Intestinal microbiota promoted NiONPs-induced liver fibrosis via effecting serum metabolism.

Nickel oxide nanoparticles (NiONPs) are toxic heavy metal compounds that induce liver fibrosis and metabolic disorders. Current research shows that the intestinal microbiota regulates liver metabolism through the gut-liver axis. However, it is unclear whether NiONPs affect the intestinal microbiota and the relationship between microbiota and liver metabolic disorders. Therefore, in this study, we established liver fibrosis model by administering 0.015, 0.06 and 0.24 mg/mL NiONPs through tracheal instillation twice a week for 9 weeks in rats, then we collected serum and fecal sample for whole metabolomics and metagenomic sequencing. As the result of sequencing, we screened out seven metabolites (beta-D-glucuronide, methylmalonic acid, linoleic acid, phosphotidylcholine, lysophosphatidylinositol, docosapentaenoic acid and progesterone) that related to functional alterations (p < 0.05), and obtained a decrease of probiotics abundances (p < 0.05) as well as a variation of the microbiota enzyme activity (p < 0.05), indicating that NiONPs inhibited the proliferation of probiotics. As the result of correlation analysis, we found a positive correlation between differential metabolites and probiotics, such as lysophosphatidylinositol was positively correlated with Desulfuribacillus, Jeotgallibacillus and Rummeliibacillus (p < 0.05). We also found that differential metabolites had correlations with differential proteins and enzymes of intestinal microbiota, such as glucarate dehydratase, dihydroorotate dehydrogenase and acetyl-CoA carboxylase (p < 0.05). Finally, we screened six metabolic pathways with both differential intestinal microbiota enzymes and metabolites were involved, such as pentose and glucuronate interconversions, and linoleic acid metabolism. In vitro experiments showed that NiONPs increased the transcriptional expression of Col1A1 in LX-2 cells, while reducing the mRNA expression of serine/threonine activators, acetyl coenzyme carboxylase, and lysophosphatidylinositol synthase, and short chain fatty acid sodium butyrate can alleviate these variation trends. The results proved that the intestinal microbiota enzyme systems were associated with serum metabolites, suggesting that the disturbance of intestinal microbiota and reduction of probiotics promoted the occurrence and development of NiONPs-induced liver fibrosis by affecting metabolic pathways.

Skeletal anatomy of the pectoral fin in mudskipper species from terrestrial and aquatic habitats.

Mudskippers are a group of amphibious fishes in the family Oxudercidae, whose species inhabit a range of habitats from mostly aquatic to mostly terrestrial. Most of our understanding about habitat preference comes from natural history observations, particularly where they are collected (i.e., low intertidal vs. high intertidal regions). Mudskippers have undergone several morphological changes to accommodate a terrestrial life, including major changes to the pectoral and pelvic girdles. These changes result in a novel crutching gait, which mudskippers use to move over land. Though the appendicular morphology and crutching gait of mudskippers have been described in some species, few studies have compared skeletal structures across the family. In our study, we use microcomputed tomography (µCT) scans to compare the skeletal anatomy of 16 species of aquatic and terrestrial mudskippers. Linear discriminant analysis is used to analyze measurements obtained through geometric morphometrics (landmarks). We found bone structures of the pectoral region in the terrestrial group were significantly longer and wider than those in the aquatic group. Furthermore, a significant difference in anatomy is shown between terrestrial and aquatic genera with both axial and appendicular elements contributing to the separation between groups. This work describes the differences in skeletal morphology associated with terrestriality in mudskippers and provides valuable insights into specific anatomical characteristics contributing to their adaptation to novel environments.

Adaptive Neural Network Event-Triggered Output-Feedback Containment Control for Nonlinear MASs With Input Quantization.

