Advanced Biomaterials Derived from Functional Polyphosphoesters: Synthesis, Properties, and Biomedical Applications.

Polyphosphoesters (PPEs) represent an innovative class of biodegradable polymers, with the phosphate ester serving as the core repeating unit of their polymeric backbone. Recently, biomaterials derived from functionalized PPEs have garnered significant interest in biomedical applications because of their commendable biocompatibility, biodegradability, and the capacity for functional modification. This review commences with a brief overview of synthesis methodologies and the distinctive properties of PPEs, including thermoresponsiveness, degradability, stealth effect, and biocompatibility. Subsequently, the review delves into the latest applications of PPEs-based nanocarriers for drug or gene delivery and PPEs-based polymeric prodrugs and scaffolds in the biomedical field, presenting several illustrative examples for each application. By encapsulating the advancements of recent years, this review aims to offer an enhanced understanding and serve as a reference for the synthesis and biomedical applications of functional PPEs.

Dietary Bacillus subtilis benefits meat quality by regulating the muscle fiber type and antioxidant capacity of broilers.

The effects of dietary Bacillus subtilis (BS) on the meat quality of broilers were evaluated, with an emphasis on the regulation of muscle fiber types and antioxidant capabilities. One hundred and forty-four Arbor Acres male broilers were divided into 3 treatment groups (0, 300 mg/kg and 500 mg/kg dietary BS) and raised for 35 d. The results suggested that BS improved meat quality by improving the muscular pH, meat color, water holding capacity and shear force. Immunofluorescence staining revealed a positive impact of BS on the muscle fiber transformation in thigh muscles, and the gene/protein expression data from specific muscle fiber types confirmed this finding. BS activated AMP-activated protein kinase (AMPK), silent information regulator 1 and peroxisome proliferator-activated receptor gamma coactivator 1alpha. The postmortem analysis revealed that BS increased the activity of glutathione peroxidase and total antioxidant capacity while decreasing the malondialdehyde content. Additionally, BS increased the gene and protein expression of nuclear factor-like 2 (Nrf2) and activated the Nrf2 signaling pathway, including its downstream factors, such as heme oxygenase-1, catalase, superoxide dismutase and glutathione peroxidase. In conclusion, dietary BS improved meat quality by modifying muscle fiber types and enhancing the antioxidant capacity in broilers.

Machine learning-based discrimination of unipolar depression and bipolar disorder with streamlined shortlist in adolescents of different ages.

BACKGROUND: Variations in symptoms and indistinguishable depression episodes of unipolar depression (UD) and bipolar disorder (BD) make the discrimination difficult and time-consuming. For adolescents with high disease prevalence, an efficient diagnostic tool is important for the discrimination and treatment of BU and UD. METHODS: This multi-center cross-sectional study involved 1587 UD and 246 BD adolescents aged 12-18. A combination of standard questionnaires and demographic information was collected for the construction of a full-item list. The unequal patient number was balanced with three data balancing algorithms, and 4 machine learning algorithms were compared for the discrimination ability of UD and BD in three age groups: all ages, 12-15 and 16-18. Random forest (RF) with the highest accuracy were used to rank the importance of features/items and construct the 25-item shortlist. A separate dataset was used for the final performance evaluation with the shortlist, and the discrimination ability for UD and BD was investigated. RESULTS: RF performed the best for UD and BD discrimination in all 3 age groups (AUC 0.88-0.90). The most important features that differentiate UD from BD belong to Parental Bonding Instrument (PBI) and Loneliness Scale of the University of California at Los Angeles (UCLA). With RF and the 25-item shortlist, the diagnostic accuracy can still reach around 80 %, achieving 95 % of the accuracy levels obtained with all features. CONCLUSIONS: Through machine learning algorithms, the most influencing factors for UD and BD classification were recombined and applied for rapid diagnosis. This highly feasible method holds the potential for convenient and accurate diagnosis of young patients in research and clinical practice.

Simultaneously Controlling Inflammation and Infection by Smart Nanomedicine Responding to the Inflammatory Microenvironment.

