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The present work aims to evaluate the tolerance, osmoregulation, metabolism, and antioxidant ability of saline water immersed grass goldfish (Carassius auratus) during the recovery in freshwater. Grass goldfish (38.15 ±5.48g) acclimated in freshwater were immersed by two salinities (20 ‰ or 30 ‰) for different time durations (10min, 20min, 30min, and 60min); and the physiological stress responses were measured during a recovery period of 24 h. Resultly, osmotic pressure kept unchanged in all treated fish, whereas the decline of sodium ions, potassium ions, and the ratio of Na+/Cl- was observed in saline treated fish. Differently, concentrations of chloride ion in saline treated fish were higher than control fish, but decreased as recovery time went. Soon after freshwater recovery, the gill Na+/K+—ATPase in saline treated fish kept lower than control group except for the fish immersed by salinity 20 for 10 – 30 min. Specifically, gill Na+/K+—ATPase levels showed a decreased trend in all saline treated fish, but the mRNA of NKA-α and NKA-β both significantly increased at 1h and 6h in salinity 20 treated fish.Compared with control group, cortisol levels were increased in all salinity 20 treated fish at 1h of recovery, but then gradually declined. However, in salinity 30 treated group, cortisol levels showed a rise trend and maintained high levels until 24 h post recovery. As for serum lactic acid, fish treated by salinity 20 for 10 or 20 min did not show any fluctuation. Whereas there was a rise trend of lactic acid in fish immersed by salinity 20 for 30 min and 60 min as recovery time went on. Fish treated by salinity 30 exhibited a relative high level of serum lactic acid at 1h and then gradually decreased at 24 post recovery. What’s more, antioxidant capacities were higher at salinity 20 treated fish than salinity 30 immersed fish. The limited results indicated that grass goldfish could well osmoregulate and survive by immersion in salinity 20 less than 60 min or salinity 30 less than 30min, even though immersion by salinity 20 could minimize the negative effect.

Purpose To summarize the magnetic resonance imaging manifestations of hepatocellular carcinoma (HCC) with and without progression after stereotactic body radiation therapy (SBRT) and evaluate the treatment effect using the modified Liver Reporting and Data System (LI-RADS). Methods Between January 2015 and December 2020, 102 patients with SBRT-treated HCC were included. Tumor size, signal intensity, and enhancement patterns at each follow-up period were analyzed. Three different patterns of enhancement: APHE and wash-out, non-enhancement, and delayed enhancement. For modified LI-RADS, delayed enhancement with no size increase were considered to be a “treatment-specific expected enhancement pattern” for LR-TR non-viable. Results Patients were divided into two groups: without (n = 96) and with local progression (n = 6). Among patients without local progression, APHE and wash-out pattern demonstrated conversion to the delayed enhancement (71.9%) and non-enhancement (20.8%) patterns, with decreased signal intensity on T1WI(92.9%) and DWI(99%), increased signal intensity on T1WI (99%), and decreased size. The signal intensity and enhancement patterns stabilized after 6–9 months. Six cases with progression exhibited tumor growth, APHE and wash-out, and increased signal intensity on T2WI/DWI. Based on the modified LI-RADS criteria, 74% and 95% showed LR-TR-nonviable in 3 and 12 months post-SBRT, respectively. Conclusions After SBRT, the signal intensity and enhancement patterns of HCCs showed a temporal evolution. Tumor growth, APHE and wash-out, and increased signal intensity on T2WI/DWI indicates tumor progression. Modified LI-RADS criteria showed good performance in evaluating nonviable lesions after SBRT.

Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor α

This study aims to longitudinally explore whether and how rapid eye movement sleep behavior disorder (RBD), depression, and anxiety mediate the association between dopaminergic replacement therapy (DRT) and impulse control disorders (ICDs) in patients with Parkinson's disease (PD).Subjects were selected from the Parkinson's Progression Markers Initiative. After excluding missing data, 268, 223, 218, 238, and 219 patients with PD diagnosed at 12, 24, 36, 48, and 60 months prior, respectively, were included. We used the Questionnaire for Impulsive-Compulsive Disorders, RBD Screening Questionnaire, Geriatric Depression Scale, and State-Trait-Anxiety Inventory to assess ICBs, RBD, depression, and anxiety, respectively. We constructed three causal mediation analysis models to infer potential contingent pathways from DRT to ICD mediated by depression, anxiety, and RBD separately.DRT was associated with an increased risk of PD incidence. Aggravation of ICDs was partly explained by improvements in depression (the average causal mediation effect accounted for 8.0% of the total effect) and RBD (the average causal mediation effect of RBD accounted for 16.4% of the total effect). This suggested that anxiety (the average causal mediation effect accounted for 12.7% of the total effect) plays a mediating role.Focusing on changes in RBD, depression, and anxiety associated with hyperdopaminergic status should be an essential part of strategies to prevent ICDs in patients with Parkinson's disease.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase ubiquitously expressed mainly in the cytoplasm of several tissues. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. SHP2 acts as both a phosphatase and a scaffold, and plays prominently oncogenic functions but can be tumor suppressor in a context-dependent manner. It typically acts as a positive regulator of RTKs signaling with some inhibitory functions reported as well. SHP2 expression and activity is regulated by such factors as allosteric autoinhibition, microRNAs, ubiquitination and SUMOylation. Dysregulation of SHP2 expression or activity causes many developmental diseases, and hematological and solid tumors. Moreover, upregulated SHP2 expression or activity also decreases sensitivity of cancer cells to anticancer drugs. SHP2 is now considered as a compelling anticancer drug target and several classes of SHP2 inhibitors with different mode of action are developed with some already in clinical trial phases. Moreover, novel SHP2 substrates and functions are rapidly growing both in cell and cancer. In view of this, we comprehensively and thoroughly reviewed literatures about SHP2 regulatory mechanisms, substrates and binding partners, biological functions, roles in human cancers, and different classes of small molecule inhibitors target this oncoprotein in cancer.

Sepsis-induced acute kidney injury (AKI) is a common in clinic. Circular RNAs (circRNAs) play significant roles in ameliorating AKI. The purpose of this study was aimed to identify the role of circ_0074371 and the potential action mechanism in sepsis-induced AKI.AKI patients and healthy individual serum samples were collected and the relative expression of circ_0074371 was measured by real-time polymerase chain reaction (RT-PCR). HK2 cells were treated with different dose (0, 2.5, 5 and 10 μg/ml) lipopolysaccharide (LPS) to establish the AKI cell model. The cell viability and apoptosis of HK2 cells were detected using cell counting kit-8 (CCK-8) and flow cytometry, respectively. The contents of malondialdehyde (MDA), and superoxide dismutase (SOD) were evaluated using the relative commercial kits. The IL-1β and TNF-α levels in cell culture supernatants were measured by ELISA. The interaction relationship between miR-330-5p and circ_0074371 or ELK1 was predicted by Targetscan database and further confirmed by the dual-luciferase reporter assay system.The circ_0074371 expression was up-regulated in sepsis patients and LPS-induced HK2 cells. Silencing circ_0074371 promoted HK2 cells viability and inhibited the HK2 cells apoptosis. miR-330-5p inhibitor weakened circ_0074371 inhibitor-induced cell viability, apoptosis and oxidative stress. Further mechanism analysis showed that circ_0074371 acted as a sponge for miR-330-5p to increase ELK1 expression level. Importantly, miR-330-5p downregulation or ELK1 upregulation reversed the action of circ_0074371 knockdown on LPS-induced HK2 cells.Knockdown of circ_0074371 ameliorated LPS-induced HK2 cells apoptosis, inflammation and oxidative stress via regulating miR-330-5p/ELK1, opening a new window into the pathogenesis AKI.

Background Neonatal hyperoxic brain injury is caused by exposure to hyperphysiological oxygen content during the period of incomplete development of the oxidative stress defence system, resulting in a large number of reactive oxygen species (ROS) and causing damage to brain tissue. Mitochondrial biogenesis refers to the synthesis of new mitochondria from existing mitochondria, mostly through the PGC-1α/Nrfs/TFAM signalling pathway. Resveratrol (Res), a silencing information regulator 2-related enzyme 1 (Sirt1) agonist, has been shown to upregulate the level of Sirt1 and the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We speculate that Res has a protective effect on hyperoxia-induced brain injury through mitochondrial biogenesis. Methods Sprague-Dawley (SD) pups were randomly divided into the nonhyperoxia (NN) group, the nonhyperoxia with dimethyl sulfoxide (ND) group, the nonhyperoxia with Res (NR) group, the hyperoxia (HN) group, the hyperoxia with dimethyl sulfoxide (HD) group, and the hyperoxia with Res (HR) group within 12 h after birth. The HN, HD, and HR groups were placed in a high-oxygen environment (80‒85%), and the other three groups were placed in the standard atmosphere. The NR and HR groups were given 60 mg/kg Res every day, the ND and HD groups were given the same dose of dimethyl sulfoxide (DMSO) every day, and the NN and HN groups were given the same dose of normal saline every day. On postnatal day (PN) 1, PN7, and PN14, brain samples were acquired for HE staining to assess pathology, TUNEL to detect apoptosis, and real-time quantitative polymerase chain reaction and immunoblotting to detect the expression levels of Sirt1, PGC-1α, nuclear respiratory factor 1 (Nrf1), nuclear respiratory factor 2 (Nrf2) and mitochondrial transcription factor A (TFAM) in brain tissue. Results Hyperoxia induced brain tissue injury; increased brain tissue apoptosis; inhibited Sirt1, PGC-1α, Nrf1, Nrf2, TFAM mRNA expression in mitochondria; diminished the ND1 copy number and ND4/ND1 ratio; and decreased Sirt1, PGC-1α, Nrf1, Nrf2, and TFAM protein levels in the brain. In contrast, Res reduced brain injury and attenuated brain tissue apoptosis in neonatal pups and increased the levels of the corresponding indices. Conclusion Res has a protective effect on hyperoxia-induced brain injury in neonatal SD pups by upregulating Sirt1 and stimulating the PGC-1α/Nrfs/TFAM signalling pathway for mitochondrial biogenesis.

