High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration.

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Loss of GCN5L1 exacerbates damage in alcoholic liver disease through ferroptosis activation.

BACKGROUND AND AIMS: Iron overload, oxidative stress and ferroptosis are associated with liver injury in alcohol-associated liver disease (ALD), however, the crosstalk among these regulatory pathways in ALD development is unclear. METHODS: ALD mouse model and general control of amino acid synthesis 5 like 1 (GCN5L1) liver knockout mice were generated to investigate the role of GCN5L1 in ALD development. Proteomic screening tests were performed to identify the key factors mediating GCN5L1 loss-induced ALD. RESULTS: Gene Expression Omnibus data set analysis indicates that GCN5L1 expression is negatively associated with ALD progression. GCN5L1 hepatic knockout mice develop severe liver injury and lipid accumulation when fed an alcohol diet. Screening tests identified that GCN5L1 targeted the mitochondrial iron transporter CISD1 to regulate mitochondrial iron homeostasis in ethanol-induced ferroptosis. GCN5L1-modulated CISD1 acetylation and activity were crucial for iron accumulation and ferroptosis in response to alcohol exposure. CONCLUSION: Pharmaceutical modulation of CISD1 activity is critical for cellular iron homeostasis and ethanol-induced ferroptosis. The GCN5L1/CISD1 axis is crucial for oxidative stress and ethanol-induced ferroptosis in ALD and is a promising avenue for novel therapeutic strategies.

FXR/Menin-mediated epigenetic regulation of E2F3 expression controls ß-cell proliferation and is increased in islets from diabetic GK rats after RYGB.

Farnesoid X receptor (FXR) improves the function of islets, especially in the setting of Roux-en-Y gastric bypass (RYGB). Here we investigated how FXR activation regulates ß-cell proliferation and explored the potential link between FXR signaling and the menin pathway in controlling E2F3 expression, a key transcription factor for controlling adult ß-cell proliferation. Stimulation with the FXR agonist GW4064 or chenodeoxycholic acid (CDCA) increased E2F3 expression and ß-cell proliferation. Consistently, E2F3 knockdown abolished GW4064-induced proliferation. Treatment with GW4064 increased E2F3 expression in ß-cells via enhancing Steroid receptor coactivator-1 (SRC1) recruitment, increasing the pro-transcriptional acetylation of histone H3 at the E2f3 promoter. GW4064 treatment also decreased the association between FXR and menin, leading to the induction of FXR-mediated SRC1 recruitment. Mimicking the impact of FXR agonists, RYGB also increased E2F3 expression and ß-cell proliferation in GK rats and SD rats. These findings unravel the crucial role of the FXR/menin signaling in epigenetically controlling E2F3 expression and ß-cell proliferation, a mechanism possibly underlying RYGB-induced ß-cell proliferation.

3dDNAscoreA: A scoring function for evaluation of DNA 3D structures.

DNA molecules are vital macromolecules that play a fundamental role in many cellular processes and have broad applications in medicine. For example, DNA aptamers have been rapidly developed for diagnosis, biosensors, and clinical therapy. Recently, we proposed a computational method of predicting DNA 3D structures, called 3dDNA. However, it lacks a scoring function to evaluate the predicted DNA 3D structures, and so they are not ranked for users. Here, we report a scoring function, 3dDNAscoreA, for evaluation of DNA 3D structures based on a deep learning model ARES for RNA 3D structure evaluation but using a new strategy for training. 3dDNAscoreA is benchmarked on two test sets to show its ability to rank DNA 3D structures and select the native and near-native structures.

Discovery of BMP10 as a new gene underpinning congenital heart defects.

