein 1 (ZBP1) remains unclear. METHODS: The expression of ZBP1 in SVA-infected 3D/421 cells was analyzed by quantitative real-time PCR (qRT-PCR) and western blot. Western blot and qRT-PCR were used to detect the effects of over and interference expression of ZBP1 on SVA VP2 gene and protein. Viral growth curves were prepared to measure the viral proliferation. The effect on type I interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines in SVA infection was analyzed by qRT-PCR. Western blot was used to analysis the effect of ZBP1 on NF-κB signaling pathway and inhibitor are used to confirm. RESULTS: ZBP1 is shown to inhibit the replication of SVA by enhancing NF-κB signaling pathway mediated antiviral response. SVA infection significantly up-regulated the expression of ZBP1 in 3D4/21 cells. Infection of cells with overexpression of ZBP1 showed that the replication of SVA was inhibited with the enhanced expression of IFNs (IFN-α, IFN-ß), ISGs (ISG15, PKR, and IFIT1) and pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while, infected-cells with interference expression of ZBP1 showed opposite effects. Further results showed that antiviral effect of ZBP1 is achieved by activation the NF-κB signaling pathway and specific inhibitor of NF-κB also confirmed this. CONCLUSIONS: ZBP1 is an important host antiviral factor in SVA infection and indicates that ZBP1 may be a novel target against SVA.

Research Progress of Organic Field-Effect Transistor Based Chemical Sensors.

Due to their high sensitivity and selectivity, chemical sensors have gained significant attention in various fields, including drug security, environmental testing, food safety, and biological medicine. Among them, organic field-effect transistor (OFET) based chemical sensors have emerged as a promising alternative to traditional sensors, exhibiting several advantages such as multi-parameter detection, room temperature operation, miniaturization, flexibility, and portability. This review paper presents recent research progress on OFET-based chemical sensors, highlighting the enhancement of sensor performance, including sensitivity, selectivity, stability, etc. The main improvement programs are improving the internal and external structures of the device, as well as the organic semiconductor layer and dielectric structure. Finally, an outlook on the prospects and challenges of OFET-based chemical sensors is presented.

A Stable and Scalable Digital Composite Neurocognitive Test for Early Dementia Screening Based on Machine Learning: Model Development and Validation Study.

BACKGROUND: Dementia has become a major public health concern due to its heavy disease burden. Mild cognitive impairment (MCI) is a transitional stage between healthy aging and dementia. Early identification of MCI is an essential step in dementia prevention. OBJECTIVE: Based on machine learning (ML) methods, this study aimed to develop and validate a stable and scalable panel of cognitive tests for the early detection of MCI and dementia based on the Chinese Neuropsychological Consensus Battery (CNCB) in the Chinese Neuropsychological Normative Project (CN-NORM) cohort. METHODS: CN-NORM was a nationwide, multicenter study conducted in China with 871 participants, including an MCI group (n=327, 37.5%), a dementia group (n=186, 21.4%), and a cognitively normal (CN) group (n=358, 41.1%). We used the following 4 algorithms to select candidate variables: the F-score according to the SelectKBest method, the area under the curve (AUC) from logistic regression (LR), P values from the logit method, and backward stepwise elimination. Different models were constructed after considering the administration duration and complexity of combinations of various tests. Receiver operating characteristic curve and AUC metrics were used to evaluate the discriminative ability of the models via stratified sampling cross-validation and LR and support vector classification (SVC) algorithms. This model was further validated in the Alzheimer's Disease Neuroimaging Initiative phase 3 (ADNI-3) cohort (N=743), which included 416 (56%) CN subjects, 237 (31.9%) patients with MCI, and 90 (12.1%) patients with dementia. RESULTS: Except for social cognition, all other domains in the CNCB differed between the MCI and CN groups (P<.008). In feature selection results regarding discrimination between the MCI and CN groups, the Hopkins Verbal Learning Test-5 minutes Recall had the best performance, with the highest mean AUC of up to 0.80 (SD 0.02) and an F-score of up to 258.70. The scalability of model 5 (Hopkins Verbal Learning Test-5 minutes Recall and Trail Making Test-B) was the lowest. Model 5 achieved a higher level of discrimination than the Hong Kong Brief Cognitive test score in distinguishing between the MCI and CN groups (P<.05). Model 5 also provided the highest sensitivity of up to 0.82 (range 0.72-0.92) and 0.83 (range 0.75-0.91) according to LR and SVC, respectively. This model yielded a similar robust discriminative performance in the ADNI-3 cohort regarding differentiation between the MCI and CN groups, with a mean AUC of up to 0.81 (SD 0) according to both LR and SVC algorithms. CONCLUSIONS: We developed a stable and scalable composite neurocognitive test based on ML that could differentiate not only between patients with MCI and controls but also between patients with different stages of cognitive impairment. This composite neurocognitive test is a feasible and practical digital biomarker that can potentially be used in large-scale cognitive screening and intervention studies.