Background Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated. Results Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m3. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice. Conclusions These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

High-precision microelectromechanical system (MEMS) gyroscopes are significant in many applications. Bias instability (BI) is an important parameter that indicates the performance of a MEMS gyroscope and is affected by the 1/f noise of the MEMS resonator and readout circuit. Since the bandgap reference (BGR) is an important block in the readout circuit, reducing its 1/f noise is key to improving a gyroscope’s BI. In a traditional BGR, the error amplifier is applied to provide a virtual short-circuit point, but it introduces the main low-frequency noise sources. This paper proposes an ultralow 1/f noise BGR by removing the error amplifier and applying an optimized circuit topology. In addition, a simplified but accurate noise model of the proposed BGR is obtained to optimize the BGR’s output noise performance. To verify this design, the proposed BGR has been implemented in a 180 nm CMOS process with a chip area of 545 × 423 μm. The experimental results show that the BGR’s output integrated noise from 0.1 to 10 Hz is 0.82 μV and the thermal noise is 35 nV/√Hz. Furthermore, bias stability tests of the MEMS gyroscope fabricated in our laboratory with the proposed BGR and some commercial BGRs are carried out. Statistical results show that reducing the BGR’s 1/f noise can nearly linearly improve the gyroscope’s BI.

Objective Recent studies indicated that transmembrane protein 40 (TMEM40) is associated with several types of cancers but is not clear in cervical cancer (CC). The study aimed to examine the role of TMEM40 in CC and related mechanisms. Methods The expression of TMEM40 in CC tissues and cell lines was studied with western blot and real-time quantitative RT-PCR. The effect of TMEM40 on proliferation was evaluated by CCK-8, EdU and colony formation assay. The migration, invasion, cell cycle and apoptosis of CC cells were studied with wound healing, transwell assays and flow cytometry. Tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. Results The results revealed that the TMEM40 elevation in CC tissues and cell lines was closely correlated with tumor size and lymph node metastasis in clinical patients. Upregulation of TMEM40 with OE-TMEM40 vector promoted the invasion, migration and proliferation, inhibited the apoptosis and led to distinct S cell cycle arrest in CC cell lines. Silencing TMEM40 with shRNA inhibited the invasion, migration and proliferation, promoted apoptosis and led to a G0/G1 cell cycle arrest in CC cell lines. Silence of TMEM40 downregulated the expression of c-MYC, Cyclin D1, matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-9 (MMP-9), but in contrast, activated p53 and several apoptosis related proteins such as p53, Caspase-3, Caspase-9 and PARP1. In addition, TMEM40 silencing dramatically decreased tumor growth in mice models. Conclusion The present study demonstrates that TMEM40 upregulation can be a potential prognostic biomarker and contribute to CC development.

Aqueous zinc metal batteries are appealing candidates for grid energy storage. However, the inadequate electrochemical reversibility of the zinc metal negative electrode inhibits the battery performance at the large-scale cell level. Here, we develop practical ampere-hour-scale aqueous Zn metal battery pouch cells by engineering the electrolyte solution. After identifying the proton reduction as the primary source of H2 evolution during Zn metal electrodeposition, we design an electrolyte solution containing reverse micelle structures where sulfolane molecules constrain water in nanodomains to hinder proton reduction. Furthermore, we develop and validate an electrochemical testing protocol to comprehensively evaluate the cell’s coulombic efficiency and zinc metal electrode cycle life. Finally, using the reverse micelle electrolyte, we assemble and test a practical ampere-hour Zn||Zn0.25V2O5•nH2O multi-layer pouch cell capable of delivering an initial energy density of 70 Wh L−1 (based on the volume of the cell components), capacity retention of about 80% after 390 cycles at 56 mA g−1cathode and ~25 °C and prolonged cycling for 5 months at 56 mA g−1cathode and ~25 °C.

