Search

Abstract The application of artificial neural networks (ANNs) can be found in numerous fields, including image and speech recognition, natural language processing, and autonomous vehicles. As well, intrusion detection, the subject of this paper, relies heavily on it. Different intrusion detection models have been constructed using ANNs. While ANNs are relatively mature to construct intrusion detection models, some challenges remain. Among the most notorious of these are the bloated models caused by the large number of parameters, and the non-interpretability of the models. Our paper presents Convolutional Kolmogorov-Arnold Networks (CKANs), which are designed to overcome these difficulties and provide an interpretable and accurate intrusion detection model. Kolmogorov-Arnold Networks (KANs) are developed from the Kolmogorov-Arnold representation theorem. Meanwhile, CKAN incorporates a convolutional computational mechanism based on KAN. The model proposed in this paper is constructed by incorporating attention mechanisms into CKAN’s computational logic. The datasets CICIoT2023 and CICIoMT2024 were used for model training and validation. From the results of evaluating the performance indicators of the experiments, the intrusion detection model constructed based on CKANs has an attractive application prospect. As compared with other methods, the model can predict a much higher level of accuracy with significantly fewer parameters. However, it is not superior in terms of memory usage, execution speed and energy consumption.

Abstract Balanced self-renewal and differentiation of stem cells are crucial for maintaining tissue homeostasis, but the underlying mechanisms of this process remain poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Pax, which is orthologous to mammalian PXN, coordinates the proliferation and differentiation of ISCs during both normal homeostasis and injury-induced midgut regeneration in Drosophila. Loss of Pax promotes ISC proliferation while suppressing its differentiation into absorptive enterocytes (ECs). Mechanistically, our findings demonstrate that Pax is a conserved target gene of the Hippo signaling pathway in both Drosophila and mammals. Subsequent investigations have revealed Pax interacts with Yki and enhances its cytoplasmic localization, thereby establishing a feedback regulatory mechanism that attenuates Yki activity and ultimately inhibits ISCs proliferation. Additionally, Pax induces the differentiation of ISCs into ECs by activating Notch expression, thus facilitating the differentiation process. Overall, our study highlights Pax as a pivotal component of the Hippo and Notch pathways in regulating midgut homeostasis, shedding light on this growth-related pathway in tissue maintenance and intestinal function.

Abstract For the purpose of enhancing the performance of interior permanent magnet synchronous motors (IPMSMs) sensorless control, a flux observer based on a third‐order generalized integrator with enhanced frequency‐locked loop (TOGI‐EFLL) is introduced in this paper. Compared with the traditional second‐order generalized integrator with frequency‐locked loop (SOGI‐FLL), the proposed TOGI‐EFLL can effectively mitigate the direct current (DC) bias stemming from non‐ideal factors, such as the inverter non‐linearities and detection errors, without introducing additional parameters. Initially, the active flux observer model and the limitations of the conventional SOGI‐FLL are presented. Subsequently, the proposed flux observer based on TOGI‐EFLL has been intensively investigated. Furthermore, the design of the damping factor and the digital implementation of the algorithm are developed to ensure seamless integration into digital systems. Finally, the effectiveness of the proposed sensorless control strategy is validated through the comprehensive experimental results.

Objective As the core function of urban rail transit brake control devices, the structural principle design of pressure control is crucial for the brake control system. High-frequency switching solenoid valve pressure control method is the mainstream control approach, studying its structural characteristics is particularly important for enhancing the reliability of brake control devices. Method By analyzing different configurations of solenoid valves, the basic structures of five high-frequency switching solenoid valve pressure control methods are identified, including series exhaust, series pressure-holding, parallel exhaust, parallel pressure-holding, and parallel inflation. Their characteristics and applicable scenarios based on their failure modes are summarized. Result & Conclusion According to T/CAMET 04004.4—2018 ′Brake systems of urban rail vehicles Part 4: Technical specification of brake control units′, the exhaust-type pressure control structure is suitable for normal braking air circuits, while pressure-holding and inflation-type pressure control structures are suitable for emergency braking air circuits. The series pressure control structure maintains output pressure stability better than the parallel pressure control structure does, whereas the parallel pressure control structure has a faster inflation rate compared to the series pressure control structure. When designing the pressure control structure of brake control devices, it is essential to comprehensively consider factors such as the target pressure control accuracy, inflation and exhaust rate requirements, and solenoid valve control strategies, and to configure the chamber volume and pipeline diameter appropriately.