The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti-inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti-inflammation and anti-infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory-microenvironment-responsive nanomedicine is designed by using poly(lactic-co-glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non-toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus-induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET-based nanoparticles by simultaneously controlling infections and inflammation may be promising nano-therapeutics for treatment of severe infectious diseases.

[Clinical and genetic analysis of a child with Focal segmental glomerulosclerosis due to a novel variant of PLCE1 gene].

OBJECTIVE: To explore the genetic basis and clinical phenotype of a Chinese pedigree affected with Focal segmental glomerulosclerosis (FSGS). METHODS: A male patient who was admitted to the First Affiliated Hospital of Zhengzhou University on July 26, 2018 was selected as the study subject. Clinical data of the patient was collected. Next generation sequencing and Sanger sequencing were carried out to detect the variant sites. Bioinformatic software was used to simulate the effect of candidate variant on the protein functions. RESULTS: Ultrasound exam of the patient showed enhanced echo for the renal parenchyma. Kidney biopsy had confirmed the pathological diagnosis of FSGS (non-specific). Electronic microscopy displayed segmental sclerosis of the glomeruli, mild hyperplasia of mesangial cells and matrix. The proband was found to harbor two novel variants of the PLCE1 gene, namely c.3199delA (p.N1067Mfs*15) and c.4441_4443delATC (p.1481_1481del), which were respectively inherited from his mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as pathogenic (PVS1+PM2_Supporting+PP3; PM2_Supporting+PM3+PP3). Bioinformatic simulation suggested that both variants could significantly affect the tertiary structure of the PLCE1 protein. CONCLUSION: The c.4441_4443delATC and c.3199delA variants of the PLCE1 gene probably underlay the pathogenesis of the FSGS in this pedigree.

Metal-Organic Framework-Derived Au-Doped In2O3 Nanotubes for Monitoring CO at the ppb Level.

Achieving selective detection of ppb-level CO is important for air quality testing at industrial sites to ensure personal safety. Noble metal doping enhances charge transfer, which in turn reduces the detection limit of metal oxide gas sensors. In this work, metal-organic framework-derived Au-doped In2O3 nanotubes with high electrical conductivity are synthesized by pyrolysis of the Au-doped metal-organic framework (In-MIL-68) as a template. Gas-sensing experiments reveal that the detection limit of 0.2% Au-doped In2O3 nanotubes (0.2% Au, mass fraction) is as low as 750 ppb. Meanwhile, the sensing material shows a response value of 18.2 to 50 ppm of CO at 240 °C, which is about 2.8 times higher than that of pure In2O3. Meanwhile, the response and recovery times are short (37 s/86 s). The gas-sensing mechanism of CO is uncovered by in situ DRIFTS through the reaction intermediates. In addition, first-principles calculations suggest that Au doping of In2O3 significantly enhances its adsorption energy for CO and improves the electron transfer properties. This study reveals a novel synthesis pathway for Au-doped In2O3 nanotubular structures and their potential application in low concentration CO detection.

Increasing Cyetpyrafen Spray Volume and Ozone Spray Improves the Control Effects against Two-Spotted Spider Mite (Tetranychus urticae) in Strawberries.