Tetrahedral Imidazolate Frameworks with Auxiliary Ligands (TIF-Ax): Synthetic Strategies and Applications.

Zeolitic imidazolate frameworks (ZIFs) are an important subclass of metal-organic frameworks (MOFs). Recently, we reported a new kind of MOF, namely tetrahedral imidazolate frameworks with auxiliary ligands (TIF-Ax), by adding linear ligands (Hint) into the zinc-imidazolate system. Introducing linear ligands into the M2+-imidazolate system overcomes the limitation of imidazole derivatives. Thanks to the synergistic effect of two different types of ligands, a series of new TIF-Ax with interesting topologies and a special pore environment has been reported, and they have attracted extensive attention in gas adsorption, separation, catalysis, heavy metal ion capture, and so on. In this review, we give a comprehensive overview of TIF-Ax, including their synthesis methods, structural diversity, and multi-field applications. Finally, we also discuss the challenges and perspectives of the rational design and syntheses of new TIF-Ax from the aspects of their composition, solvent, and template. This review provides deep insight into TIF-Ax and a reference for scholars with backgrounds of porous materials, gas separation, and catalysis.

Integration of an anti-resonant hollow-core fiber with a multimode Yb-doped fiber for high power near-diffraction-limited laser operation.

We proposed and demonstrated mode cleaning in a high-power fiber laser by integrating an anti-resonant hollow-core fiber (AR-HCF) into a multimode laser cavity of an ytterbium (Yb)-doped fiber (YDF). An in-house mode-matched AR-HCF was fusion-spliced to a commercial multimode LMA-YDF, ensuring efficient fundamental mode coupling. The AR-HCF inflicts a high propagation loss selectively on higher-order modes, facilitating fundamental mode operation. Thus, the AR-HCF works as an efficient spatial mode filter embedded in the multimode fiber laser cavity and reinforces preferential amplification of the fundamental mode. Beam quality factor enhancement was achieved from M2 = 2.09 to 1.39 at an output power of 57.7 W (pump-power limited). The beam quality can be further improved by refining the AR-HCF fabrication. The proposed technique has a great potential to be exploited in other multimode fiber laser cavities involving erbium- or thulium-doped fibers and obviates the need for complicated specialty active fiber designs. Compared with the commonly used fiber bending technique, our method can achieve an efficient higher-order mode suppression without inducing mode-field deterioration.

Linearly polarized ytterbium laser enabled by an antiresonant hollow-core fiber inline polarizer.

We report a linearly polarized ytterbium-doped fiber (YDF) laser cavity configured by integrating an antiresonant hollow-core fiber-based inline polarizer. The 5-cm-long compact fiber polarizer was fusion spliced to a commercial large-mode-area, polarization-maintaining YDF. Near-diffraction-limited linearly polarized signal output with a polarization extinction ratio of > 21 dB was achieved for up to 25 W of power that was limited only by the available pump power. The performance of the hollow-core fiber polarizer was found to be temperature insensitive, which obviates the need for the precise temperature control required in all-fiber, high-power polarized laser cavities employing crossed fiber Bragg gratings. We used the tapering technique to scale down the geometry of the polarizing fiber and shift its operating wavelength by ∼100 nm, which makes it an attractive candidate for a variety of fiber laser applications.

Cyclophilin A is a key positive and negative feedback regulator within interleukin-6 trans-signaling pathway.

Cyclophilin A (CypA), a member of the cyclophilin family, plays a vital role in microorganismal infections, inflammatory diseases, and cancers. Interleukin-6 (IL-6) is a pleiotropic cytokine, exerting variety of effects on inflammation, immune response, hematopoiesis, and tumor proliferation. Binding of IL-6 to soluble IL-6 receptor (sIL-6R) induces pro-inflammatory trans-signaling, which has been described to be stronger than anti-inflammatory classic signaling triggered by the binding of IL-6 to membrane-bound IL-6 receptor. Here we found that upon the treatment of IL-6 and sIL-6R, CypA inhibited the ubiquitination-mediated degradation of IL-6 membrane receptor gp130 and enhanced its dimerization, thereby positively regulated the IL-6 trans-signaling and increased the expression of downstream iNOS, IL-6, and CypA. Furthermore, CypA expression could be negatively regulated by suppressor of cytokine signaling 1 (SOCS1). The SH2 and Box domains of SOCS1 interacted with CypA and promoted its K48-linked ubiquitination-mediated degradation, which inhibited the IL-6 trans-signaling pathway. Collectively, our findings reveal an important role of CypA in the positive and negative feedback regulation of the IL-6 trans-signaling pathway.

TGF-ß1 regulates chondrocyte proliferation and extracellular matrix synthesis via circPhf21a-Vegfa axis in osteoarthritis.