High nitrogen stainless steel has wide application prospects in many fields such as aerospace, petrochemical industry, marine engineering, energy, and military. Nitrogen is added as an alloying element to replace the more expensive element, nickel, thereby reducing the cost. Since nitrogen serves as an austenite stabilizer and has a higher nickel equivalent, it can improve the corrosion resistance and other mechanical properties of the alloy, yet it could also cause porosity and cracks. As the most upstream process of material processing, the solidification process largely determines the structure and performance of the product. High temperature confocal microscope can provide in-situ observations of phase transformation in metals and alloys. Thermodynamic calculations and other research articles show that the solidification of high nitrogen stainless steel usually involves multiple phases, δ-ferrite, γ-austenite, and liquid (L). Present research utilizes a unique concentric solidification technique to manually create a solid/liquid interface for studying the coexistence of multi-phase. It was found that during the solidification process of a high nitrogen stainless steel, the γ grows along the L/δ interface (L + δ → γ), and then, the pre-formed γ through peritectic reaction grows into δ and L phase. This two-step solidification mode is a typical peritectic solidification. The intervention of N makes the solidification process of high nitrogen stainless steel extremely complicated, because N is a strong γ stabilizer, and its content dramatically affects the formation of the primary phase. The rarely reported peritectic solidification in high nitrogen stainless steel was observed, and these findings could help improve the continuous casting process of high N alloys.

Abstract METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.

ABSTRACT: The aim of the present study was to investigate the activity of AMPK and mTORC1 as well as TFEB transcriptional activity and autophagy-lysosomal function in the liver of dairy cows with mild fatty liver (FL) and cows with moderate FL. Liver and blood samples were collected from healthy dairy cows (n = 10; hepatic triglyceride content

Although the pathogenesis and mechanism of congenital skeletal dysplasia are better understood, progress in drug development and intervention research remains limited. Here we report that melatonin treatment elicits a mitigating effect on skeletal abnormalities caused by SLC26A2 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon SLC26A2 deficiency, we found calcium (Ca2+) overload jointly contributed to SLC26A2-associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca2+ overload in turn triggered apoptosis of growth plate chondrocytes. Melatonin, known for its anti-oxidant and anti-inflammatory properties, emerged as a promising therapeutic approach in our study, which enhanced survival, proliferation, and maturation of chondrocytes by attenuating endoplasmic reticulum stress and Ca2+ overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of SLC26A2-deficient chondrocytes in vitro but also underscored its role in partially alleviating the skeletal dysplasia seen in Col2a1-CreERT2; Slc26a2fl/fl mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum in vivo. Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for SLC26A2-related chondrodysplasias.

The stability analysis of spherical hybrid sliding bearings includes exploring its dynamic characteristics and critical speed, its stiffness and damping coefficient have an important impact on the stability of the bearing-rotor system, and the study of critical speed can effectively avoid whirl instability in the bearing-rotor system. The boundary slip conditions are considered to analyze the stability of spherical hybrid sliding bearings. Taking the flow of the small hole restrictor into the oilcavity equal to the flow out of the oil sealing edge as the boundary condition, the Reynolds equation in the boundary slip state is solved to obtain the oil cavity pressure and the oil sealing edge pressure. For the transient Reynolds equation in the boundary slipstate, the equation uses the small perturbation method to derive the partial differential equation of the perturbation pressure, and combines the finite difference method and the relaxation iterative method to solve the equation to obtain the stiffness and damping coefficient of the ball bearing under the state of boundary slip, and then establish the shafting trajectory equation to solve the instability speed. The influence of slip coefficient, oil supply pressure, rotor speed on the dynamic characteristics of the bearingand the variation law of the instability speed on the slip coefficient are discussed. The results show that the increase of the slipcoefficient will lead to the decrease of the four stiffness coefficients and the cross damping coefficients, and the increase of thedirect dampings. The increase of the oil supply pressure will lead to the increase of the eight dynamic characteristic coefficients, and the increase of the rotational speed will lead to the increase of the stiffness and the decrease of the dampings, and the occurrence of slip effect does not affect the above rules. The instability speed decreases with the increase of slip coefficient, so the system stability decreases.

Frequent itemset mining (FIM) faces significant challenges with the expansion of large-scale datasets. Traditional algorithms such as Apriori, FP-Growth, and Eclat suffer from poor scalability and low efficiency when applied to modern datasets characterized by high dimensionality and high-density features. These algorithms demand substantial memory resources and multiple database scans, which diminishes their practicality for rapid data processing. To address these challenges, this study proposes the Inverted Index Automata Frequent Itemset Mining (IA-FIM) algorithm. IA-FIM integrates the swift retrieval of an inverted index with the robust pattern recognition of finite automata, enabling efficient processing of extensive datasets. Distinct from conventional FIM algorithms, IA-FIM utilizes an inverted index automata to efficiently reduce the search space and memory footprint, eliminating repetitive database scans and multiple tree constructions. The proposed algorithm employs a single-pass scan strategy, constructing a dynamic and adjustable inverted index for a streamlined and compact representation of data. IA-FIM demonstrates superior performance in processing large sparse dataset, enhancing the processing speed of large dataset and fulfilling the demands of the big data era. At the same time, it improves the efficiency and practicality of FIM by reducing repeated scans and large memory dependencies, making it more feasible when processing large dataset.

