Identification of potential PIM-2 inhibitors via ligand-based generative models, molecular docking and molecular dynamics simulations.

Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors. First, we designed a generative model based on a Bi-directional Long Short-Term Memory (BiLSTM) framework combined with a transfer learning strategy and generated a new PIM-2 small molecule library using existing active drug databases. The generated compound library was then virtually screened by molecular docking and scaffold similarity comparison, identifying 10 initial hit compounds with better performance. Next, using the inhibitor in the crystal structure as a positive control, we performed two rounds of MD simulations, with lengths of 100 ns and 500 ns, respectively, to study the dynamic stability of the protein-ligand systems of the 10 compounds with PIM-2. Analyzed the interactions with key hinge region residues, binding free energies, and changes in the ATP pocket size. The generative model demonstrates good molecular generation capability and can generate efficient novel molecules with similar physicochemical properties as active PIM-2 drugs. Among the 10 initially selected hit compounds, 5 compounds C3 (- 29.69 kcal/mol), C4 (- 33.31 kcal/mol), C5 (- 28.59 kcal/mol), C8 (- 34.68 kcal/mol), and C9 (- 25.88 kcal/mol) have higher binding energies with PIM-2 than the positive drug 3YR (- 26.18 kcal/mol). The MD simulation results are consistent with the docking analysis, these compounds have lower and more stable RMSD values for the complex systems with the reported positive drug 3YR and PIM-2 complex system. They can form long-term stable interactions with active site and the hinge region of PIM-2, which suggests these compounds are likely to have potent inhibitory effects on PIM-2. This study provides an efficient generative model for PIM-2 inhibitor research and discovers 5 potential novel PIM-2 inhibitors.

Recent Progress in Nonconventional Luminescent Macromolecules and their Applications.

Traditional π-conjugated luminescent macromolecules typically suffer from aggregation-caused quenching (ACQ) and high cytotoxicity, and they require complex synthetic processes. In contrast, nonconventional luminescent macromolecules (NCLMs) with nonconjugated structures possess excellent biocompatibility, ease of preparation, unique luminescence behavior, and emerging applications in optoelectronics, biology, and medicine. NCLMs are currently believed to produce inherent luminescence due to through-space conjugation of overlapping electron orbitals in solid/aggregate states. However, as experimental facts continue to exceed expectations or even overturn some previous assumptions, there is still controversy about the detailed luminous mechanism of NCLMs, and extensive studies are needed to further explore the mechanism. This Perspective highlights recent progress in NCLMs and classifies and summarizes these advances from the viewpoint of molecular design, mechanism exploration, applications, and challenges and prospects. The aim is to provide guidance and inspiration for the huge fundamental and practical potential of NCLMs.

Synergistic effect of additional anlotinib and immunotherapy as second-line or later-line treatment in pancreatic cancer: A retrospective cohort study.

Background: Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of a second-line or later-line treatment strategy. We aimed to analyze the efficacy and safety of additional anlotinib, specifically anlotinib in combination with immunotherapy, in patients with PDAC who have failed first-line therapy. Methods: Patients with pathological diagnosis of PDAC were additionally treated with anlotinib, and some patients were treated with anti-PD-1 agents at the same time, which could be retrospectively analyzed. The efficacy and safety of additional anlotinib were evaluated. Results: A total of 23 patients were included. In patients treated with additional anlotinib, the overall median progression-free survival (PFS) was 1.8 months and the median overall survival (OS) was 6.3 months, regardless of anti-PD-1 agents. Among patients receiving additional anlotinib in combination with anti-PD-1 agents, median PFS and OS were 1.8 and 6.5 months, respectively. Adverse events (AEs) were observed in 16 patients (69.6%). In patients treated with additional anlotinib, the majority of AEs were grade 1-3. Univariate analysis revealed that patients with baseline red blood cell distribution width (RDW) <14% treated with additional anlotinib plus anti-PD-1 agents had significantly longer OS than patients with baseline RDW ≥14% (p = 0.025). Patients with additional anlotinib plus anti-PD-1 agents as second-line therapy had a longer OS than those treated as later-line therapy (p = 0.012). Multivariate analysis showed that baseline RDW was the only independent risk factor for OS (p = 0.042). Conclusion: The combination of anlotinib and immunotherapy represents an effective add-on therapy with tolerable AEs as second- or later-line therapy in patients with PDAC, particularly in patients with baseline RDW <14%.