The two-spotted spider mite (Tetranychus urticae) is a constant threat to greenhouse strawberry production. The application of synthetic acaricides is the main method of controlling T. urticae. However, resistance development to traditional acaricides reduces their efficacy and eventually leads to control failure. It is important for strawberry growers to look for new acaricides and application technologies that can limit the harmfulness of T. urticae in environmentally friendly ways. In the current study, laboratory toxicity tests and field trials were performed to screen high-efficiency acaricides, and then application technologies were improved to enhance the management of T. urticae. In the laboratory toxicity tests, the results showed that the LC50 (median lethal concentration) value of cyetpyrafen, cyenopyrafen, cyflumetofen, bifenazate, abamectin, azocyclotin, pyridaben, spirodiclofen, and etoxazole against adult T. urticae was 0.226, 0.240, 0.415, 3.583, 5.531, 25.58, 39.69, 140.3, and 267.7 mg/L, respectively. In addition, the LC50 value of the nine acaricides against eggs of T. urticae was 0.082, 0.097, 0.931, 18.56, 25.52, 45.61, 36.32, 1.954, and 0.040 mg/L, respectively. The field trial results showed that the best control effect was obtained in cyetpyrafen at 300 mL/ha treatment. Cyetpyrafen was chosen for further application technology tests. In the spray volume tests, the results showed that increasing the spray volume from 900 to 1050 L/ha significantly improved the control of T. urticae. In addition, the results from the spray instrument tests demonstrated that the control effects on T. urticae in the ozone spray treatments were significantly higher than those of the conventional and electrostatic sprays 1 and 3 days after treatment (DAT). Therefore, this study suggested that cyetpyrafen effectively controlled T. urticae both in the laboratory tests and in the field trials. Increasing the spray volume and application of ozone spray significantly improved T. urticae management.

Understanding the influence of cytokines in intrauterine hepatitis B transmission: A cross-sectional study in China.

Cytokines may related to intrauterine Hepatitis B virus (HBV) transmission. 205 HBsAg(+) pregnant cases and 74 HBsAg(-) women were included. Neonatal blood samples were taken within 24 h of delivery and before HBV vaccinations. Serological HBV biomarkers and cytokines were detected. 21.9 % of the newborns from HBsAg(+) women were intrauterinally transmitted, including 7.3 % with dominant transmission (DBT) and 14.6 % occult transmission (OBT). HBV DNA load (odd ratio [OR], 1.44; 95 % confidence interval [CI], 1.05-1.98), interferon-γ (IFN-γ) (OR, 1.01; 95 %CI, 1.00-1.02) and toll-like receptor 9 (TLR9) (OR, 1.27; 95 %CI, 1.06-1.52) positively correlated with DBT. Only IFN-γ (OR, 1.01; 95 %CI, 1.00-1.01) positively associated with OBT. According to the generated restricted cubic spline, TLR9 was positively correlates with rise of DBT in a log-shape. It may be possible to develop a nomogram which intercalates these factors to predict intrauterine HBV transmissions. Further research should consider immune processes involved in chorioamnionitis.

The Impact of Different Dietary Ratios of Soluble Carbohydrate-to-Neutral Detergent Fiber on Rumen Barrier Function and Inflammation in Dumont Lambs.

Appropriate soluble carbohydrate (SCHO)-to-NDF ratios in the diet are essential for rumen health. The effects of different SCHO-to-NDF ratios (1.0, 1.5, and 2.0) on rumen barrier function and inflammation in Dumont lambs (n = 18, 6 replicates per treatment) was investigated. The SCHO:NDF ratio was altered by replacing the forage (Leynus chinensis) with corn grain. With an increase in the proportion of SCHO, the final body weight (FBW), average daily gain (ADG), soluble carbohydrate intake (SCHOI), and LPS level increased; and the neutral detergent fiber intake (NDFI), ruminal papillae height, papillae area, and pH decreased (p < 0.05, plin < 0.05). The medium CHO:NDF group had increased claudin-1 mRNA (p < 0.05, plin = 0.005, pquad = 0.003) and protein (p < 0.05, pquad < 0.001) levels; the high CHO:NDF group had increased occludin mRNA and protein (p < 0.05, plin = 0.001) levels. The level of the anti-inflammatory cytokine IL-10 was significantly greater in the medium CHO:NDF group than in the high CHO:NDF group (p < 0.05, pquad < 0.001). With an increase in the ratio of SCHO, the mRNA level and concentration of the proinflammatory cytokines IL-1ß, IL-6, and TNF-α linearly increased (p < 0.05, plin < 0.05), and those in the high CHO:NDF group were significantly greater than those in the low CHO:NDF group. The levels of phosphorylated p65 (plin = 0.003), IκB-α (plin < 0.001), and JNK (plin = 0.001) increased linearly, and those in the high CHO:NDF group were significantly greater than those in the other two groups (p < 0.05). Therefore, when the SCHO-to-NDF ratio was increased to 1.5, the rumen epithelium was not affected, but when the ratio was increased to 2.0, NF-κB and MAPK were activated in the rumen epithelium, leading to impaired barrier function and inflammation. The suitable NFC:NDF ratio for the short-term fattening of Dumont lambs was found to be 1.50.