ABSTRACT: Excessive free fatty acid (FFA) oxidation and related metabolism are the major cause of oxidative stress and liver injury in dairy cows during the early postpartum period. In nonruminants, activation of transcription factor EB (TFEB) can improve cell damage and reduce the overproduction of mitochondrial reactive oxygen species. As a downstream target of TFEB, peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α, gene name PPARGC1A) is a critical regulator of oxidative metabolism. Nuciferine (Nuc), a major bioactive compound isolated from the lotus leaf, has been reported to possess hepatoprotective activity. Therefore, the objective of this study was to investigate whether Nuc could protect bovine hepatocytes from FFA-induced lipotoxicity and the underlying mechanisms. A mixture of FFA was diluted in RPMI-1640 basic medium containing 2% low fatty acid bovine serum albumin to treat hepatocytes. Bovine hepatocytes were isolated from newborn calves and treated with various concentrations of FFA mixture (0, 0.3, 0.6, or 1.2 mM) or Nuc (0, 25, 50, or 100 μM), as well as co-treated with 1.2 mM FFA and different concentrations of Nuc. For the experiments of gene silencing, bovine hepatocytes were transfected with small interfering RNA targeted against TFEB or PPARGC1A for 36 h followed by treatment with 1.2 mM FFA for 12 h in presence or absence of 100 μΜ Nuc. The results revealed that FFA treatment decreased protein abundance of nuclear TFEB, cytosolic TFEB, total (t)-TFEB, lysosome-associated membrane protein 1 (LAMP1) and PGC-1α and mRNA abundance of LAMP1, but increased phosphorylated (p)-TFEB. In addition, FFA treatment increased the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) and decreased the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in bovine hepatocytes. Moreover, FFA administration enhanced the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactose dehydrogenase (LDH) in the medium of FFA-treated hepatocytes, but reduced the content of urea. In FFA-treated bovine hepatocytes, Nuc administration increased TFEB nuclear localization and the protein abundance of t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, decreased the contents of MDA and H2O2 and the protein abundance of p-TFEB, and enhanced the activities of CAT and GSH-Px in a dose-dependent manner. Consistently, Nuc administration reduced the activities of ALT, AST, and LDH and increased the content of urea in the medium of FFA-treated hepatocytes. Importantly, knockdown of TFEB reduced the protein abundance of p-TFEB, t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, and impeded the beneficial effects of Nuc on FFA-induced oxidative damage in bovine hepatocytes. In addition, PPARGC1A silencing did not alter Nuc-induced nuclear translocation of TFEB, increase of the protein abundance of t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, or decrease of the protein abundance of p-TFEB, whereas it partially reduced the beneficial effects of Nuc on FFA-caused oxidative injury. Taken together, Nuc exerts protective effects against FFA-induced oxidative damage in bovine hepatocytes through activation of the TFEB/PGC-1α signaling pathway.

Skin cancer is one of the most common types of cancer globally. Despite the remarkable advancements of deep learning methods in computer vision, automatic diagnosis of skin diseases still faces challenges such as limited data and class imbalance. Generative Adversarial Networks (GANs), which can synthesize realistic data, appear as an alternative to mitigate these issues. However, for imbalanced data, unconditional GANs either generate uneven data distribution or neglect universal knowledge of the whole dataset, while state-of-the-art (SOTA) conditional GANs suffer from performance degradation due to the mode collapse of minority classes. This paper proposes a two-stage GAN-based method to synthesize fine-grained and diverse $256 \times 256$ pixels skin lesion images for the imbalanced dataset, named Self-Transfer GAN (STGAN). STGAN first learns universal knowledge from all classes then transfers this shared knowledge to each class and fuses it with class-specific knowledge to synthesize high-quality images. Furthermore, based on STGAN, a framework to enhance the classification performance is established. Both data generation and classification tasks are evaluated on HAM10000 dataset. In terms of Fréchet Inception Distance (FID), Inception Score, Precision, and Recall, STGAN improved by 16%, 16%, 4%, 33% compared with SOTA conditional StyleGAN2. For classification, the STGAN-based framework achieves remarkable results, with an Accuracy of 98.23%, Sensitivity of 88.85%, Precision of 90.23%, F1-score of 89.48%, and Specificity of 98.34%.