BACKGROUND: The transforming growth factor-beta (TGF-ß) signaling pathway is an important pathway associated with the pathogenesis of osteoarthritis (OA). This study was to investigate the involvement of circRNAs in the TGF-ß signaling pathway. METHODS: Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to detect the proliferation of primary mouse chondrocytes (PMCs). RNA-sequencing together with bioinformatics analysis were used to systematically clarify TGF-ß1 induced alternations of circRNAs in PMCs. The regulatory and functional role of circPhf21a was examined in PMCs. Downstream targets of circPhf21a were explored by RNA-sequencing after overexpression of circPhf21a and verified by RT-qPCR in PMCs. Finally, the role and mechanism of circPhf21a in OA were explored in mouse models. RESULTS: We found that TGF-ß1 promoted the proliferation of PMCs. Meanwhile, RT-qPCR and western blotting indicated that TGF-ß1 promoted extracellular matrix (ECM) anabolism. RNA-sequencing revealed that a total of 36 circRNAs were differentially expressed between PMCs treated with and without TGF-ß1. Of these, circPhf21a was significantly decreased by TGF-ß1. Furthermore, circPhf21a knockdown promoted the proliferation and ECM synthesis of PMCs, whereas overexpression of circPhf21a showed the opposite effects. Mechanically, the expression profiles of the mRNAs revealed that Vegfa may be the target of circPhf21a. Additionally, we found that circPhf21a was significantly upregulated in the mouse OA model, and inhibition of circPhf21a significantly relieved the progression of OA. CONCLUSIONS: Our results found that TGF-ß1 promoted the proliferation and ECM synthesis of PMCs via the circPhf21a-Vegfa axis, which may provide novel therapeutic targets for OA treatment. Video abstract.

ABI2-mediated MEOX2/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence.

Tumour recurrence and drug resistance in hepatocellular carcinoma remain challenging. Cancer stem cells (CSCs) are responsible for tumour initiation because of their stemness characteristics. CSCs accounting for drug resistance and tumour relapse are promising therapeutic targets. We report that Abelson interactor 2 (ABI2) is a novel therapeutic target of HCC CSCs. First, ABI2 was upregulated in HCC tissues compared with liver tissues and was associated with tumour size, pathological grade, liver cirrhosis, worse prognosis and a high recurrence rate. Functional studies illustrate that ABI2 knockdown suppresses cell growth, migration, invasion and sorafenib resistance in vitro. Furthermore, ABI2 knockdown inhibited HCC sphere formation and decreased the CD24+ , CD133+ and CD326+ CSCs populations, suggesting the suppression of HCC stemness characteristics. A tumour xenograft model and limiting dilution assay demonstrated the inhibition of tumorigenicity and tumour initiation. Moreover, molecular mechanism studies showed that ABI2 recruits and directly interacts with the transcription factor MEOX2, which binds to the KLF4 and NANOG promoter regions to activate their transcription. Furthermore, overexpression of MEOX2 restored HCC malignant behaviour and the CSC population. The ABI2-mediated transcriptional axis MEOX2/KLF4-NANOG promotes HCC growth, metastasis and sorafenib resistance by maintaining the CSC population, suggesting that ABI2 is a promising CSC target in HCC treatment.

Medium-chain triglycerides reduce diarrhea with improved immune status and gut microbiomics in tunnel workers in China.

BACKGROUND AND OBJECTIVES: Adverse environmental factors in tunnels increase the occurrence of respiratory and intestinal inflammatory disease, which is seriously harmful to worker health. It is reported that medium-chain triglycerides (MCT) can improve immune status and alter the gut microflora. This study investigates MCT effects on immune status and gut microbiota among tunnel workers. METHODS AND STUDY DESIGN: Forty-five workers were randomly divided into an MCT group (n=30) and control group (n=15), where they ingested MCT-milk or a placebo milk for 12 weeks, respectively. The primary outcome measure was the incidence of respiratory infection and diarrhea. Secondary outcomes were changes in serum immune-related markers and changes in gut microbiota. RESULTS: The incidence of diarrhea in MCT group was significantly decreased after 4 weeks (p<0.01), with no significant differences in the control group. MCT reduced the level of pro-inflammatory cytokines (TNF-α, CRP, and IL-6) and enhanced the anti-inflammatory cytokines (IL-10, C3, C4, IgA, IgG, and IgM), respectively (p<0.01). The Chao index was reduced (p<0.01) and microbiota composition changed significantly after 12 weeks of MCT intervention. MCT reduced the abundance of Bacteroides, Roseburia, Ruminococcus_1, Lachnospira and increased that of Blautia and Fusicatenibacter at the genus level (p<0.01). CONCLUSIONS: The consumption of MCT reduces diarrhea occurrence and improves serum immune profiles together with gut microbiomics in tunnel workers.