[Examination of the Thermal Stability and Swallowing Safety of a Self-Developed Enteral Nutrition Thickening Agent]. / è‡ªåˆ¶è‚ å† è¥å »æ¶²å¢žç¨ å‰‚çš„çƒ­ç¨³å®šæ€§åŠåžå’½å®‰å ¨æ€§æŽ¢ç´¢.

Objective: To experimentally validate the effects of a self-developed heat-stable thickening agent on the textual characteristics of enteral nutrition solutions of standard concentration and its applicability in improving dysphagia. Methods: A gradient of different doses of the self-developed thickening agent (1.0 g, 1.5 g, 2.0 g, 2.5 g, and3.0 g) and three commonly used commercial thickeners were mixed with 23.391 g of a complete nutrition formula powder dissolved in 85 mL of purified water to prepare 100 mL standard concentration nutrition solutions. The textual parameters (cohesiveness, viscosity, thickness, and hardness) of these nutrition solutions were measured using a texture analyzer at various temperature gradients (20 ℃, 40 ℃, 60 ℃, and 80 ℃) to compare their thermal stability. A dysphagia rat model was created via epiglottectomy to explore the effects of the thickener on lung tissue damage scores and levels of inflammatory markers. The rats were divided into a test intervention group, a positive control group, a negative control group, and a blank control group (no surgery and normal feeding after fasting for one day), with 15 rats in each group. After fasting for one day post-surgery, the test intervention group was fed with the standard concentration nutrition solution thickened with the self-developed thickener, while the positive control group was given a standard concentration nutrition solution thickened with product 3, and the negative control group was fed a normal diet. All groups were fed for two weeks with food dyed with food-grade green dye. General conditions, body mass, and food intake were observed and recorded. After two weeks, abdominal aorta blood was collected, and heart, liver, spleen, lung, and kidney tissues were harvested and weighed to calculate the lung tissue organ coefficient. The organ conditions were evaluated using routine H&E staining, and lung damage was semi-quantitatively analyzed based on the Mikawa scoring criteria. Blood supernatants were collected to measure the total serum protein and albumin levels to determine the nutritional status of the rats. The expression of IL-6 and TNF-α genes in lung tissues was measured by RT-qPCR. IL-6 and TNF-α protein expression levels in lung tissues, lung tissue homogenate, and serum were measured by ELISA. The aspiration incidence rate was calculated. Results: Within the dosage range of 1.0 g to 3.0 g, the self-developed thickener in the test samples exhibited superior thermal stability in cohesiveness compared to the three commercially available thickeners, with a statistically significant difference (P<0.01). The differences in the thermal stability of viscosity and hardness between the self-developed thickener and the three commercially available thickeners were not statistically significant. The viscosity stability was optimal for the self-developed thickener, followed by the commercially available thickeners 1 and 3, with thickeners 2 being the least stable, though the differences were not statistically significant (P>0.05). Product 1 showed the best thermal stability in thickness, followed by the self-developed thickener and product 2, while the product 3 exhibited the worst performance, with the difference being statistically significant (P<0.01). The self-developed thickener had the best thermal stability in hardness at temperatures ranging from 20℃ to 80 ℃, followed by products 1 and 2, with product 3 being the least stable. However, the differences were not statistically significant (P>0.05). Animal experiment results indicated that the body weight gain in the positive control group and the test intervention group was lower than that in the blank and negative control groups (P<0.01). The spleen coefficient of the intervention group was lower than that of the positive control group and the blank control group (P<0.01), while the heart, liver, and kidney coefficients were lower than those of the blank control group (P<0.01). The differences in the lung coefficient of the intervention group and those of the other three groups were no statistically significant. Levels of TP and ALB in the test intervention group, the positive control group, and the negative control group were all lower than those in the blank control group, with statistically significant differences (P<0.01). ELISA results showed that serum IL-6 levels in the blank and test intervention groups were lower than those in the negative and positive control groups (P<0.05), while the difference in the other indicators across the four groups were not statistically significant (P>0.05). There were no statistically significant differences among the four groups in terms of lung tissue damage pathology scores, or in the levels of IL-6 and TNF-α gene expression in lung tissues. The aspiration incidence rate was 0% in all groups. Conclusion: The self-developed enteral nutrition thickening agent demonstrated excellent thermal stability and swallowing safety. Further research to explore its application in patients with dysphagia is warranted.