This article investigates the adaptive neural network (NN) event-triggered containment control problem for a class of nonlinear multiagent systems (MASs). Since the considered nonlinear MASs contain unknown nonlinear dynamics, immeasurable states, and quantized input signals, the NNs are adopted to model unknown agents, and an NN state observer is established by using the intermittent output signal. Subsequently, a novel event-triggered mechanism consisting of both the sensor-to-controller and controller-to-actuator channels are established. By decomposing quantized input signals into the sum of two bounded nonlinear functions and based on the adaptive backstepping control and first-order filter design theories, an adaptive NN event-triggered output-feedback containment control scheme is formulated. It is proved that the controlled system is semi-globally uniformly ultimately bounded (SGUUB) and the followers are within a convex hull formed by the leaders. Finally, a simulation example is given to validate the effectiveness of the presented NN containment control scheme.

Genotyping of cerebrospinal fluid in lung cancer patients with leptomeningeal metastasis.

BACKGROUND: The prognosis of non-small-cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is poor. Detection of cell-free DNA (cfDNA) by next generation sequencing (NGS) in cerebrospinal fluid (CSF) may facilitate diagnosis of LM and identification of drug resistance mechanisms, yet its clinical use needs to be further verified. METHODS: We performed a retrospective cohort study to assess the genetic profiles of paired CSF and plasma samples in lung cancer patients with LM. Of 17 patients screened, a total of 14 patients with LM and paired NGS tests were enrolled. RESULTS: All patients harbor driver gene mutations, including 12 epidermal growth factor receptor (EGFR) activating mutations, 1 anaplastic lymphoma kinase (ALK) rearrangement, and 1 ROS-1 fusion. Genetic mutations were detected in CSF cfDNA from 92.9% patients (13/14), which was significantly higher than that from the plasma (9/14, 64.2%). The mutations were highly divergent between CSF and plasma cfDNA, with a concordance rate of 24.38% and 10 mutations shared by the two media. CSF cfDNA could also benefit the analysis of resistance mechanisms to targeted therapies. In five patients who experienced progression on 1st or 2nd generation EGFR-tyrosine kinase inhibitors (TKIs), RB1 mutation, and amplification of MET and EGFR were detected in CSF cfDNA only. In eight patients with LM progression on osimertinib resistance, EGFR amplification was detected in CSF cfDNA from four patients, whereas no CNVs were detected in the matched plasma samples. CONCLUSIONS: In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments.

EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation.

Tumor cells use metabolic reprogramming to keep up with the need for bioenergy, biosynthesis, and oxidation balance needed for rapid tumor division. This phenomenon is considered a marker of tumors, including colon cancer (CRC). As an important pathway of cellular energy metabolism, fatty acid metabolism plays an important role in cellular energy supply and oxidation balance, but presently, our understanding of the exact role of fatty acid metabolism in CRC is limited. Currently, no lipid metabolism therapy is available for the treatment of CRC. The establishment of a lipidmetabolism model regulated by oncogenes/tumor suppressor genes and associated with the clinical characteristics of CRC is necessary to further understand the mechanism of fatty acid metabolism in CRC. In this study, through multi-data combined with bioinformatic analysis and basic experiments, we introduced a tumor suppressor gene, EPHX2, which is rarely reported in CRC, and confirmed that its inhibitory effect on CRC is related to fatty acid degradation.

Repeat hepatic resection versus percutaneous ablation for the treatment of recurrent hepatocellular carcinoma: meta-analysis.

BACKGROUND: The efficacy of repeat hepatic resection (rHR) in the treatment of recurrent hepatocellular carcinoma compared with radiofrequency or microwave ablation after resection of the primary tumour remains controversial. A systematic review and meta-analysis were performed to compare the safety and efficacy of these procedures. METHODS: PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure databases were systematically searched to identify related studies published before 10 October 2021. Overall and recurrence-free survival after different treatments were compared based on pooled hazard ratios with a random-effects model. RESULTS: Two randomized clinical trials and 28 observational studies were included, involving 1961 and 2787 patients who underwent rHR and ablation respectively. Median perioperative mortality in both groups was zero but patients in the rHR group had higher median morbidity rates (17.0 per cent) than those in the ablation group (3.3 per cent). rHR achieved significantly longer recurrence-free survival than ablation (HR 0.79, 95 per cent c.i. 0.70 to 0.89, P < 0.001), while both groups had similar overall survival (HR 0.93, 95 per cent c.i. 0.83 to 1.04, P = 0.18). CONCLUSION: rHR and ablation based on radio- or microwaves are associated with similar overall survival in patients with recurrent hepatocellular carcinoma after resection of the primary tumour.