Myocardial infarction (MI) is a life-threatening condition among patients with cardiovascular diseases. MI increases the risk of stroke and heart failure and is a leading cause of morbidity and mortality worldwide. Several genetic and epigenetic factors contribute to the development of MI, suggesting that further understanding of the pathomechanism of MI might help in the early management and treatment of this disease. Toll-like receptors (TLRs) are well-known members of the pattern recognition receptor (PRR) family and contribute to both adaptive and innate immunity. Collectively, studies suggest that TLRs have a cardioprotective effect. However, prolonged TLR activation in the response to signals generated by damage-associated molecular patterns (DAMPs) results in the release of inflammatory cytokines and contributes to the development and exacerbation of myocardial inflammation, MI, ischemia-reperfusion injury, myocarditis, and heart failure. The objective of this review is to discuss and summarize the association of TLRs with MI, highlighting their therapeutic potential for the development of advanced TLR-targeted therapies for MI.

The multicenter study aimed to explore the relationship between the growth pattern of liver metastases on preoperative MRI and early recurrence in patients with colorectal cancer liver metastases (CRCLM) after surgery.A total of 348 CRCLM patients from 3 independent centers were enrolled, including 130 patients with 339 liver metastases in the primary cohort and 218 patients in validation cohorts. Referring to the gross classification of hepatocellular carcinoma (HCC), the growth pattern of each liver metastasis on MRI was classified into four types: rough, smooth, focal extranodular protuberant (FEP), and nodular confluent (NC). Disease-free survival (DFS) curve was constructed using the Kaplan-Meier method.In primary cohort, 42 (12.4%) of the 339 liver metastases were rough type, 237 (69.9%) were smooth type, 29 (8.6%) were FEP type, and 31 (9.1%) were NC type. Those patients with FEP- and/or NC-type liver metastases had shorter DFS than those without such metastases (p0.05). However, there were no significant differences in DFS between patients with rough- and smooth-type liver metastases and those without such metastases. The patients with FEP- and/or NC-type liver metastases also had shorter DFS than those without such metastases in two external validation cohorts. In addition, 40.5% of high-risk-type (FEP and NC) liver metastases converted to low-risk types (rough and smooth) after neoadjuvant chemotherapy.The FEP- and NC-type liver metastases were associated with early recurrence, which may facilitate the clinical treatment of CRCLM patients.• In the primary cohort, patients with FEP- and NC-type metastases had shorter disease-free survival (DFS) and a higher intrahepatic recurrence rate than patients without such metastases in the liver. • In the primary cohort, there were no significant differences in DFS or intrahepatic recurrence rate between patients with rough- and smooth-type metastases and those without such metastases in the liver. • High-risk patients had shorter DFS and a higher intrahepatic recurrence rate than low-risk patients in primary and external validation cohorts.

Vertical joints with different lengths and slope distances (the horizontal distance from joints to slope shoulder) are generated at the top of the loess slope because of the unloading and collapsibility of the loess. The existence of vertical joints is a significant risk factor for loess landslides. This paper applies three methods, including laboratory tests, numerical simulation and theoretical analysis, to analyze the influence of vertical joints on the stability of loess slope. Firstly, the typical failure mode and strength characteristics of the samples containing vertical joints are analyzed through the unconfined compressive strength test and triaxial compression test. Further, the effects of vertical joints with different lengths and the slope distance on the slope safety coefficient and sliding surface position are calculated by finite element numerical analysis. Finally, the formula for calculating the safety coefficient of loess slope with vertical joints is derived. The results show that: the joint bonding degree affects the sample's strength and failure rate. The strength of the sample with open vertical joints is less than that of closed ones, and the failure rate is greater than that of closed ones. When the length and the slope distances of the vertical joint are less than 5 m, the influence of vertical joints on the shape and position of the sliding surface will be small. When the length of the vertical joint is more than 5 m and less than 15 m, the safety factor of the slope decreases with the increase in the length of vertical joints. When the length of vertical joints reaches 15 m, and the slope distance is 10 m, the deterioration degree of vertical joints on the slope comes up to the peak. Statistical analysis shows that the dominant dip angle of shear fracture at the back edge of the landslide affected by the vertical joint surface is between 45° and 65°. The research results can be used for rapid calculation of the safety coefficient and rapid evaluation of slope stability of loess slope with vertical joints.