A novel prediction approach driven by graph representation learning for heavy metal concentrations.

The potential risk of heavy metals (HMs) to public health is an issue of great concern. Early prediction is an effective means to reduce the accumulation of HMs. The current prediction methods rarely take internal correlations between environmental factors into consideration, which negatively affects the accuracy of the prediction model and the interpretability of intrinsic mechanisms. Graph representation learning (GraRL) can simultaneously learn the attribute relationships between environmental factors and graph structural information. Herein, we developed the GraRL-HM method to predict the HM concentrations in soil-rice systems. The method consists of two modules, which are PeTPG and GCN-HM. In PeTPG, a graphic structure was generated using graph representation and communitization technology to explore the correlations and transmission paths of different environmental factors. Subsequently, the GCN-HM model based on the graph convolutional neural network (GCN) was used to predict the HM concentrations. The GraRL-HM method was validated by 2295 sets of data covering 21 environmental factors. The results indicated that the PeTPG model simplified correlation paths between factor nodes from 396 to 184, reducing by 53.5 % graph scale by eliminating the invalid paths. The concise and efficient graph structure enhanced the learning efficiency and representation accuracy of downstream prediction models. The GCN-HM model was superior to the four benchmark models in predicting the HM concentration in the crop, improving R2 by 36.1 %. This study develops a novel approach to improve the prediction accuracy of pollutant accumulation and provides valuable insights into intelligent regulation and planting guidance for heavy metal pollution control.

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Effect of sodium hyaluronate combined with rehabilitation training on knee joint injury caused by golf.

BACKGROUND: In high-intensity sports like golf, knee joints are prone to injury, leading to pain, limited mobility, and decreased quality of life. Traditional treatment methods typically involve rehabilitation exercises, but their effectiveness may be limited. In recent years, sodium hyaluronate has emerged as a widely used biomedical material in the treatment of joint diseases. AIM: To explore the effect of sodium hyaluronate combined with rehabilitation training on pain degree, flexion range of motion and motor function of knee joint injured by golf. METHODS: Eighty patients with knee joint injury caused by golf were randomly divided into control (group B) and observation group (group A). The group B was treated with rehabilitation training, and the group A was treated with sodium hyaluronate combined with rehabilitation training. The clinical efficacy, range of motion and function of knee joint, quality of life and inflammatory factors were compared. RESULTS: The excellent and good rate of rehabilitation in the group A was raised than group B. At 6 weeks and 3 months after treatment, the range of motion of the two groups was raised than that before treatment, and that of the group A was raised than group B. After treatment, the scores of Lysholm and International Knee Documentation Committee (IKDC) in the group A were raised, and those in the group A were raised than group B. The VAS score of the two groups was reduced than that of the group B, and the SF-36 score of the group A was reduced than group B. The interleukin (IL)-1 ß, IL-8 and tumor necrosis factor-α in the two groups were reduced, and those in the group A were reduced than group B. CONCLUSION: Sodium hyaluronate combined with rehabilitation training has a good clinical effect in the treatment of patients with knee joint injury caused by golf, which relieve pain, maintain knee joint function and improve patients' life quality.

PRAME promotes proliferation of multiple myeloma cells through CTMP/Akt/p21/CCND3 axis by ubiquitinating CTMP and p21.