Retrospective analysis of the efficacy of adjuvant cytokine-induced killer cell immunotherapy combined with chemotherapy in colorectal cancer patients after surgery.

OBJECTIVES: Even though postoperative chemotherapy can eliminate residual tumor cells in patients with colorectal cancer (CRC), severe adversity, weakened immunity and drug resistance are still problems. Adjuvant cytokine-induced killer (CIK) cell therapy is an alternative to CRC patients after surgery. The present study investigated the efficacy of adjuvant CIK cell therapy combined with chemotherapy in postoperative CRC patients. METHODS: This retrospective analysis included 137 postoperative CRC patients, including 71 who received adjuvant chemotherapy alone (control group) and 66 who received adjuvant immunotherapy based on CIK cells combined with chemotherapy (CIT group). RESULTS: Long-term follow-up study indicated that overall survival (OS) and progression-free survival (PFS) were significantly longer in the CIT group than in the control group. Subgroup analyses showed that CIT treatment significantly improved OS and PFS of CRC patients classified as stage II and N0 stage and in patients with primary tumors in the rectum. Increasing the number of CIK infusions resulted in better prognosis. CRC patients aged < 65 years were found to benefit more from CIT-based therapy than patients aged ≥ 65 years. A retrospective case-control study indicated that the primary tumor expression of signalling lymphocytes activating molecule family 7 (SLAMF7) was associated with increased efficacy of CIT treatment. CONCLUSIONS: Adjuvant CIT therapy was an effective therapeutic strategy for postoperative CRC patients prolonging OS and PFS. Patient age, tumor stage and expression of SLAMF7 may be potential indicators of the efficacy of CIT therapy.

Decreased m6A Modification of CD34/CD276(B7-H3) Leads to Immune Escape in Colon Cancer.

Previous studies have reported that m6a modification promotes tumor immune escape by affecting tumor microenvironment (TME). Due to the complexity of TME, a single biomarker is insufficient to describe the complex biological characteristics of tumor and its microenvironment. Therefore, it is more meaningful to explore a group of effective biomarkers reflecting different characteristics of cancer to evaluate the biological characteristics of solid tumors. Here, the immune gene CD34/CD276 with different m6A peak was obtained by m6A sequencing (MeRIP-seq) of colon cancer (CRC)clinical samples and combined with MsIgDB database, which was used to perform cluster analysis on TCGA-COAD level 3 data. The CD34/CD276 as a molecular marker for CRC prognosis was confirmed by survival analysis and immunohistochemical assay. Further bioinformatics analysis was carried out to analyze the molecular mechanism of CD34/CD276 affecting the TME through m6a-dependent down-regulation and ultimately promoting immune escape of CRC.

Psychophysiological data-driven multi-feature information fusion and recognition of miner fatigue in high-altitude and cold areas.

Fatigue-induced human error is a leading cause of accidents. The purpose of this exploratory study in China was to perform field tests to measure fatigue psychophysiological parameters, such as electrocardiography (ECG), electromyography (EMG), pulse, blood pressure, reaction time and vital capacity (VC), in miners in high-altitude and cold areas and to perform multi-feature information fusion and fatigue identification. Forty-five miners were randomly selected as subjects for a field test, and feature signals were extracted from 90 psychophysiological features as basic signals for fatigue analysis. Fatigue sensitivity indices were obtained by Pearson correlation analysis, t-test and receiver operating characteristic (ROC) curve performance evaluation. The ECG time-domain, ECG frequency-domain, EMG, VC, systolic blood pressure (SBP), and pulse were significantly different after miner fatigue. The support vector machine (SVM) and random forest (RF) techniques were used to classify and identify fatigue by information fusion and factor combination. The optimal fatigue classification factors were ECG-FD (CV Accuracy = 85.0%) and EMG (CV Accuracy = 90.0%). The optimal combination of factors was ECG-TD + ECG-FD + EMG (CV accuracy = 80.0%). Furthermore, SVM machine learning had a good recognition effect. This study shows that SVM and RF can effectively identify miner fatigue based on fatigue-related factor combinations. ECG-FD and EMG are the best indicators of fatigue, and the best performance and robustness are obtained with three-factor combination classification. This study on miner fatigue identification provides a reference for research on clinical medicine and the identification of human fatigue under high-altitude, cold and low-oxygen conditions.

