A toe-inspired rigid-flexible coupling wheel design method for improving the terrain adaptability of a sewer robot.

The human toe, characterized by its rigid-flexible structure comprising hard bones and flexible joints, facilitates adaptive and stable movement across varied terrains. In this paper, we utilized a motion capture system to study the adaptive adjustments of toe joints when encountering obstacles. Inspired by the mechanics of toe joints, we proposed a novel design method for a rigid-flexible coupled wheel. The wheel comprises multiple elements: a rigid skeleton, supporting toes, connecting shafts, torsion springs, soft tendons, and damping pads. The torsion springs connect the rigid frame to the supporting toes, enabling them to adapt to uneven terrains and pipes with different diameters. The design was validated through kinematic and dynamic modeling, rigid-flexible coupled dynamics simulation, and stress analysis. Different stiffness coefficients of torsion springs were compared for optimal wheel design. Then, the wheel was applied to a sewer robot, and its performance was evaluated and compared with a pneumatic rubber tire in various experiments, including movement on flat surfaces, overcoming small obstacles, adaptability tests in different terrains, and active driving force tests in dry and wet pipelines. The results prove that the designed wheel showed better stability and anti-slip properties than conventional tires, making it suitable for diverse applications such as pipeline robots, desert vehicles, and lunar rovers.

TOX3 deficiency mitigates hyperglycemia by suppressing hepatic gluconeogenesis through FoxO1.

BACKGROUND: Excessive hepatic glucose production is a hallmark that contributes to hyperglycemia in type 2 diabetes (T2D). The regulatory network governing this process remains incompletely understood. Here, we demonstrate that TOX3, a high-mobility group family member, acts as a major transcriptional driver for hepatic glucose production. METHODS: Tox3-overexpressed and knockout mice were constructed to explore its metabolic functions. Transcriptomic and chromatin-immunoprecipitation sequencing (ChIP-seq) were used to identify downstream targets of TOX3. Both FoxO1 silencing and inhibitor approaches were used to assess the contribution of FoxO1. TOX3 expression levels were examined in the livers of mice and human subjects. Finally, Tox3 was genetically manipulated in diet-induced obese mice to evaluate its therapeutic potential. RESULTS: Hepatic Tox3 overexpression activates the gluconeogenic program, resulting in hyperglycemia and insulin resistance in mice. Hepatocyte-specific Tox3 knockout suppresses gluconeogenesis and improves insulin sensitivity. Mechanistically, integrated hepatic transcriptomic and ChIP-seq analyses identify FoxO1 as a direct target of TOX3. TOX3 stimulates FoxO1 transcription by directly binding to and activating its promoter, whereas FoxO1 silencing abrogates TOX3-induced dysglycemia in mice. In human subjects, hepatic TOX3 expression shows a significant positive correlation with blood glucose levels under normoglycemic conditions, yet is repressed by high glucose during T2D. Importantly, hepatic Tox3 deficiency markedly protects against and ameliorates the hyperglycemia and glucose intolerance in diet-induced diabetic mice. CONCLUSIONS: Our findings establish TOX3 as a driver for excessive gluconeogenesis through activating hepatic FoxO1 transcription. TOX3 could serve as a promising target for preventing and treating hyperglycemia in T2D.

Higher temperature variability in deforested mountain regions impacts the competitive advantage of nocturnal species.

Deforestation is a major contributor to biodiversity loss, yet the impact of forest loss on daily microclimate variability and its implications for species with different daily activity patterns remain poorly understood. Using a recently developed microclimate model, we investigated the effects of deforestation on the daily temperature range (DTR) in low-elevation tropical regions and high-elevation temperate regions. Our results show that deforestation substantially increases DTR in these areas, suggesting a potential impact on species interactions. To test this hypothesis, we studied the competitive interactions between nocturnal burying beetles and all-day-active blowfly maggots in forested and deforested habitats in Taiwan. We show that deforestation leads to increased DTR at higher elevations, which enhances the competitiveness of blowfly maggots during the day and leads to a higher failure rate of carcass burial by the beetles at night. Thus, deforestation-induced temperature variability not only modulates exploitative competition between species with different daily activity patterns, but also likely exacerbates the negative impacts of climate change on nocturnal organisms. In order to limit potential adverse effects on species interactions and their ecological functions, our study highlights the need to protect forests, especially in areas where deforestation can greatly alter temperature variability.

THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic ß-cell function and preserving ß-cell mass.

Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and ß-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced ß-cell function and decreased ß-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in ß-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving ß-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.

Metabolic Rewiring of Kynurenine Pathway during Hepatic Ischemia-Reperfusion Injury Exacerbates Liver Damage by Impairing NAD Homeostasis.

Hepatic ischemia-reperfusion (IR) injury remains a common issue lacking effective strategy and validated pharmacological targets. Here, using an unbiased metabolomics screen, this study finds that following murine hepatic IR, liver 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) decline while kynurenine and kynurenic acid (KYNA) increase. Kynurenine aminotransferases 2, functioning at the key branching point of the kynurenine pathway (KP), is markedly upregulated in hepatocytes during ischemia, shifting the kynurenine metabolic route from 3-HAA and QA to KYNA synthesis. Defects in QA synthesis impair de novo nicotinamide adenine dinucleotide (NAD) biosynthesis, rendering the hepatocytes relying on the salvage pathway for maintenance of NAD and cellular antioxidant defense. Blocking the salvage pathway following IR by the nicotinamide phosphoribosyltransferase inhibitor FK866 exacerbates liver oxidative damage and enhanced IR susceptibility, which can be rescued by the lipid peroxidation inhibitor Liproxstatin-1. Notably, nicotinamide mononucleotide administration once following IR effectively boosts NAD and attenuated IR-induced oxidative stress, inflammation, and cell death in the murine model. Collectively, the findings reveal that metabolic rewiring of the KP partitions it away from NAD synthesis in hepatic IR pathophysiology, and provide proof of concept that NAD augmentation is a promising therapeutic measure for IR-induced liver injury.

The value of gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase for predicting post-hepatectomy liver failure in HCC patients.

OBJECTIVES: To determine the value of gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase for predicting post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: Patients with HCC who underwent gadobenate dimeglumine-enhanced hepatobiliary magnetic resonance imaging prior to hepatectomy were collected in two centers. The relative enhancement ratio of the biliary system (REB) and the liver to muscle ratio (LMR) were measured at the hepatobiliary phase. Potential risk factors for PHLF were analyzed by logistic regression. The capacity of the REB and LMR to predict PHLF was analyzed via receiver operating characteristic curve. RESULTS: Of the 221 patients, post-hepatectomy liver failure occurred in 60 patients (27.1%). The REB was an independent risk factor for PHLF (odds ratio [OR] = 0.127 [0.047-0.348], p < 0.001). Although the LMR tended to be associated with PHLF (p = 0.063), it was not an independent risk factor in the multivariable analysis (OR = 0.624 [0.023-16.709], p = 0.779). Moreover, the area under the receiver operating characteristic curve of the REB and LMR was 0.87 and 0.60. The most appropriate cutoff value for the REB was 2.21. The HCC patients with the REB ≤ 2.21 had a higher incidence of post-hepatectomy liver failure than those with the REB > 2.21 (60.0% versus 8.5%, p < 0.001). CONCLUSIONS: Gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase was valuable in predicting post-hepatectomy liver failure in HCC patients. KEY POINTS: • The relative enhancement ratio of the biliary system (REB) was an independent risk factor for post-hepatectomy liver failure in HCC patients. • HCC patients with the REB ≤ 2.21 had significantly higher incidence of post-hepatectomy liver failure than those with the REB > 2.21 (60.0% versus 8.5%).