Multiple myeloma (MM) is a Ubiquitin Proteasome System (UPS)-dysfunction disease. We previously reported that high PRAME transcript levels associated with unfavorable progression free survival (PFS) in patients with no bortezomib therapy, and bortezomib-containing regimen significantly improved PFS in patients with high PRAME transcript levels, which indicated that PRAME expression was prognostic for MM patients, and was related to proteasome inhibitor treatment. However, molecular mechanisms underlying the above clinical performance remain unclear. In the present study, MM cell models with PRAME knockdown and overexpression were established, and PRAME was identified to play the role of promoting proliferation in MM cells. P-Akt signaling was found to be activated as PRAME overexpressed. As a substrate recognizing subunit (SRS) of the E3 ubiquitin ligase, PRAME targets substrate proteins and mediates their degradation. CTMP and p21 were found to be the novel targets of PRAME in the Cul2-dependent substrate recognition process. PRAME interacted with and mediated ubiquitination and degradation of CTMP and p21, which led to accumulation of p-Akt and CCND3 proteins, and thus promoted cell proliferation and increased bortezomib sensitivity in MM cells.

The Role of microRNA in Schizophrenia: A Scoping Review.

Schizophrenia is a serious mental disease that is regulated by multiple genes and influenced by multiple factors. Due to the complexity of its etiology, the pathogenesis is still unclear. MicroRNAs belong to a class of small non-coding RNAs that are highly conserved in endogenous evolution and play critical roles in multiple biological pathways. In recent years, aberrant miRNA expression has been implicated in schizophrenia, with certain miRNAs emerging as potential diagnostic and prognostic biomarkers for this disorder. In this review, our objective is to investigate the differential expression of miRNAs in schizophrenia, elucidate their potential mechanisms of action, and assess their feasibility as biomarkers. The PubMed electronic database and Google Scholar were searched for the years 2003 to 2024. The study focused on schizophrenia and miRNA as the research topic, encompassing articles related to biomarkers, etiology, action mechanisms, and differentially expressed genes associated with schizophrenia and miRNA. A total of 1488 articles were retrieved, out of which 49 were included in this scope review. This study reviewed 49 articles and identified abnormal expression of miRNA in different tissues of both schizophrenia patients and healthy controls, suggesting its potential role in the pathogenesis and progression of schizophrenia. Notably, several specific miRNAs, including miR-34a, miR-130b, miR-193-3p, miR-675-3p, miR-1262, and miR-218-5p, may serve as promising biological markers for diagnosing schizophrenia. Furthermore, this study summarized potential mechanisms through which miRNAs may contribute to the development of schizophrenia. The studies within the field of miRNA's role in schizophrenia encompass a broad spectrum of focus. Several selected studies have identified dysregulated miRNAs associated with schizophrenia across various tissues, thereby highlighting the potential utility of specific miRNAs as diagnostic biomarkers for this disorder. Various mechanisms underlying dysregulated miRNAs in schizophrenia have been explored; however, further investigations are needed to determine the exact mechanisms by which these dysregulated miRNAs contribute to the pathogenesis of this condition. The exploration of miRNA's involvement in the etiology and identification of biomarkers for schizophrenia holds significant promise in informing future clinical trials and advancing our understanding in this area.

Bridging the Intention-Behavior Gap in Organic Food Consumption: Empirical Evidence from China.

The transition to a low-carbon economy emphasizes the importance of green and low-carbon consumption; yet, there is often a discrepancy between consumers' intentions and their actual behavior regarding organic foods. This study aims to identify strategies to bridge this gap. The research model of organic food consumption intention and behavior is constructed, and a structural equation model is used to test the research hypotheses based on a valid sample of 480 residents of Guangdong Province through an online questionnaire survey. Further, the intention‒behavior gap is defined and its determinants are investigated through multiclass logistic regression. Finally, we categorize and forecast the alignment between consumption intentions and behaviors using machine learning algorithms. The results reveal that attitudes, social interactions, and cognitive information play crucial roles in aligning intentions with behaviors. By enhancing social information exchange or improving cognitive understanding, consumers can reduce their intention‒behavior discrepancy. This research offers valuable policy recommendations for fostering green consumption among residents from various perspectives.

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

Preservation strategies for processed grass carp products: Analyzing quality and microbial dynamics during chilled and ice temperature storage.