Embryonic movement stimulates joint formation and development: Implications in arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous syndrome where multiple joints have reduced range of motion due to contracture formation prior to birth. A common cause of AMC is reduced embryonic movement in utero. This reduction in embryonic movement can perturb molecular mechanisms and signaling pathways involved in the formation of joints during development. The absence of mechanical stimuli can impair joint cavitation, resulting in joint fusion, and ultimately eliminate function. In turn, mechanical stimuli are critical for proper joint formation during development and for mitigating AMC. Studies in experimental animal models have provided a greater understanding on the molecular pathophysiology of congenital contracture formation as a consequence of embryonic immobilization. Elucidation of how the mechanical signaling environment is transduced to initiate a biological response will be necessary to gain a deeper understanding of how mechanical stimuli are intertwined in the molecular regulation of joint development.

Reversibility of marrow adipose accumulation and reduction of trabecular bone in the epiphysis of the proximal tibia.

Mechanical stimuli play an important role in the homeostasis of trabecular bone and marrow adipose tissue, particularly for the weight-bearing skeleton. Prolonged immobilization and disuse have been shown to reduce trabecular bone content and increase marrow adipose tissue in the bones of lower limb joints such as the knee. However, details on the temporal response of this relationship to prolonged immobilization and its reversibility is limited. Forty rats had one knee immobilized at 45° of flexion for 2, 4, 8, or 16 weeks and subsequently remobilized for 0 or 8 weeks. The contralateral knees were used as controls. Histomorphometric measures of trabecular bone and marrow adipose tissue (MAT) areas were conducted in the epiphysis of the proximal tibia. Knee immobilization for 4, 8, and 16 weeks significantly reduced trabecular bone area by -0.125, -0.139, and -0.161 mm2/mm2, respectively, with corresponding 95 % CIs of [-0.012, -0.239], [-0.006, -0.273], and [-0.101, -0.221]. MAT area significantly increased at 2 and 16 weeks by +0.008 and +0.027 mm2/mm2, respectively, with 95 % CIs of [0.014, 0.002] and [0.039, 0.016]. Remobilization for 8 weeks restored trabecular bone area compared to the contralateral knee and the magnitude of change was significantly greater for 8 and 16 weeks of immobilization with effect sizes of 1.69 and 1.86, respectively. The difference in MAT area between immobilized and contralateral knees were eliminated with remobilization. These results characterize the temporal response of trabecular bone and MAT in the epiphysis of the proximal tibia to joint immobilization and remobilization.

Hyperplasia and accelerated hypertrophy of marrow adipocytes with knee immobilization were sustained despite remobilization.