Introduction: Developmental engineering based on endochondral ossification has been proposed as a potential strategy for repairing of critical bone defects. Bone development is driven by growth plate-mediated endochondral ossification. Under physiological conditions, growth plate chondrocytes undergo compressive forces characterized by micro-mechanics, but the regulatory effect of micro-mechanical loading on endochondral bone formation has not been investigated.Methods: In this study, a periodic static compression (PSC) model characterized by micro-strain (with 0.5% strain) was designed to clarify the effects of biochemical/mechanical cues on endochondral bone formation. Hydrogel scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were incubated in proliferation medium or chondrogenic medium, and PSC was performed continuously for 14 or 28 days. Subsequently, the scaffold pretreated for 28 days was implanted into rat femoral muscle pouches and femoral condylar defect sites. The chondrogenesis and bone defect repair were evaluated 4 or 10 weeks post-operation.Results: The results showed that PSC stimulation for 14 days significantly increased the number of COL II positive cells in proliferation medium. However, the chondrogenic efficiency of BMSCs was significantly improved in chondrogenic medium, with or without PSC application. The induced chondrocytes (ichondrocytes) spontaneously underwent hypertrophy and maturation, but long-term mechanical stimulation (loading for 28 days) significantly inhibited hypertrophy and mineralization in ichondrocytes. In the heterotopic ossification model, no chondrocytes were found and no significant difference in terms of mineral deposition in each group; However, 4 weeks after implantation into the femoral defect site, all scaffolds that were subjected to biochemical/mechanical cues, either solely or synergistically, showed typical chondrocytes and endochondral bone formation. In addition, simultaneous biochemical induction/mechanical loading significantly accelerated the bone regeneration.Discussion: Our findings suggest that microstrain mechanics, biochemical cues, and in vivo microenvironment synergistically regulate the differentiation fate of BMSCs. Meanwhile, this study shows the potential of micro-strain mechanics in the treatment of critical bone defects.

Mixed-dimensional van der Waals systems could improve terahertz modulators’ performance by utilizing the advantages of different dimensional materials. However, the reported available mixed-dimensional heterojunctions using two-dimensional (2D) and three-dimensional materials usually sacrifice the modulation speed to realize a higher modulation depth. Here, we creatively integrate one-dimensional (1D) nanowires with 2D nanofilms to construct the novel mixed-dimensional tellurium (Te) homojunction and achieve optimal indices with an ultrahigh modulation depth and a shorter carrier lifetime. In addition, a Te-based large-array imaging element was fabricated to successfully reproduce the painting colors under specific pump conditions as well as the dynamic multicolor display. Further measurements with the introduction of metamaterials prove that the required energy consumption can be significantly reduced by one order of magnitude. Our proposed 1D/2D integration strategy opens a new way to build high-performance terahertz functional devices and greatly expands the application fields of Te nanomaterials.

Abstract Using 22‐year ground observations on meteorological variables, we conducted a statistical analysis to reveal fog characteristics at Shanghai Pudong International Airport (SPIA). Fog events were classified by fog types using an objective method. Two types of advection fogs are dominant in fog events at SPIA, followed by radiation fogs. Different fogs have evident annual and monthly variations in frequency. Advection fog mostly appear from February to April, while radiation fog is mainly between November and February. Six synoptic patterns associated with fogs were determine by a self‐organizing maps cluster method, two of which, namely ‘west of marine high pressure’ and ‘inverted trough’, are most favourable for the formation of advection fogs, whereas ‘bottom of weak cold high‐pressure’ is favourable for radiation fogs. The frequency of advection fog occurrence exhibits temporal fluctuations with distinct peaks occurring 2–3 h after sunset, around midnight, and 1–2 h before sunrise, while almost all radiation fog occur in the second half of the night, and favourable conditions for fog onset become more effective with the length of the night. Radiation fog exhibits a longer duration than advection fog and tends to result in lower visibility. The prevalent wind direction for the formation of advection fog is generally from the east to the southeast, whereas radiation fog is typically associated with westerly winds. The temperature and air pressure during the formation of both advection and radiation fogs follow a normal distribution in most seasons. More fog characteristics were categorized by fog types and seasons.