OBJECTIVE: Aggregating evidence convincingly establishes the predominant genetic basis underlying congenital heart defects (CHD), though the heritable determinants contributing to CHD in the majority of cases remain elusive. In the current investigation, BMP10 was selected as a prime candidate gene for human CHD mainly due to cardiovascular developmental abnormalities in Bmp10-knockout animals. The objective of this retrospective study was to identify a new BMP10 mutation responsible for CHD and characterize the functional effect of the identified CHD-causing BMP10 mutation. METHODS: Sequencing assay of BMP10 was fulfilled in a cohort of 276 probands with various CHD and a total of 288 non-CHD volunteers. The available family members from the proband harboring an identified BMP10 mutation were also BMP10-genotyped. The effect of the identified CHD-causative BMP10 mutation on the transactivation of TBX20 and NKX2.5 by BMP10 was quantitatively analyzed in maintained HeLa cells utilizing a dual-luciferase reporter assay system. RESULTS: A novel heterozygous BMP10 mutation, NM_014482.3:c.247G>T;p.(Glu83*), was identified in one proband with patent ductus arteriosus (PDA), which was confirmed to co-segregate with the PDA phenotype in the mutation carrier's family. The nonsense mutation was not observed in 288 non-CHD volunteers. Functional analysis unveiled that Glu83*-mutant BMP10 had no transactivation on its two representative target genes TBX20 and NKX2.5, which were both reported to cause CHD. CONCLUSION: These findings provide strong evidence indicating that genetically compromised BMP10 predisposes human beings to CHD, which sheds light on the new molecular mechanism that underlies CHD and allows for antenatal genetic counseling and individualized precise management of CHD.

Elucidating Hedgehog pathway's role in HNSCC progression: insights from a 6-gene signature.

With the emergence of targeted inhibition strategies for Hedgehog signaling in cancer, multiple Hedgehog signaling pathway-related biomarkers have become the focus of research. SsGSEA algorithm was employed to analyze the Hedgehog pathway scores of samples in TCGA-HNSC dataset and divide them into two groups. Weighted co-expression network analysis was performed to identify modules strongly associated with the Hedgehog pathway. Differentially up-regulated genes in tumor samples in comparison to the normal ones were screened by Limma, in which genes belonging to modules strongly related to Hedgehog pathway were further filtered by LASSO reduction and multivariate Cox regression analysis to develop a model. ESTIMATE and CIBERSORT were served to characterize the tumor microenvironment (TME). TIDE assessed immunotherapy response. Hedgehog pathway activity was significantly higher in head and neck squamous cell carcinoma (HNSCC) tissues than in normal tissues and was correlated with HNSCC survival, glycan, cofactors and vitamins, drug metabolism, and matrix scores. Six genes (SLC2A3, EFNB2, OAF, COX4I2, MT2A and TXNRD1) were captured to form a Hedgehog associated 6-gene signature, and the resulting risk score was an independent indicator of HNSCC prognosis. It was significantly positively correlated with stromal score, metabolism, angiogenesis and inflammatory response. Patients in low-risk group with a low TIDE score had higher immunotherapy sensitivity relative to those in high-risk group. This study revealed novel findings of the Hedgehog pathway in HNSCC progression and opened up a Hedgehog pathology-related signature to help identify risk factors contributing to HNSCC progression and help predict immunotherapy outcomes.

Emulsification Characteristics of Insoluble Dietary Fibers from Pomelo Peel: Effects of Acetylation, Enzymatic Hydrolysis, and Wet Ball Milling.

To improve the application potential of pomelo peel insoluble dietary fiber (PIDF) in emulsion systems, acetylation (PIDF-A), cellulase hydrolysis (PIDF-E), and wet ball milling (PIDF-M) were investigated in this paper as methods to change the emulsification properties of PIDF. The impact of the methods on PIDF composition, structure, and physicochemical properties was also assessed. The results demonstrated that both acetylation modification and cellulase hydrolysis could significantly improve the emulsification properties of PIDF. The emulsions stabilized with PIDF-A and PIDF-E could be stably stored at 25 °C for 30 d without phase separation at particle concentrations above 0.8% (w/v) and had higher storage stability: The D4,3 increments of PIDF-A- and PIDF-E-stabilized emulsions were 0.98 µm and 0.49 µm, respectively, at particle concentrations of 1.2% (w/v), while the storage stability of PIDF-M-stabilized emulsion (5.29 µm) significantly decreased compared with that of PIDF (4.00 µm). Moreover, PIDF-A showed the highest water retention capacity (21.84 g/g), water swelling capacity (15.40 mL/g), oil retention capacity (4.67 g/g), and zeta potential absolute (29.0 mV) among the PIDFs. In conclusion, acetylation modification was a promising method to improve the emulsifying properties of insoluble polysaccharides.