Skeletal disuse can cause an accumulation of bone marrow adipose tissue (MAT) characterized by a combination of marrow adipocyte hyperplasia and/or hypertrophy. The malleability of MAT accumulation and of the hyperplasia and hypertrophy upon remobilization is unknown. In this study, we showed extensive hyperplasia and accelerated hypertrophy of bone marrow adipocytes in the proximal tibia epiphysis of rat knees immobilized for durations between 1 and 32 wk. Similar histomorphometric measures of adipocytes carried out in unoperated controls allowed distinguishing the effects of immobilization from the effects of aging. Although both knee immobilization and aging led to adipocyte hypertrophy, adipocyte hyperplasia was the hallmark signature effect of immobilization on MAT. Both bone marrow adipocyte hyperplasia and hypertrophy were sustained despite knee remobilization for durations up to four times the duration of immobilization. These results suggest that adipocyte hyperplasia is the predominant mechanism explaining MAT accumulation in skeletal disuse. In this model, the changes were unremitting for the investigated time points. Investigating the cellular and molecular mechanisms of marrow adipocyte mechanoregulation will be important to better understand how adipocytes adapt to changes in mechanical environments.NEW & NOTEWORTHY This longitudinal study elucidates the response of marrow adipose tissue adipocytes in weight-bearing joints to changes in different mechanical environments, and we provide insight on the malleability of the changes over time. In a rat animal model, knee immobilization induced hyperplasia and accelerated the age-dependent hypertrophy of adipocytes. Changes in adipocyte number and size were sustained despite unassisted remobilization. Multimodal distributions of cell size were characteristic of bone marrow adipocytes.

Mechanical adaptation of synoviocytes A and B to immobilization and remobilization: a study in the rat knee flexion model.

The objective of this study was to quantify the in vivo response of synoviocytes type A and B in the posterior joint capsule to knee immobilization and remobilization. Also, to correlate the immunohistochemical data with selected mRNA expression in the posterior joint capsule. Forty-two adult male Sprague-Dawley rats had one knee joint immobilized in flexion for durations of 1-4 weeks. Fifteen were harvested after immobilization and 15 were remobilized for 4 weeks. They were analyzed immunohistochemically with CD68 and CD55 antibodies as markers for synoviocytes type A and type B, respectively. Controls were 15 age-matched rats. The remaining 12 rats had their posterior capsule harvested and synoviocyte-specific CD68, CD55, and uridine diphosphoglucose dehydrogenase (UDPGD) mRNA expression was measured. Controls were 12 sham-operated knees. Knee immobilization for 2 weeks significantly increased synoviocytes A:B staining ratio compared to controls (3.88 ± 1.39 vs. 1.83 ± 0.76; p < 0.05). Remobilization for 4 weeks abolished the increase. Remobilization of knees that were immobilized for 1 week also significantly lowered the synoviocytes A:B staining ratios compared to immobilized-only knees (0.66 ± 0.23 vs. 2.19 ± 0.54; p < 0.05) and to controls (0.66 ± 0.23 vs. 1.32 ± 0.29; p < 0.05). Consistent with the immunohistochemistry, mRNA expression of synoviocyte type B-specific CD55 and UDPGD genes were significantly lower in the capsules immobilized for 2 weeks (both p < 0.05). Knee immobilization and remobilization significantly modulated synoviocytes in vivo, stressing their mechanosensitive nature and possible contribution to immobility-induced changes of the joint capsule.

Up-regulation of S100A4 expression by HBx protein promotes proliferation of hepatocellular carcinoma cells and its correlation with clinical survival.

BACKGROUND: Hepatocellular carcinoma is one of the most common cancers worldwide. HBV-related HCC has characteristics of faster progression and worse prognosis. Previous studies have confirmed that HBx protein plays numbers of important roles in development of HBV-HCC. However, the molecular mechanism of carcinogenicity of HBx is still not well documented. METHODS: Firstly, a HCC cell line over-expressing HBx was established and its function was verified. Subsequently, the differentially expressed genes were detected by transcriptome sequencing technology and use the Western Blot technology to detect the up-regulated genes in HBx overexpressed cells, and the functional correlation of the genes was analyzed. Finally, tissue microarray was used to correlate up-regulated gene with clinical follow-up data to verify correlation with clinical prognosis. RESULTS: Over-expression of HBx could promote cell proliferation, and over-expression of HBx could up-regulate the expression of S100A4 protein. ShRNA experiments showed that HBx promoted cell proliferation by upregulating the expression of S100A4. IFN-α2b can down-regulate the expression of S100A4 and inhibit the proliferation of HCC cells. The expression of S100A4 in cancer was significantly up-regulated compared with adjacent tissues, and was also significantly associated with tumors volume, the expression of PD-L1 and the survival time of patients with HCC. CONCLUSION: In general, S100A4 may be an effective therapeutic target for HBV-HCC. And the connection between S100A4 and HBV are not clear yet. This study may play a guiding role in the future clinical treatment of HCC.