This study investigated the impact of ice temperature storage on quality and bacterial composition of processed fish paste products (PFP). Freezing curve revealed the ice temperature was -1 °C. Electric nose (e-nose) showed significant changes in volatile components within 8 days. Results of total volatile basic nitrogen (TVB-N) showed that PFP stored at 4 °C reached its limit after 2 days, whereas PFP stored at ice temperature remained stable for 6 days. Thiobarbituric acid reactive substances (TBARS) demonstrated delayed oxidation in PFP stored at ice temperature compared to 4 °C. TCA-soluble peptides indicated that the protein degradation was suppressed by ice temperature. Additionally, ice temperature inhibited microbial growth and altered bacterial composition. High-throughput sequencing revealed that Pseudomonas, Brochothrix, Carnobacterium were dominant at 4 °C, while Acinetobacter, Pseudomonas, Janthinobacterium and Brochothrix were dominant at ice temperature. In summary, ice temperature might be a potential method for maintaining the freshness of PFP.

The joint association of lipoprotein(a) and Lp-PLA2 with the risk of stroke recurrence.

BACKGROUND AND PURPOSE: Currently little is known about the joint association of lipoprotein (a) [Lp(a)] and Lipoprotein-associated phospholipase A2 (Lp-PLA2) with stroke recurrence. METHODS: In this prospective multicenter cohort study, 10,675 consecutive acute ischemic stroke (IS) and transient ischemic attack patients (TIA) with Lp(a) and Lp-PLA2 were enrolled. The association of stroke recurrence within 1 year with Lp(a) and Lp-PLA2 was assessed using Cox proportional hazards models and Kaplan-Meier curves. The interaction between Lp(a) and Lp-PLA2 with stroke recurrence was evaluated by multiplicative and additive scales. RESULTS: A significant joint association of Lp(a) and Lp-PLA2 with the risk of stroke recurrence was observed. Multivariate cox regression analysis demonstrated that the combination of elevated Lp(a) (≥ 50 mg/dL) and Lp-PLA2 (≥175.1 ng/ml) was independently associated with the risk of stroke recurrence (adjusted hazard ratio: 1.42; 95 % CI: 1.15-1.76). Both significant multiplicative [(exp(ß3):1.63, 95 % CI: 1.17-2.29, P = 0.004] and additive interaction (RERI:0.55, 95 % CI: 0.20-0.90, P = 0.002; AP: 0.39, 95 %CI, 0.24-0.53) were observed between Lp(a) and Lp-PLA2. CONCLUSIONS: Our results indicated that Lp(a) and Lp-PLA2 have a joint association with the risk of stroke recurrence in IS/TIA patients. Patients with concomitant presence of elevated Lp(a) and Lp-PLA2 have greater risk of stroke recurrence.

[Identification of the binding proteins of organic acid metabolites by matrix thermal shift assay].