ABSTRACT: Adiponectin (encoded by ADIPOQ) is an adipokine that orchestrates energy homeostasis by modulating glucose and fatty acid metabolism in peripheral tissues. During the periparturient period, dairy cows often develop adipose tissue inflammation and decreased plasma adiponectin levels. Proinflammatory cytokine tumor necrosis factor-α (TNF-α) plays a pivotal role in regulating the endocrine functions of adipocytes, but whether it affects adiponectin production in calf adipocytes remains obscure. Thus, the present study aimed to determine whether TNF-α could affect adiponectin production in calf adipocytes and to identify the underlying mechanism. Adipocytes isolated from Holstein calves were differentiated and used for (1) BODIPY493/503 staining; (2) treatment with 0.1 ng/mL TNF-α for different times (0, 8, 16, 24, or 48 h); (3) transfection with peroxisome proliferator-activated receptor-γ (PPARG) small interfering RNA for 48 h followed by treatment with or without 0.1 ng/mL TNF-α for 24 h; and (4) overexpression of PPARG for 48 h followed by treatment with or without 0.1 ng/mL TNF-α for 24 h. After differentiation, obvious lipid droplets and secretion of adiponectin were observed in adipocytes. Treatment with TNF-α did not alter mRNA abundance of ADIPOQ but reduced the total and high molecular weight (HMW) adiponectin content in the supernatant of adipocytes. Quantification of mRNA abundance of endoplasmic reticulum (ER)/Golgi resident chaperones involved in adiponectin assembly revealed that ER protein 44 (ERP44), ER oxidoreductase 1α (ERO1A), and disulfide bond-forming oxidoreductase A-like protein (GSTK1) were downregulated in TNF-α-treated adipocytes, while 78-kDa glucose-regulated protein and Golgi-localizing γ-adaptin ear homology domain ARF binding protein-1 were unaltered. Moreover, TNF-α diminished nuclear translocation of PPARγ and downregulated mRNA abundance of PPARG and its downstream target gene fatty acid synthase, suggesting that TNF-α suppressed the transcriptional activity of PPARγ. In the absence of TNF-α, overexpression of PPARG enhanced the total and HMW adiponectin content in supernatant and upregulated the mRNA abundance of ADIPOQ, ERP44, ERO1A, and GSTK1 in adipocytes. However, knockdown of PPARG reduced the total and HMW adiponectin content in supernatant and downregulated the mRNA abundance of ADIPOQ, ERP44, ERO1A, and GSTK1 in adipocytes. In the presence of TNF-α, overexpression of PPARG decreased, while knockdown of PPARG further exacerbated TNF-α-induced reductions in total and HMW adiponectin secretion and gene expression of ERP44, ERO1A, and GSTK1. Overall, TNF-α reduces adiponectin assembly in the calf adipocyte, which may be partly mediated by attenuation of PPARγ transcriptional activity. Thus, locally elevated levels of TNF-α in adipose tissue may be one reason for the decrease in circulating adiponectin in periparturient dairy cows.

Here, Elbasir et al. develop viRNAtrap, a deep learning approach for detection of viruses from tumor RNA sequencing data, which they showcase on an RNA dataset of different cancer types, revealing tumor expression of divergent viruses that had not been previously implicated in cancer.

The oil film temperature of the spherical hybrid sliding bearings would increase due to the friction and shear of the lubricating oil at high speed or super high speed, which leads to the thermal deformation of bearing and rotor. As a result, the deformation seriously affects the rotation accuracy of the spindle, because it is in the same order of magnitude as the oil film thickness. Therefore, the fluid lubrication mathematical model is established by taking the spherical hybrid sliding bearings with orifice throttling mode as the research object, and the Reynolds equation and energy equation of lubricating oil film are derived. The pressure distribution and temperature distribution of oil film of the spherical hybrid sliding bearings are calculated by combining the finite difference method and relaxation iteration method. The influence of working parameters on bearing capacity and oil film temperature rise was investigated. The results show that the oil film shear effect is stronger and the temperature rise increases with the increase of rotating speed and the decrease of oil film thickness. When the speed is 3 000 r/min and the oil film thickness is 28 μm, the maximum temperature rise of the bearing is 18.65 K higher than that of 1 000 r/min. When the speed is 3 000 r/min and the oil film thickness is 20 μm, the maximum temperature rise of the bearing is 27.685 K higher than that of the oil film thickness of 28 μm.