Experimental Investigation for Proton Exchange Membrane Fuel Cells in Marine Salt Spray Environment.

In the maritime setting, Proton Exchange Membrane Fuel Cells (PEMFCs) are subjected to salt spray, posing a risk of contaminating internal components and leading to irreversible degradation in the performance of the PEMFCs. Thus, it is crucial to assess the impact of sodium chloride contamination on PEMFC operation. To address challenges related to prolonged cycle times, high costs, and intricate sample preparation in sodium chloride contamination experiments for PEMFCs, this Article replicates the marine atmospheric conditions using a standard salt spray experimental chamber. The liquid nitrogen fracture method is employed for cost-effective and efficient preparation of experimental samples. The meteorological environment with varying salt content in the salt spray is achieved through precise control of sodium chloride concentration. The Article systematically presents the salt spray experimental method for the membrane electrode assembly (MEA) of PEMFCs. A dedicated salt spray experimental rig was constructed to validate this method for the MEA of PEMFCs. The results indicate that the salt spray experimental method for the MEA of PEMFCs can effectively explore internal component contamination and is well-suited for analyzing the physicochemical effects of NaCl on MEA components, along with their microscopic characterization under salt spray conditions.

Methyl jasmonate enhances the safe production ability of Cd-stressed wheat by regulating the antioxidant capacity, Cd absorption, and distribution in wheat.

Identifying green and effective measures for reducing wheat Cd toxicity and grain Cd accumulation is crucial. This study used seedling sand culture and full-grown pot experiments of wheat cultivars 'Luomai23' (LM) and 'Zhongyu10' (ZY). The purpose was to determine the effects of exogenous MeJA on the phenotype, photosynthesis, antioxidant system, Cd accumulation and distribution, transporter gene expression, and cell wall properties of Cd-stressed wheat. Compared with Cd treatment alone, the plant height and maximum root length treated with 0.001 µM MeJA increased by more than 6.3% and 16.6%, respectively. Under 5 mg⋅kg-1 Cd treatment, spraying 10 µM MeJA increased the photosynthetic rate of LM and ZY by 23.5% and 35.8% at the filling stage, respectively. Methyl jasmonate significantly reduced the H2O2 and MDA contents by increasing the activities of POD, DHAR, MDHAR, and GR and the contents of AsA and GSH. Applicating MeJA increased the content of chelate substances, cell wall polysaccharides, and cell wall functional groups. Besides, MeJA regulated the expression of Cd transporter genes, with shoot and root Cd content decreasing by 46.7% and 27.9% in LM, respectively. Spraying 10 µM MeJA reduced Cd absorption and translocation from vegetative organs to grains, thus reducing the grain Cd content of LM and ZY by 36.1 and 39.9% under 5 mg⋅kg-1 Cd treatment, respectively. Overexpressing TaJMT significantly increased the MeJA content and Cd tolerance of Arabidopsis. These results have improved the understanding of the mechanism through which MeJA alleviates Cd toxicity and reduces Cd accumulation in wheat.

Path to autonomous soil sampling and analysis by ground-based robots.