Organic acid metabolites exhibit acidic properties. These metabolites serve as intermediates in major carbon metabolic pathways and are involved in several biochemical pathways, including the tricarboxylic acid (TCA) cycle and glycolysis. They also regulate cellular activity and play crucial roles in epigenetics, tumorigenesis, and cellular signal transduction. Knowledge of the binding proteins of organic acid metabolites is crucial for understanding their biological functions. However, identifying the binding proteins of these metabolites has long been a challenging task owing to the transient and weak nature of their interactions. Moreover, traditional methods are unsuitable for the structural modification of the ligands of organic acid metabolites because these metabolites have simple and similar structures. Even minor structural modifications can significantly affect protein interactions. Thermal proteome profiling (TPP) provides a promising avenue for identifying binding proteins without the need for structural modifications. This approach has been successfully applied to the identification of the binding proteins of several metabolites. In this study, we investigated the binding proteins of two TCA cycle intermediates, i.e., succinate and fumarate, and lactate, an end-product of glycolysis, using the matrix thermal shift assay (mTSA) technique. This technique involves combining single-temperature (52 ℃) TPP and dose-response curve analysis to identify ligand-binding proteins with high levels of confidence and determine the binding affinity between ligands and proteins. To this end, HeLa cells were lysed, followed by protein desalting to remove endogenous metabolites from the cell lysates. The desalted cell lysates were treated with fumarate or succinate at final concentrations of 0.004, 0.04, 0.4, and 2 mmol/L in the experimental groups or 2 mmol/L sodium chloride in the control group. Considering that the cellular concentration of lactate can be as high as 2-30 mmol/L, we then applied lactate at final concentrations of 0.2, 1, 5, 10, and 25 mmol/L in the experimental groups or 25 mmol/L sodium chloride in the control group. Using high-sensitivity mass spectrometry coupled with data-independent acquisition (DIA) quantification, we quantified 5870, 5744, and 5816 proteins in succinate, fumarate, and lactate mTSA experiments, respectively. By setting stringent cut-off values (i.e., significance of changes in protein thermal stability (p-value)<0.001 and quality of the dose-response curve fitting (square of Pearson's correlation coefficient, R2)>0.95), multiple binding proteins for these organic acid metabolites from background proteins were confidently determined. Several known binding proteins were identified, notably fumarate hydratase (FH) as a binding protein for fumarate, and α-ketoglutarate-dependent dioxygenase (FTO) as a binding protein for both fumarate and succinate. Additionally, the affinity data for the interactions between these metabolites and their binding proteins were obtained, which closely matched those reported in the literature. Interestingly, ornithine aminotransferase (OAT), which is involved in amino acid biosynthesis, and 3-mercaptopyruvate sulfurtransferase (MPST), which acts as an antioxidant in cells, were identified as lactate-binding proteins. Subsequently, an orthogonal assay technique developed in our laboratory, the solvent-induced precipitation (SIP) technique, was used to validate the mTSA results. SIP identified OAT as the top target candidate, validating the mTSA-based finding that OAT is a novel lactate-binding protein. Although MPST was not identified as a lactate-binding protein by SIP, statistical analysis of MPST in the mTSA experiments with 10 or 25 mmol/L lactate revealed that MPST is a lactate-binding protein with a high level of confidence. Peptide-level empirical Bayes t-tests combined with Fisher's exact test also supported the conclusion that MPST is a lactate-binding protein. Lactate is structurally similar to pyruvate, the known binding protein of MPST. Therefore, assuming that lactate could potentially occupy the binding site of pyruvate on MPST. Overall, the novel binding proteins identified for lactate suggest their potential involvement in amino acid synthesis and redox balance regulation.

Serum macroelements and microelements levels in periparturient dairy cows in relation to fatty liver diseases.

BACKGROUND: Fatty liver in dairy cows is a common metabolic disease defined by triglyceride (TG) buildup in the hepatocyte. Clinical diagnosis of fatty liver is usually done by liver biopsy, causing considerable economic losses in the dairy industry owing to the lack of more effective diagnostic methods. Therefore, this study aimed to investigate the potential utility of blood biomarkers for the diagnosis and early warning of fatty liver in dairy cows. RESULTS: A total of twenty-four lactating cows within 28 days after parturition were randomly selected as experimental animals and divided into healthy cows (liver biopsy tested, n = 12) and cows with fatty liver (liver biopsy tested, n = 12). Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the macroelements and microelements in the serum of two groups of cows. Compared to healthy cows (C), concentrations of calcium (Ca), potassium (K), magnesium (Mg), strontium (Sr), selenium (Se), manganese (Mn), boron (B) and molybdenum (Mo) were lower and copper (Cu) was higher in fatty liver cows (F). Meanwhile, the observed differences in macroelements and microelements were related to delivery time, with the greatest major disparity between C and F occurring 7 days after delivery. Multivariable analysis was used to test the correlation between nine serum macroelements, microelements and fatty liver. Based on variable importance projection and receiver operating characteristic (ROC) curve analysis, minerals Ca, Se, K, B and Mo were screened as the best diagnostic indicators of fatty liver in postpartum cows. CONCLUSIONS: Our data suggested that serum levels of Ca, K, Mg, Se, B, Mo, Mn, and Sr were lower in F than in C. The most suitable period for an early-warning identification of fatty liver in cows was 7 days after delivery, and Ca, Se, K, B and Mo were the best diagnostic indicators of fatty liver in postpartum cows.