ABSTRACT: Sustained lipolysis and insulin resistance increase the risk of metabolic dysfunction in dairy cows during the transition period. Proinflammatory cytokines are key regulators of adipose tissue metabolism in nonruminants, but biological functions of these molecules in ruminants are not well known. Thus, the objective of this study was to investigate whether tumor necrosis factor-α (TNF-α) could affect insulin sensitivity and lipolysis in bovine adipocytes as well as the underlying mechanisms. Bovine adipocytes (obtained from the omental and mesenteric adipose depots) isolated from 5 Holstein female calves (1 d old) with similar body weight (median: 36.9 kg, range: 35.5–41.2 kg) were differentiated and used for (1) treatment with different concentrations of TNF-α (0, 0.1, 1, or 10 ng/mL) for 12 h; (2) pretreatment with 10 μM lipolytic agonist isoproterenol (ISO) for 3 h, followed by treatment with or without 10 ng/mL TNF-α for 12 h; and (3) pretreatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 (20 μM for 2 h) and nuclear factor kappa B (NF-κB) inhibitor BAY 11–7082 (10 μM for 1 h) followed by treatment with or without 10 ng/mL TNF-α for 12 h. The TNF-α increased glycerol content in supernatant, decreased triglyceride content and insulin-stimulated phosphorylation of protein kinase B suggesting activation of lipolysis and impairment of insulin sensitivity. The TNF-α reduced cell viability, upregulated mRNA abundance of Caspase 3 (CASP3), an apoptosis marker, and increased activity of Caspase 3. In addition, increased phosphorylation of NF-κB and JNK, upregulation of mRNA abundance of interleukin-6 (IL-6), TNFA, and suppressor of cytokine signaling 3 (SOCS3) suggested that TNF-α activated NF-κB and JNK signaling pathways. Furthermore, ISO plus TNF-α-activated NF-κB and JNK signaling pathway to a greater extent than TNF-α alone. Combining TNF-α and ISO aggravated TNF-α-induced apoptosis, insulin insensitivity and lipolysis. In the absence of TNF-α, inhibition of NF-κB and JNK did not alter glycerol content in supernatant, triglyceride content or insulin-stimulated phosphorylation of protein kinase B. In the presence of TNF-α, inhibition of NF-κB and JNK alleviated TNF-α-induced apoptosis, insulin insensitivity and lipolysis. Overall, TNF-α impairs insulin sensitivity and induces lipolysis and apoptosis in bovine adipocytes, which may be partly mediated by activation of NF-κB and JNK. Thus, the data suggested that NF-κB and JNK are potential therapeutic targets for alleviating lipolysis dysregulation and insulin resistance in adipocytes.

ABSTRACT: Mitochondria are the main site of fatty acid oxidation and reactive oxygen species (ROS) formation. Damaged or dysfunctional mitochondria induce oxidative stress and increase the risk of lipid accumulation. During the process of mitophagy, PTEN induced kinase 1 (PINK1) accumulates on damaged mitochondria and recruits cytoplasmic Parkin to mitochondria. As an autophagy receptor protein, sequestosome-1 (p62) binds Parkin-ubiquitinated outer mitochondrial membrane proteins and microtubule-associated protein 1 light chain 3 (LC3) to facilitate degradation of damaged mitochondria. In nonruminants, clearance of dysfunctional mitochondria through the PINK1/Parkin-mediated mitophagy pathway contributes to reducing ROS production and maintaining metabolic homeostasis. Whether PINK1/Parkin-mediated mitophagy plays a similar role in dairy cow liver is not well known. Thus, the objective of this study was to investigate mitophagy status in dairy cows with fatty liver and its role in free fatty acid (FFA)-induced oxidative stress and lipid accumulation. Liver and blood samples were collected from healthy dairy cows (n = 10) and cows with fatty liver (n = 10) that had a similar number of lactations (median = 3, range = 2 to 4) and days in milk (median = 6 d, range = 3 to 9 d). Calf hepatocytes were isolated from 5 healthy newborn female Holstein calves (1 d of age, 30–40 kg). Hepatocytes were transfected with small interfering RNA targeted against PRKN for 48 h or transfected with PRKN overexpression plasmid for 36 h, followed by treatment with FFA (0.3 or 1.2 mM) for 12 h. Mitochondria were isolated from fresh liver tissue or calf hepatocytes. Serum concentrations of β-hydroxybutyrate were higher in dairy cows with fatty liver. Hepatic malondialdehyde (MDA) and hydrogen peroxide (H2O2) were greater in cows with fatty liver. The lower protein abundance of PINK1, Parkin, p62, and LC3-II in hepatic mitochondrial fraction of dairy cows with fatty liver indicated the mitophagy was impaired. In hepatocytes, knockdown of PRKN decreased protein abundance of p62 and LC3-II in the mitochondrial fraction, and increased contents of triacylglycerol (TG), MDA, and H2O2. In addition, protein abundances of PINK1, Parkin, p62, and LC3-II were lower in the mitochondrial fraction from hepatocytes treated with 1.2 mM FFA than the hepatocytes treated with 0.3 mM FFA, whereas the content of TG, MDA, and H2O2 increased. In 1.2 mM FFA-treated hepatocytes, PRKN overexpression increased protein abundance of p62 and LC3-II in the mitochondrial fraction and decreased contents of TG, MDA, and H2O2. Together, our data demonstrate that low abundance of mitophagy markers is associated with ROS overproduction in dairy cows with fatty liver and impaired mitophagy induced by a high concentration of FFA promotes ROS production and lipid accumulation in female calf hepatocytes.