Shrinkage Reduction in Nanopore-Rich Cement Paste Based on Facile Organic Modification of Montmorillonite.

The organic modification of montmorillonite was successfully achieved using cetyltrimethyl ammonium bromide under facile conditions. The modified montmorillonite was subsequently used for the fabrication of montmorillonite-induced nanopore-rich cement paste (MNCP), and the shrinkage behavior and fundamental performance of MNCP were also investigated. The results indicate that alkali cations on a montmorillonite layer surface were exchanged by using CTAB under 80 °C, successfully achieving the organic modification of montmorillonite. As a pore-forming agent, the modified montmorillonite caused a reduction in shrinkage: the 28-day autogenous shrinkage at a design density of 400 kg/m3 and 800 kg/m3 was reduced to 2.05 mm/m and 0.24 mm/m, and the highest reduction percentages during the 28-day drying shrinkage were 68.1% and 62.2%, respectively. The enlarged interlamellar pores and hydrophobic effects caused by the organic modification of montmorillonite aided this process. Organic-modified montmorillonite had a minor influence on dry density and thermal conductivity and could contribute to an enhancement of strength in MNCP.

Immunomodulatory effects of iTr35 cell subpopulation and its research progress.

The spotlight in recent years has increasingly focused on inducible regulatory T cells 35 (iTr35), a novel subpopulation of regulatory T cells characterized by phenotypic stability, heightened reactivity, and potent immunosuppressive function through the production of IL-35. Despite being in the exploratory phase, research on iTr35 has garnered significant interest. In this review, we aim to consolidate our understanding of the biological characteristics and immunomodulatory mechanisms of iTr35, offering fresh perspectives that may pave the way for its potential applications in disease diagnosis and treatment.

The effect of incentive policies on the diffusion of construction and demolition waste recycling: A government perspective.

Construction and demolition (C&D) waste recycling plays a significant role in waste reduction and carbon reduction, which is critical for sustainable development. However, due to various limitations such as financial problems, C&D waste recycling industry is not well developed in developing countries. To address this problem, this study combines complex network theory and evolutionary game theory to analyse the diffusion of C&D waste recycling behaviour among enterprises under governmental incentive policies within a complex network context. The results demonstrate that the size of the network has limited effects on behaviour diffusion in Watts-Strogatz small-world network. Additionally, the study highlights the clear impact of governmental incentive probability, initial rate and connection degree on the diffusion path. By quantitatively investigating the effects of incentive tools, this study contributes to the knowledge of C&D waste management and provides valuable implications for stakeholders seeking to promote the diffusion of C&D waste recycling.

GLP-1 signaling-regulated SNAP25 is involved in improved insulin secretion in diabetic GK rats after Roux-en-Y gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass surgery (RYGB) improves glucose-stimulated insulin secretion (GSIS) in type 2 diabetes (T2D) patients. SNAP25 plays an essential role in GSIS. Clinical studies indicate that enhanced GLP-1 signaling is an important contributor to the improved ß-cell function in T2D. We aimed to explore whether GLP-1-regulated SNAP25 is involved in the enhanced secretory function of ß-cells in diabetic Goto-Kakizaki (GK) rats after RYGB. METHODS AND RESULTS: RYGB or sham surgery was conducted in GK rats. mRNA and protein expression of SNAP25 was assessed by qPCR and Western blot, respectively. Occupancy of CREB and acetyltransferase CBP and acetylation of histone H3 (ACH3) at the Snap25 promoter were determined using ChIP assay. RYGB led to increased SNAP25 expression and CREB phosphorylation in islets from GK rats. Increased SNAP25 improved GSIS in ß-cells cultured in high glucose conditions. Consistent with increased plasma GLP-1 after RYGB, GLP-1R agonist exendin4 increased SNAP25 expression and CREB phosphorylation in ß-cells. Mechanistically, exendin4 promoted the recruitment of CREB and CBP, thereby increasing ACH3 at the Snap25 promoter. Consistently, inhibition of CBP attenuated the effect of exendin4 on SNAP25 expression. Furthermore, the knockdown of SNAP25 diminished the increase of GSIS potentiated by chronic GLP-1 culture in INS-1 832/13 cells. CONCLUSIONS: Our findings unravel the novel mechanisms of RYGB-enhanced SNAP25 expression in ß-cells, and SNAP25 may contribute to the improved ß-cell secretory function induced by RYGB.

Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing.

Sequence-specific RNA-binding proteins (RBPs) play central roles in splicing decisions. Here, we describe a modular splicing architecture that leverages in vitro-derived RNA affinity models for 79 human RBPs and the annotated human genome to produce improved models of RBP binding and activity. Binding and activity are modeled by separate Motif and Aggregator components that can be mixed and matched, enforcing sparsity to improve interpretability. Training a new Adjusted Motif (AM) architecture on the splicing task not only yields better splicing predictions but also improves prediction of RBP-binding sites in vivo and of splicing activity, assessed using independent data.

Comparison of moving bed biofilm reactor and bio-contact oxidation reactor start-up with heterotrophic nitrification-aerobic denitrification bacteria and activated sludge inoculation under high ammonia nitrogen conditions.

To overcome poor ammonia tolerance and removal performance of bio-contact oxidation (BCO) reactor inoculated with activated sludge for high-ammonia nitrogen (NH4+-N) chemical wastewater treatment, this study compared inoculating heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria in moving bed biofilm reactor (MBBR) with activated sludge inoculation in BCO reactor under simulated high NH4+-N conditions. Results revealed that MBBR achieved faster biofilm formation (20 days vs. 100 days for BCO) with notable advantages: 27.6 % higher total nitrogen (TN) and 29.9 % higher NH4+-N removal efficiency than BCO. Microbial analysis indicated optimal enrichment of the key nitrogen removal (NR) bacterium Alcaligenes, leading to increased expression of NR enzymes hydroxylamine reductase, ensuring the superior NR efficiency of the MBBR. Additionally, functional enzymes and genes analysis speculated that the NR pathway in MBBR was: NH4+-N â†’ NH2OH â†’ NO3--N â†’ NO2--N â†’ NO â†’ N2O â†’ N2. This research offers a practical and theoretical foundation for extending HN-AD bacteria-inoculated MBBR processes.

Somatic GATA4 mutation contributes to tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.

High-Performance, Multifunctional, and Designable Carbon Fiber Felt Skeleton Epoxy Resin Composites EP/CF-(CNT/AgBNs)x for Thermal Conductivity and Electromagnetic Interference Shielding.

In this work, high-performance epoxy resin (EP) composites with simultaneous excellent thermal conductivity (TC) and outstanding electromagnetic shielding properties are fabricated through the structural synergy of 1D carbon nanotubes and 2D silver-modified boron nitride nanoplates (CNT/AgBNs) to erect microscopic 3D networks on long-range carbon fiber (CF) felt skeletons. The line-plane combination of CNT/AgBNs improve the interfacical bonding involving EP and CF felts and alleviate the phonon scattering at the interface. Eventually, the TC of the EP composites is enhanced by 333% (up to 0.91 W m-1 K-1 ) with respect to EP due to the efficient and orderly transmission of phonons along the 3D pathway. Meanwhile, the unique anisotropic structure of CF felt and exceptional insulating BNs diminishes the electronic conduction between CNT and CFs, which protects the through-plane insulating properties of EP composites. Furthermore, the EP composites present favorable electromagnetic shielding properties (51.36 dB) attributed to the multiple reflection and adsorption promoted by the multiple interfaces of stacked AgBNs and heterointerface among CNT/AgBNs, CF felt and EP. Given these distinguishing features, the high-performance EP composites open a convenient avenue for electromagnetic wave (EMW) shielding and thermal management applications.

[Research progress on natural guaiane-type sesquiterpenoids and their biological activities].