Death associated protein like 1 acts as a novel tumor suppressor in melanoma by increasing the stability of P21 protein.

Melanoma is a primary malignant tumor with high lethality, which occurs in the skin and eye tissues, while the molecular mechanisms of melanomagenesis remain largely unknown. Here, we show that death-associated protein-like 1 (DAPL1) expression is lower in melanoma tissues than in paracancerous tissues or nevus tissues, and Uveal melanoma patients with lower DAPL1 expression have a poorer survival rate than those with higher expression of DAPL1. Overexpression of DAPL1 inhibits proliferation of cultured melanoma cells, whereas knockdown of DAPL1 increases cell proliferation. Tumor transplantation experiment results also demonstrate that DAPL1 inhibits tumorigenesis of melanoma cells both in subretinal and subcutaneous tissues of nude mice in vivo. Finally, DAPL1 inhibits proliferation of melanoma cells by increasing the protein level of P21 via decreasing the ubiquitin mediated degradation of P21 and promoting its stability. Conversely, knockdown of P21 neutralizes the effects of inhibition of DAPL1 on melanoma cell proliferation and enhances the severity of melanoma tumorigenesis. These results suggest that DAPL1 is a novel melanoma tumor suppressor gene and thus a potential therapeutic target for melanoma.

Magnetic-guided nanocarriers for ionizing/non-ionizing radiation synergistic treatment against triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. METHODS: In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs' in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. RESULTS: INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. CONCLUSIONS: INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.

Zebrafish gender-specific anxiety-like behavioral and physiological reactions elicited by caffeine.

Caffeine exerts a biphasic effect on zebrafish behavior. High doses of caffeine have been associated with increased stress and anxiety, whereas low doses have been found to enhance performance on tasks requiring focus and attention. However, the sex-specific nature of these biphasic effects on behavior and physiology remains unclear. This study assessed the behavioral responses and hormone levels in male and female zebrafish after acute exposure to caffeine ranging from 0.3 to 600mg/L. The results showed no significant difference in caffeine intake between males and females after acute exposure at each concentration. Caffeine-induced behavioral and physiological responses indicated a threshold dosage existed between 30 and 300mg/L. Female fish displayed increased anxiety-like behavioral phenotypes, i.e., latency to upper and freezing, whereas males exhibited more erratic movement following acute exposure to a high-dose treatment. In addition, females exhibited a significant increase in whole-body cortisol levels, while males experienced a testosterone elevation at 300mg/L of caffeine acute exposure. There was a significant decrease in the duration of erratic movements in males treated with the androgen receptor antagonist flutamide compared to the control group. The transcriptome analysis uncovered 511 and 592 up-regulated and 761 and 922 down-regulated differential expression genes in males and females, respectively, compared to the control. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis revealed that caffeine has the potential to impact various pathways in zebrafish, including phototransduction and steroid hormone biosynthesis. Our findings demonstrate that testosterone and cortisol play a combined role in regulating stress responses in both behavior and physiology. Furthermore, our study highlights the significance of encompassing both male and female zebrafish as a model system.

Nanoindentation Test of Ion-Irradiated Materials: Issues, Modeling and Challenges.

Exposure of metals to neutron irradiation results in an increase in the yield strength and a significant loss of ductility. Irradiation hardening is also closely related to the fracture toughness temperature shift or the ductile-to-brittle transition temperature (DBTT) shift in alloys with a body-centered cubic (bcc) crystal structure. Ion irradiation is an indispensable tool in the study of the radiation effects of materials for nuclear energy systems. Due to the shallow damage depth in ion-irradiated materials, the nanoindentation test is the most commonly used method for characterizing the changes in mechanical properties after ion irradiation. Issues that affect the analysis of irradiation hardening may arise due to changes in the surface morphology and mechanical properties, as well as the inherent complexities in nanoscale indentation. These issues, including changes in surface roughness, carbon contamination, the pile-up effect, and the indentation size effect, with corresponding measures, were reviewed. Modeling using the crystal plasticity finite element method of the nanoindentation of ion-irradiated materials was also reviewed. The challenges in extending the nanoindentation test to high temperatures and to multiscale simulation were addressed.