Senescence is a complex cellular process that is implicated in various physiological and pathological processes. It is characterized by a stable state of cell growth arrest and by a secretome of diverse pro‐inflammatory factors, chemokines and growth factors. In this review, we summarize the context‐dependent role of cellular senescence in ageing and in age‐related diseases, such as cancer. We discuss current approaches to targeting senescence to develop therapeutic strategies to combat cancer and to promote healthy ageing, and we outline our vision for future research directions for senescence‐based interventions in these fields.

PurposeTo explore the characteristics, mechanism, treatment, and prognosis of head–neck separation type of Monteggia equivalent fractures in children.MethodsPatients with this injury were reviewed retrospectively. The lesion was characterized by a fracture of the ulnar with radial neck fracture but without dislocation of the radial head. Our classification was based on the direction of displacement and angulation of fractures on radiographs, divided into the extension-valgus type and flexion-varus type. The fractures were treated with reduction and internal fixation, depending on the fracture type. The clinical results were evaluated by using radiology and the Mayo Elbow Performance Score (MEPS).ResultsA total of 12 patients were followed up for an average of 40.5 months. The ulnar fractures were treated with closed reduction (CR) and K-wire fixation in one patient, elastic stable intramedullary nail (ESIN) fixation in four patients, open reduction (OR) and plate fixation in five, with no fixation in two. CR with ESIN fixation was successful in 11 patients with radial neck fractures, but one underwent OR and K-wire fixation. All fractures healed on time, with fewer complications (avascular necrosis in one patient, and bulk formation of metaphysis in another). The therapeutic efficacy was evaluated by using MEPS and was found to be excellent in 10 patients, good in one, and fair in another.ConclusionsThe head–neck separation type of Monteggia equivalent fractures in children is rare. Its characteristics are different from that of Monteggia fracture. The length and anatomic structure of the ulna should be restored and stabilized first, while the radial neck fracture should be treated with CR and ESIN fixation. Satisfactory clinical results can be achieved with fewer complications.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease; it is reported to be associated with inflammatory responses, chondrocyte apoptosis, and cartilage degeneration. XMU-MP-1 is a selective MST1/2 inhibitor which activates the downstream effector YAP and promotes cell growth. It has displayed excellent benefits in mouse intestinal repair, as well as liver repair and regeneration. However, the effects of XMU-MP-1 on OA remain unclear. In this study, we investigated the therapeutic role of XMU-MP-1 on interleukin-1β (IL-1β)-induced inflammation in mice chondrocytes and the destabilization of the medial meniscus surgery (DMM)-induced OA model. In chondrocytes, treatment with XMU-MP-1 elevated the matrix metalloproteinases (Mmp3, Mmp13) and decreased the extracellular matrix (Col2, Acan) induced by IL-1β. Moreover, XMU-MP-1 strongly inhibited IL-1β-induced chondrocyte apoptosis and significantly promoted chondrocyte proliferation. Furthermore, XMU-MP-1 demonstrated a protective and therapeutic influence on the mouse OA model. These findings indicate that XMU-MP-1 may have a protective effect on cartilage degradation and may be a new potential therapeutic option for OA.

Abstract Greenhouse gas (GHG) emissions from rivers and lakes have been shown to significantly contribute to global carbon and nitrogen cycling. In spatiotemporal-variable and human-impacted rivers in the grassland region, simultaneous carbon dioxide, methane and nitrous oxide emissions and their relationships under the different land use types are poorly documented. This research estimated greenhouse gas (CO2, CH4, N2O) emissions in the Xilin River of Inner Mongolia of China using direct measurements from 18 field campaigns under seven land use type (such as swamp, sand land, grassland, pond, reservoir, lake, waste water) conducted in 2018. The results showed that CO2 emissions were higher in June and August, mainly affected by pH and DO. Emissions of CH4 and N2O were higher in October, which were influenced by TN and TP. According to global warming potential, CO2 emissions accounted for 63.35% of the three GHG emissions, and CH4 and N2O emissions accounted for 35.98% and 0.66% in the Xilin river, respectively. Under the influence of different degrees of human-impact, the amount of CO2 emissions in the sand land type was very high, however, CH4 emissions and N2O emissions were very high in the artificial pond and the wastewater, respectively. For natural river, the greenhouse gas emissions from the reservoir and sand land were both low. The Xilin river was observed to be a source of carbon dioxide and methane, and the lake was a sink for nitrous oxide.

