Preliminary construction of non-coding RNAs and ceRNA regulatory networks mediated by exosomes in porcine follicular fluid.

BACKGROUND: Follicles are fundamental units of the ovary, regulated intricately during development. Exosomes and ovarian granulosa cells (OGCs) play pivotal roles in follicular development, yet the regulatory mechanisms governing exosomes remain elusive. RESULTS: High-throughput sequencing was employed to evaluate the complete transcript expression profiles of six samples (three porcine ovarian granulosa cells-exosome co-culture samples (GCE) and three porcine ovarian granulosa cells (POGCs) samples). Differential expression analysis revealed 924 lncRNAs, 35 circRNAs, 49 miRNAs, and 9823 mRNAs in the GCE group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated enrichment of differentially expressed transcripts in pathways related to cell proliferation and apoptosis. Furthermore, a ceRNA regulatory network comprising 43 lncRNAs, 6 circRNAs, 11 miRNAs, and 126 mRNAs was constructed based on intergene co-expression correlations. Seven miRNAs associated with cell proliferation and apoptosis regulation were identified within this network, encompassing 92 subnet pairs as candidate genes for further exploration of exosome regulatory mechanisms. Additionally, preliminary verification at the cellular level demonstrated that exosomal miR-200b enhances the viability of POGCs. CONCLUSIONS: Transcriptome analysis unveiled a pivotal candidate ceRNA network potentially implicated in exosome-mediated regulation of granulosa cell proliferation and apoptosis, thereby influencing porcine follicular development. These findings offer insights into the molecular mechanisms of follicular fluid exosome regulation, encompassing both coding and non-coding RNA perspectives.

Chemogenetic activation of astrocytic Gi signaling promotes spinogenesis and motor functional recovery after stroke.

Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke. We found that early activation of astrocytic hM4Di after stroke by CNO modulates astrocyte activity and upregulates synaptogenic molecules including thrombospondin-1 (TSP1) as revealed by bulk RNA-sequencing, but no significant improvement was observed in dendritic spine density and behavioral performance in grid walking test. Interestingly, when the manipulation was initiated at the subacute phase of stroke, the recovery of spine density and motor function could be effectively promoted, accompanied by increased TSP1 expression. Our data highlight the important role of astrocytes in synapse remodeling during the repair phase of stroke and suggest astrocytic Gi signaling activation as a potential strategy for synapse regeneration, circuit rewiring, and functional recovery.

Design, synthesis and biological evaluation of MNK-PROTACs.

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases. In this study, DS33059, a small-molecule compound modified based on the ongoing clinical trials drug ETC-206, was chosen as the target protein ligand. A series of novel MNK-PROTACs were designed, synthesized and evaluated biological activity. Several compounds showed good inhibitory activities against MNK1/2. Besides, compounds exhibited moderate to excellent anti-proliferative activity in A549 and TMD-8 cells in vitro. In particular, compound II-5 significantly inhibited A549 (IC50 = 1.79 µM) and TMD-8 (IC50 = 1.07 µM) cells. The protein degradation assay showed that compound II-5 had good capability to degrade MNK1. The MNK-PROTACs strategy represents a new direction in treating tumors and deserves further exploration.

Technical adequacy of measuring teachers' knowledge of dyslexia.

Given the rapid growth in educational policies targeting educators' knowledge of dyslexia, this study explored the technical adequacy of a common instrument for measuring that knowledge. The responses of 1141 preservice teachers were scored in three ways: polytomously with the original 4-point Likert scale, dichotomously as true-false, and dichotomously as though the options were multiple choice. An exploratory factor analysis suggested at least one-third of the items needed to be removed. Confirmatory factor analyses suggested a one-factor model with polytomous scoring had the best fit to the data, but only six items loaded. All models demonstrated unacceptable internal consistency reliability (<0.70). Because no technically adequate version of the measure was identified, questions remain about basing policy on scores from these instruments. However, the findings indicated ways this type of measure might be improved.

An Environmental Uncertainty Perception Framework for Misinformation Detection and Spread Prediction in the COVID-19 Pandemic: Artificial Intelligence Approach.