Specific genomic alterations and prognostic analysis of perihilar cholangiocarcinoma and distal cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA), which consists of intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), is an aggressive malignancy worldwide. PCCA and dCCA are often classified as extrahepatic CCA (exCCA). However, the differences in mutational characteristics between pCCA and dCCA remain unclear. METHODS: Deep sequencing targeting of 450 cancer genes was performed for genomic alteration detection. The tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was conducted using Fisher's exact test. RESULTS: FGFR2 and ERBB2 mutations mainly occurred in iCCA and exCCA, respectively. In exCCA, the frequencies of PIK3CA, FAT4, KDM6A, MDM2, and TCF7L2 mutations were significantly higher in pCCA compared to dCCA, while the frequencies of TP53 and KRAS mutations were markedly lower in pCCA than those in dCCA. The prognosis-related mutations were different among the CCA subtypes. NF1 mutation was associated with short disease-free survival (DFS) and overall survival (OS), and ERBB2 mutation was associated with short DFS in dCCA patients. Meanwhile, MAP2K4 mutation was associated with long DFS and OS, and TERT mutation was associated with short DFS in pCCA. A series of mutations in genes, including ARID1A, ARID2, SMAD4, TERT, TP53, and KRAS, were found to be associated with the TMB. CONCLUSIONS: In this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients.

Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation.

BACKGROUND: To explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HBV-related hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size. METHODS: A total of 433 participants were enrolled in this study including 266 cases with HBV-related HCC, 87 cases with HBV DNA positive benign liver disease and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HBV-related HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HBV-related HCC patients with and without vascular invasion. RESULTS: The level of AFP and PIVKA-II in HBV-related HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P < 0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HBV-related HCC diagnosis were 0.765 (95% CI, 0.713 ~ 0.8170) for AFP, 0.901 (95% CI, 0.868 ~ 0.935) for PIVKA-II, and 0.917 (95% CI, 0.886 ~ 0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was significantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level > 64.4 ng/ml or PIVKA-II level > 957.61mAU/ml was the best critical value to predict the presence of vascular invasion. CONCLUSION: Our results validate that AFP and PIVKA-II play a significant role in the diagnosis of HBV-related HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion.

Role of ubiquitin-conjugating enzyme E2T in the carcinogenesis and progression of pancreatic cancer.

Ubiquitin-conjugating enzyme E2T (UBE2T) is a recently discovered oncogenic protein. Numerous studies reported that UBE2T is highly expressed in various types of human cancer; however, its role in the carcinogenesis and progression of pancreatic cancer remains unknown. The aim of the present study was to investigate the role of UBE2T in pancreatic cancer progression through in vitro experiments in pancreatic cancer tissues and cell lines. The results obtained in the present study demonstrated that UBE2T served an important role in the initiation and progression of pancreatic cancer. Furthermore, increased expression of UBE2T in human pancreatic cancer tissues and pancreatic cancer cells was observed compared with normal tissues and cells. The effect of upregulating and downregulating UBE2T in pancreatic cancer cell lines was investigated using the MTT, wound-healing and migration and invasion assays. The results demonstrated that overexpression of UBE2T significantly promoted pancreatic cancer cell proliferation, migration and invasion compared with controls. However, UBE2T downregulation resulted in the inhibition of pancreatic cancer cell proliferation, migration and invasion. In addition, the results demonstrated that UBE2T may promote the epithelial mesenchymal transition in pancreatic cancer cells.

Long noncoding RNA linc00467 plays an oncogenic role in hepatocellular carcinoma by regulating the miR-18a-5p/NEDD9 axis.

Increasing evidence has shown that numerous long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis. Herein, we investigated the biological role of lncRNA linc00467 in the cancer biology of hepatocellular carcinoma (HCC). We observed that linc00467 was upregulated in HCC tissues and cells. Silencing of linc00467 using small interfering RNA interference significantly inhibited the growth and motility of HCC cells, and increased cell apoptosis through regulating the Bcl-2/Bax axis and the caspase cascade, suggesting that linc00467 exerted oncogenic functions in the progression of HCC. Moreover, we found that linc00467 could target miR-18a-5p, and NEDD9 was a target for miR-18a-5p in HCC cells. Furthermore, either the miR-18a-5p inhibitor or upregulation of NEDD9 could recover the inhibitory effects caused by silencing of linc00467. In conclusion, our data highlighted the oncogenic role of linc00467 in HCC progression by regulating the miR-18a-5p/NEDD9 axis.

Long noncoding RNA CASC21 exerts an oncogenic role in colorectal cancer through regulating miR-7-5p/YAP1 axis.