Guaiane-type sesquiterpenoids are a class of terpenoids with [5,7] ring-fused system as the basic skeletal structure composed of three isoprene units, which are substituted by 4,10-dimethyl-7-isopropyl. According to the difference in functional groups and degree of polymerization, they can be divided into simple guaiane-type sesquiterpenoids, sesquiterpene lactones, sesquiterpene dimers, and sesquiterpene trimers. Natural guaiane-type sesquiterpenoids are widely distributed in plants, fungi, and marine organisms, especially in families such as Compositae, Zingiberaceae, Thymelaeaceae, Lamiaceae, and Alismataceae. Guaiane-type sesquiterpenoids have good antibacterial, anti-inflammatory, anticancer, and neuroprotective effects. In this paper, the novel guaiane-type sesquiterpenoids isolated and identified in recent 10 years(2013-2022) and their biological activities were reviewed in order to provide refe-rences for the research and development of guaiane-type sesquiterpenoids.

Research on the mechanism of plant root protection for soil slope stability.

In order to investigate the impact of herbaceous root development on soil slope stability in expansive soil areas, the research was conducted in the soil slope experimental area of Yaoshi Town, Shangzhou District, Shangluo City. Three types of herbaceous plants, namely Lolium perenne, Medicago, and Cynodon dactylon, were planted to examine their influence on slope stability. The results indicated that Lolium perenne had significantly higher root length density and root surface area density compared to Cynodon dactylon and Medicago. However, the root weight density of Cynodon dactylon was found to be highest. The roots of Lolium perenne, Cynodon dactylon, and Medicago were predominantly observed in diameter ranges of 0 < L ≤ 1.0 mm, 0 < L ≤ 2.5 mm, and 2.5 < L ≤ 3.0 mm, respectively. The roots of herbaceous plants have the ability to enhance water retention in soil, resist hydraulic erosion of slope soil, and reduce soil shrinkage and swelling. During the initial phase of herbaceous planting, there is an accelerated process of organic carbon mineralization in the soil. The roots of herbaceous plants play a crucial role in soil consolidation and slope protection. They achieve this by dispersing large clastic particles, binding small particles together, altering soil porosity, enhancing soil water retention, and reducing soil water infiltration. It was found that Lolium perenne and Medicago, which have well-developed roots, exhibited superior slope protection effects. These findings contribute to the theoretical understanding for the implementation of green ecological protection technology on soil slopes.

[An examination of the carbon metabolic pathways in Acinetobacter sp. TAC-1 in the context of poly (3-hydroxybutyrate-co-3-hydroxyvalerate) utilization].

The present study aimed to unravel the carbon metabolism pathway of Acinetobacter sp. TAC-1, a heterotrophic nitrification-aerobic denitrification (HN-AD) strain that utilizes poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as a carbon source. Sodium acetate was employed as a control to assess the gene expression of carbon metabolic pathways in the TAC-1 strain. The results of genome sequencing demonstrated that the TAC-1 strain possessed various genes encoding carbon metabolic enzymes, such as gltA, icd, sucAB, acs, and pckA. KEGG pathway database analysis further verified the presence of carbon metabolism pathways, including the glycolytic pathway (EMP), pentose phosphate pathway (PPP), glyoxylate cycle (GAC), and tricarboxylic acid (TCA) cycle in the TAC-1 strain. The differential expression of metabolites derived from distinct carbon sources provided further evidence that the carbon metabolism pathway of TAC-1 utilizing PHBV follows the sequential process of PHBV (via the PPP pathway)→gluconate (via the EMP pathway)→acetyl-CoA (entering the TCA cycle)→CO2+H2O (generating electron donors and releasing energy). This study is expected to furnish a theoretical foundation for the advancement and implementation of novel denitrification processes based on HN-AD and solid carbon sources.

Ni-Catalyzed Hydrosulfonylation of Alkenes with Aromatic Iodides and K2S2O5.

Hydrosulfonylation of alkenes with readily available aromatic iodides via a SO2-insetion strategy is presented. The combination of non-noble Ni catalysis with (iPr)3SiH as the final reductant enables the efficient formation of aryl and heteroaryl sulfinate intermediates, which undergo Michael-type additions to electron-deficient alkenes for initiating the hydrosulfonylation process. Moreover, the superiority of this protocol is demonstrated by broad substrate scope and good functional group compatibility.