Knee joint stiffness following immobilization and remobilization: A study in the rat model.

Deficits in extension can limit the function and performance of the knee joint. The range of motion (ROM) deficit in knee extension is often measured and reported at a single torque value applied in the flexion-extension axis. This static measurement of ROM omits key details about the biomechanical properties of the knee, such as its mechanical stiffness. Our objectives were (1) to quantify knee extension stiffness after various periods of immobilization and remobilization, and (2) to evaluate how stiffness correlated with the length of the posterior knee capsule. Two hundred fifty-six male Sprague Dawley rats had one knee immobilized at a 45° angle in flexion using a Delrin® plate for 6 different durations ranging from 1 to 32 weeks. Remobilization was initiated by removing the plate and lasted for 0-48 weeks. The contralateral knee and unoperated age-matched rats were used as controls. An automated arthrometer extended the knee at four pre-determined torques and these data were used to calculate mechanical stiffness. The stiffness of knees immobilized for 8 or more weeks was significantly greater than controls and persisted despite remobilization (p < 0.05). Remobilization after 16 and 32 weeks of immobilization resulted in a progressive increase in mechanical stiffness (p < 0.05). The length of the posterior capsule significantly correlated with knee stiffness in extension (p < 0.05). Deficit in knee extension was characterized by increased stiffness, which was irreversible upon unassisted remobilization.

Joint contractures and acquired deforming hypertonia in older people: Which determinants?

Joint contractures and acquired deforming hypertonia are frequent in dependent older people. The consequences of these conditions can be significant for activities of daily living as well as comfort and quality of life. They can also negatively affect the burden of care and care costs. However, etiological factors and pathophysiologic mechanisms remain only partly understood. As a result, preventive interventions and treatments focus entirely on controlling symptoms rather than the causes. Moreover, the effectiveness of these interventions remains to be validated. The purpose of this position paper is to present current data on etiological factors contributing to the development of joint contractures and acquired deforming hypertonia in older people. The pathophysiologic mechanisms of joint contractures in animal models are also presented.

Range of Extension Correlates with Posterior Capsule Length after Knee Remobilization.

INTRODUCTION: Knee injuries are common in sports, and postinjury immobilization is often required to protect healing tissues and alleviate pain, but both the injury and the immobilization can lead to a knee contracture. Knee flexion contractures limit performance. Previous research has identified posterior knee capsule fibrosis as a contributor to immobility-induced knee flexion contractures. This study aims to measure posterior knee capsule length at various durations of remobilization after knee immobilization and to correlate with the recovery of knee range of motion. METHODS: Two hundred fifty-nine male Sprague-Dawley rats had one knee extra-articularly immobilized in flexion with a Delrin® plate at a 45° angle for one of six durations: 1, 2, 4, 8, 16, or 32 wk, followed by spontaneous remobilization after plate removal, which lasted zero, one, two, and four times the duration of immobilization. The contralateral knees served as controls. The posterior knee capsule length was measured by histomorphometry. These measures were correlated with previously published range of motion data from the same cohort of specimens. RESULTS: Knees immobilized for 1 and 2 wk partially recovered posterior capsule length (P > 0.05). Knees immobilized beyond 2 wk failed to recover posterior capsule length, irrespective of the duration of remobilization (P < 0.05). The residual posterior capsule shortening correlated with the lack of knee extension (P < 0.003). CONCLUSIONS: For knee injuries requiring more than 2 wk of immobilization, unassisted remobilization will not restore posterior knee capsule shortening and the reduction in knee extension. These results support the role of the posterior capsule in knee joint contracture and the need to minimize the duration of immobility and to assist the recovery of the range of knee extension after a sport injury.