BACKGROUND: Emerging evidences show that long non-coding RNAs (lncRNAs) are widely involved in various cell processes and tumor progression. The aim of this study was to investigate the role of new lncRNA homo sapiens cancer susceptibility 21 (CASC21) in the cancer biology of colorectal cancer and explore the underlying mechanism. METHODS: We silenced the expression of CASC21 using siRNA interference in colorectal cancer cell lines HT29 and SW480, and the effects of CASC21 knockdown on cell proliferation, migration, invasion and apoptosis were assessed using CCK8, colony formation, wound-healing, Transwell and flow cytometry assays. Dual-luciferase reporter assay was performed to determine the relationship among CASC21, miR-7-5p and YAP1. Western blot analysis was used to examine expression of related proteins. RESULTS: By bioinformatics analysis, CASC21 was found to be significantly up-regulated in colorectal cancer tissues. Moreover, CASC21 knockdown displayed significant depression in cell viability, proliferation, migration, and invasion in colorectal cancer cells, as well as EMT process, while cell apoptosis was promoted by regulating the Bcl-2/Bax axis and Caspase cascade. Mechanistically, CASC21 could competently bind to miR-7-5p, resulting in increased YAP1 expression. Furthermore, up-regulation of YAP1 could rescue the inhibitory effects of CASC21 knockdown on EMT and cell invasion. CONCLUSION: Collectively, these results suggest that CASC21 functions as a ceRNA that plays an oncogenic role in the progression of colorectal cancer by regulating the miR-7-5p/YAP1 axis. LncRNA CASC21 might be a potential target for therapy of colorectal cancer.

Modulation of IGF2BP1 by long non-coding RNA HCG11 suppresses apoptosis of hepatocellular carcinoma cells via MAPK signaling transduction.

Hepatocellular carcinoma (HCC) is a common malignancy of the liver. HCG11 is a member of long non­coding family, upregulation of which in HCC was proved by our previous study. In the present study, the role of HCG11 in the development of HCC was detected by focusing on the interaction between HCG11 and its target protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The expression status of HCG11 and IGF2BP1 was first investigated with clinical HCC samples. Then the expressions of HCG11 and IGF2BP1 were both inhibited in the human HCC cell line HepG2 and the cell viability, proliferation, apoptosis and metastasis potential of HepG2 cells were assessed. At molecular level, the expression levels of p-ERK, p-JNK, p-p38, p21 and cleaved caspase-3 were also determined to explain the pathways involved in the function of HCG11 in the progression of HCC. Expression of HCG11 and IGF2BP1 were significantly higher in HCC tissues than those in para-tumor tissues. Knockdown of both indicators led to decreased cell viability, proliferation, and migration ability in HepG2 cells while the cell apoptosis and G1 cell cycle arrest were induced after knockdown of HCG11 and IGF2BP1. In addition, suppressed activity of HCG11 and IGF2BP1 blocked the phosphorylation of anti-apoptosis factors, including ERK, JNK and p38 while the mitochondrial apoptosis in HCC cells was initiated by activation of p21 and cleaved caspase-3. HCG11 exerted its effect on HCC via interaction with IGF2BP1, leading to activation of MAPK signaling, which eventually promoted the progression of HCC.

A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type.

Due to frequent phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway dysregulation, AKT is typically accepted as a promising anticancer therapeutic target. mTOR, in particular, represents a suitable therapeutic target for hepatocellular carcinoma, whilst suppressor with morphogenetic effect on genitalia family member-1 (SMG-1) is believed to serve a potential tumor suppressor role in human cancer. Despite SMG-1 and mTOR belonging to the same PI3K-related kinase family, the interactions between them are not yet fully understood. In the present study, a novel pyrrolopyrimidine-derived compound, AZD5363, was observed to suppress proliferation in liver cancer Hep-G2 and Huh-7 cells by inhibiting the phosphorylation of downstream molecules in the AKT signal pathway, in a dose- and time-dependent manner. AZD5363 activated the phosphorylation of mTOR, dependent on the liver cancer cell type, as it may have differing effects in various liver cancer cell lines. Additionally, AZD5363 also activated SMG-1 within the same liver cancer cells types, which subsequently activated the phosphorylation of mTOR. In conclusion, the present study indicates that AZD5363 inhibited phosphorylation of AKT downstream molecules, and activated phosphorylation of mTOR and SMG-1, dependent on the liver cancer type.