Good site characterization is essential for the selection of remediation alternatives for impacted soils. The value of site characterization is critically dependent on the quality and quantity of the data collected. Current methods for characterizing impacted soils rely on expensive manual sample collection and off-site analysis. However, recent advances in terrestrial robotics and artificial intelligence offer a potentially revolutionary set of tools and methods that will help to autonomously explore natural environments, select sample locations with the highest value of information, extract samples, and analyze the data in real-time without exposing humans to potentially hazardous conditions. A fundamental challenge to realizing this potential is determining how to design an autonomous system for a given investigation with many, and often conflicting design criteria. This work presents a novel design methodology to navigate these criteria. Specifically, this methodology breaks the system into four components - sensing, sampling, mobility, and autonomy - and connects design variables to the investigation objectives and constraints. These connections are established for each component through a survey of existing technology, discussion of key technical challenges, and highlighting conditions where generality can promote multi-application deployment. An illustrative example of this design process is presented for the development and deployment of a robotic platform characterizing salt-impacted oil & gas reserve pits. After calibration, the relationship between the in situ robot chloride measurements and laboratory-based chloride measurements had a good linear relationship (R2-value = 0.861) and statistical significance (p-value = 0.003).

Changes of serum cortisol during pregnancy and labor initiation: an onsite cross-sectional study.

Background: Increased maternal cortisol secretion has been observed during pregnancy and labor. However, due to the limitations in diagnostic methods, the dynamic change of cortisol during the short period between threatened labor and labor is unknown. In this study, we aim to evaluate the changes in serum cortisol during late pregnancy and full-term labor initiation, verifying if cortisol could serve as a biomarker for the diagnosis of labor initiation from threatened labor. Methods: This cross-sectional onsite study involved 564 participants of 6 different gestational stages (C: Control; T1: Trimester 1; T3: Trimester 3; E: expectant; TL: threatened labor; L: labor), all patients in the E, TL, and L groups were at full term. The serum cortisol concentration was quantified with a point-of-care test (POCT), and the gestation, age, parity, and BMI of participants were documented. Morning serum cortisol was collected between 8:00 and 10:00 a.m., except for the TL and L group women who were tested upon arrival or during latent labor. With cortisol levels or all five variables, L was distinguished from TL using machine learning algorithms. Results: Significant elevation of cortisol concentration was observed between T1 and T3, or TL and L group (P< 0.001). Women belonging to the E and TL group showed similar gestation week and cortisol levels. Diagnosis of labor initiation using cortisol levels (cutoff = 21.46 µg/dL) yielded sensitivity, specificity, and AUC of 86.50%, 88.60%, and 0.934. With additional variables, a higher specificity (89.29%) was achieved. The diagnostic accuracy of all methods ranged from 85.93% to 87.90%. Conclusion: Serum cortisol could serve as a potential biomarker for diagnosis of L form TL. The rapid onsite detection of serum cortisol with POCT could facilitate medical decision-making for admission and special treatments, either as an additional parameter or when other technical platforms are not available.

From 2D to 3D: automatic measurement of the Cobb angle in adolescent idiopathic scoliosis with the weight-bearing 3D imaging.

BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) necessitates accurate spinal curvature assessment for effective clinical management. Traditional two-dimensional (2D) Cobb angle measurements have been the standard, but the emergence of three-dimensional (3D) automatic measurement techniques, such as those using weight-bearing 3D imaging (WR3D), presents an opportunity to enhance the accuracy and comprehensiveness of AIS evaluation. PURPOSE: This study aimed to compare traditional 2D Cobb angle measurements with 3D automatic measurements utilizing the WR3D imaging technique in patients with AIS. STUDY DESIGN/SETTING: A cohort of 53 AIS patients was recruited, encompassing 88 spinal curves, for comparative analysis. PATIENT SAMPLE: The patient sample consisted of 53 individuals diagnosed with AIS. OUTCOME MEASURES: Cobb angles were calculated using the conventional 2D method and three different 3D methods: the Analytical Method (AM), the Plane Intersecting Method (PIM), and the Plane Projection Method (PPM). METHODS: The 2D cobb angle was manually measured by 3 experienced clinicians with 2D frontal whole-spine radiographs. For 3D cobb angle measurements, the spine and femoral heads were segmented from the WR3D images using a 3D-UNet deep-learning model, and the automatic calculations of the angles were performed with the 3D slicer software. RESULTS: AM and PIM estimates were found to be significantly larger than 2D measurements. Conversely, PPM results showed no statistical difference compared to the 2D method. These findings were consistent in a subgroup analysis based on 2D Cobb angles. CONCLUSION: Each 3D measurement method provides a unique assessment of spinal curvature, with PPM offering values closely resembling 2D measurements, while AM and PIM yield larger estimations. The utilization of WR3D technology alongside deep learning segmentation ensures accuracy and efficiency in comparative analyses. However, additional studies, particularly involving patients with severe curves, are required to validate and expand on these results. This study emphasizes the importance of selecting an appropriate measurement method considering the imaging modality and clinical context when assessing AIS, and it also underlines the need for continuous refinement of these techniques for optimal use in clinical decision-making and patient management.

Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm.

BACKGROUND AND OBJECTIVE: Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcome. METHODS: We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. Classification accuracy of each gene were compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. RESULTS: WSO-SVM achieved 0.80 accuracy, 0.79 sensitivity, and 0.81 specificity for classifying EGFR; 0.71 accuracy, 0.70 sensitivity, and 0.72 specificity for classifying PDGFRA; 0.80 accuracy, 0.78 sensitivity, and 0.83 specificity for classifying PTEN; these results significantly outperformed the existing ML algorithms. Using SHAP, we found that the relative contributions of the five contrast images differ between genes, which are consistent with findings in the literature. The prediction maps revealed extensive intra-tumoral region-to-region heterogeneity within each individual tumor in terms of the alteration status of the three genes. CONCLUSIONS: This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology.

Biologically-informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post-treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Mechanisms of Heavy Metal Cadmium (Cd)-Induced Malignancy.

The environmental pollution of cadmium is worsening, and its significant carcinogenic effects on humans have been confirmed. Cadmium can induce cancer through various signaling pathways, including the ERK/JNK/p38MAPK, PI3K/AKT/mTOR, NF-κB, and Wnt. It can also cause cancer by directly damaging DNA and inhibiting DNA repair systems, or through epigenetic mechanisms such as abnormal DNA methylation, LncRNA, and microRNA. However, the detailed mechanisms of Cd-induced cancer are still not fully understood and require further investigation.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Maternal exposure to particulate matter from duck houses restricts fetal growth due to inflammatory damage and oxidative stress.

The composition of particulate matter (PM) in poultry farms differs significantly from that of atmospheric PM as there is a higher concentration of microbes on farms. To assess the health effects of PM from poultry farms on pregnant animals, we collected PM from duck houses using a particulate sampler, processed it via centrifugation and vacuum concentration, and subsequently exposed the mice to airborne PM at 0.48 mg/m3 (i.e., low concentration group) and 1.92 mg/m3 (i.e., high concentration group) on the fifth day of pregnancy. After exposure until the twentieth day of pregnancy or spontaneous delivery, mice were euthanized for sampling. The effects of PM from duck houses on the pregnancy toxicity of mice were analyzed using histopathological analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction (qPCR). The results showed that exposure to PM had adverse effects on pregnant mice that reduced their feed intake in both groups. Microscopic lesions were observed in the lungs and placentas of pregnant mice, and the lesions worsened with increased PM concentrations, as shown by alveolar wall thickening, the infiltration of inflammatory cells in pulmonary interstitium, congestion, edema, and cellular degeneration of placenta. In pregnant mice in the high concentration group, exposure to PM significantly increased the expression of inflammatory cytokines in the lungs and placentas, caused oxidative stress, and decreased estrogen level in the blood. Exposure to PM also resulted in the reduced litter sizes of pregnant mice and shorter body and tail lengths in the fetuses delivered. Beyond that, exposure to PM significantly downregulated the levels of antioxidant factor superoxide dismutase and neurotrophic factor Ngf in the brains of fetuses. Collectively, exposure to a high concentration of PM by inhalation among pregnant mice caused significant pregnancy toxicity that led to abnormal fetal development due to inflammatory damage and oxidative stress. These findings established a foundation for future studies on the underlying mechanisms of pregnancy toxicity induced by exposure to PM.