Abstract Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth. However, for a significant portion of human cancer, how Hippo signaling is perturbed remains unknown. To answer this question, we performed a genome-wide screening for genes that affect the Hippo pathway in Drosophila and cross-referenced the hit genes with human cancer genome. In our screen, Prosap was identified as a novel regulator of the Hippo pathway that potently affects tissue growth. Interestingly, a mammalian homolog of Prosap, SHANK2, is the most frequently amplified gene on 11q13, a major tumor amplicon in human cancer. Gene amplification profile in this 11q13 amplicon clearly indicates selective pressure for SHANK2 amplification. More importantly, across the human cancer genome, SHANK2 is the most frequently amplified gene that is not located within the Myc amplicon. Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator, and as a potential oncogene, SHANK2 promotes cellular transformation and tumor formation in vivo. In cancer cell lines with deregulated Hippo pathway, depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation. Taken together, these results suggest that SHANK2 is an evolutionarily conserved Hippo pathway regulator, commonly amplified in human cancer and potently promotes cancer. Our study for the first time illustrated oncogenic function of SHANK2, one of the most frequently amplified gene in human cancer. Furthermore, given that in normal adult tissues, SHANK2’s expression is largely restricted to the nervous system, SHANK2 may represent an interesting target for anticancer therapy.

Excessive lipid mobilization for adipose tissue caused by severe negative energy balance is the pathological basis for subclinical ketosis (SCK) in dairy cows. In non-ruminants, transcription factor EB (TFEB) was reported to play a role in the regulation of lipid catabolism, but its role in the control of lipolysis in the bovine is unknown. The present study aimed to determine whether the enhanced TFEB transcriptional activity contributes to lipolysis of adipose tissue in SCK cows, and to explore the possibility of establishing a therapeutic strategy by using TFEB as a target to control lipolysis. Thirty cows with similar lactation number (median = 3, range = 2–4) and days in milk (median = 6 d, range = 3–9) were selected into a healthy control (n = 15) and SCK (n = 15) group, and used for subcutaneous adipose tissue biopsies and blood sampling. Adipocytes from healthy Holstein calves were used as a model for in vitro studies involving treatment with 10 μM isoproterenol (ISO) for 0, 1, 2 and 3 h, 250 nM of the TFEB activator Torin1 for 3 h, or used for transfection with TFEB small interfering RNA for 48 h followed by treatment with 10 μM ISO for 3 h. Compared with healthy cows, adipose tissue in SCK cows showed increased lipolysis accompanied by enhanced TFEB transcriptional activity. In vitro, ISO and Torin1 treatment increased lipolysis and enhanced TFEB transcriptional activity in calf adipocytes. However, knockdown of TFEB attenuated ISO-induced lipolysis in adipocytes. Overall, these findings indicated that enhanced transcriptional activity of TFEB may contribute to lipolysis of adipose tissue in dairy cows with SCK. The regulation of TFEB activity may be an effective therapeutic strategy for controlling overt lipolysis in ketotic cows.

Summary: Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted ex vivo therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8+ T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB.

We have recently discovered that AT-rich interactive domain-containing protein 1A (ARID1A) protects telomere cohesion through regulation of the cohesin subunit stromal antigen 1 (STAG1). ARID1A inactivation results in mitotic defects and negatively selects gross chromosomal aberrations, resulting in preservation of genomic stability in ARID1A-mutated cancers. These findings explain the long-standing paradox between mitotic defects caused by ARID1A inactivation and the lack of genomic instability in ARID1A-mutated cancers.

Tissue homeostasis and regeneration in the Drosophila midgut is regulated by a diverse array of signaling pathways including the Hippo pathway. Hippo signaling restricts intestinal stem cell (ISC) proliferation by sequestering the transcription co-factor Yorkie (Yki) in the cytoplasm, a factor required for rapid ISC proliferation under injury-induced regeneration. Nonetheless, the mechanism of Hippo-mediated midgut homeostasis and whether canonical Hippo signaling is involved in ISC basal proliferation are less characterized. Here we identify Lola as a transcription factor acting downstream of Hippo signaling to restrict ISC proliferation in a Yki-independent manner. Not only that Lola interacts with and is stabilized by the Hippo signaling core kinase Warts (Wts), Lola rescues the enhanced ISC proliferation upon Wts depletion via suppressing Dref and SkpA expressions. Our findings reveal that Lola is a non-canonical Hippo signaling component in regulating midgut homeostasis, providing insights on the mechanism of tissue maintenance and intestinal function.