BACKGROUND: Amidst the COVID-19 pandemic, misinformation on social media has posed significant threats to public health. Detecting and predicting the spread of misinformation are crucial for mitigating its adverse effects. However, prevailing frameworks for these tasks have predominantly focused on post-level signals of misinformation, neglecting features of the broader information environment where misinformation originates and proliferates. OBJECTIVE: This study aims to create a novel framework that integrates the uncertainty of the information environment into misinformation features, with the goal of enhancing the model's accuracy in tasks such as misinformation detection and predicting the scale of dissemination. The objective is to provide better support for online governance efforts during health crises. METHODS: In this study, we embraced uncertainty features within the information environment and introduced a novel Environmental Uncertainty Perception (EUP) framework for the detection of misinformation and the prediction of its spread on social media. The framework encompasses uncertainty at 4 scales of the information environment: physical environment, macro-media environment, micro-communicative environment, and message framing. We assessed the effectiveness of the EUP using real-world COVID-19 misinformation data sets. RESULTS: The experimental results demonstrated that the EUP alone achieved notably good performance, with detection accuracy at 0.753 and prediction accuracy at 0.71. These results were comparable to state-of-the-art baseline models such as bidirectional long short-term memory (BiLSTM; detection accuracy 0.733 and prediction accuracy 0.707) and bidirectional encoder representations from transformers (BERT; detection accuracy 0.755 and prediction accuracy 0.728). Additionally, when the baseline models collaborated with the EUP, they exhibited improved accuracy by an average of 1.98% for the misinformation detection and 2.4% for spread-prediction tasks. On unbalanced data sets, the EUP yielded relative improvements of 21.5% and 5.7% in macro-F1-score and area under the curve, respectively. CONCLUSIONS: This study makes a significant contribution to the literature by recognizing uncertainty features within information environments as a crucial factor for improving misinformation detection and spread-prediction algorithms during the pandemic. The research elaborates on the complexities of uncertain information environments for misinformation across 4 distinct scales, including the physical environment, macro-media environment, micro-communicative environment, and message framing. The findings underscore the effectiveness of incorporating uncertainty into misinformation detection and spread prediction, providing an interdisciplinary and easily implementable framework for the field.

Extrusion treatment of rice bran insoluble fiber generates specific niches favorable for Bacteroides during in vitro fermentation.

To investigate the morphological changes of insoluble fiber and their effects on microbiota modulation, particularly Bacteroides, rice bran insoluble fibers were extruded at different feed moisture levels (E20, E40, and E60). The physicochemical properties and SEM revealed that E20 exhibited the highest water holding capacity and displayed the most fragmented edges. E40 had the highest swelling holding capacity and displayed the most lamellar gaps. E60 showed minimal change in physicochemical properties but had a rough surface. After 48h fermentation, E40 showed the highest levels of Bacteroides and SCFAs. E20 and E60 resulted in a modest increase in Bacteroides abundance. SEM showed that bacteria were attached to fragmented edges, loosened lamellar gaps, and rough surfaces of the extruded insoluble fibers. The results suggested that Bacteroides gained a competitive advantage within the extrusion treatment created structural changes. Extrusion treatment can be used to generate specific niches favorable for Bacteroides.

Deep removal of trace arsenic from acidic SbCl3 solution by in-situ galvanically coupled Cu2Sb/Cu particles.

Arsenic is a harmful associated element in antimony ore, which might bring out the risk of leakage during complex industrial production of high-purity antimony. Herein, we reported a novel and efficient way to remove the trace arsenic impurity from acidic SbCl3 solution by utilizing copper-system bimetallic particles. Specifically, galvanically coupled Cu2Sb/Cu was in-situ synthesized by introducing precursor copper powder to the specific SbCl3 solution. DFT studies revealed that Sb(III) was easily reduced by Cu to form Cu2Sb due to the strong adsorption of Sb(III) on Cu (111) crystal plane. The Cu2Sb/Cu coupling exhibited excellent activity for As(III) reduction, over 99.4% arsenic were removed under optimal conditions and residual arsenic concentration dropped to only 2.7 mg L-1. Crucially, Sb(III) concentration changes could be neglected. Besides, the dearsenization residues were extensively characterized to analyze the evolvement and cause in the reaction process. The results confirmed that the arsenic removal mechanisms by Cu2Sb/Cu particles were multi-affected, including adsorption, displacement, and precipitation. And the strong electrostatic attraction of AsO+ under high HCl conditions was identified as a key step to achieving dearsenization. This research will provide a theoretical guidance for the green synthesis of high-purity antimony and related products.

Germination-Induced Enhancement of Brown Rice Noodle Nutritional Profile and Gut Microbiota Modulation.

This study explored how germination influences the starch digestion and intestinal fermentation characteristics of brown rice noodle. The study began with in vitro starch digestion tests to assess how germination affects starch digestibility in brown rice noodles, revealing an increase in rapidly digestible starch content and a decrease in resistant starch content. Subsequently, an in vitro human fecal fermentation model was used to simulate the human intestinal environment, showing that germination altered pH levels and the production of short-chain fatty acids, particularly by increasing propionate while decreasing acetate and butyrate. Additionally, the study noted a decrease in gut microbiota diversity following fermentation, accompanied by an increase in Megamonas growth and a decrease in Bacteroides and Bifidobacterium. In conclusion, these findings suggest that germination could enhance the nutritional value and intestinal probiotic properties of brown rice noodles. This research contributes valuable insights into the role of germination in improving the nutritional properties of rice-based products and provides a foundation for further exploration into the development of health-promoting rice noodles.

Mechanism of Apoptosis in Porcine Ovarian Granulosa Cells Triggered by T-2 Toxin.

T-2 toxin (T-2), an A-type mono mycotoxin produced by various Fusarium species, disrupts DNA/RNA and protein synthesis upon entering the body, resulting in pathological conditions in various tissues/organs and posing a significant threat to human and animal health. However, the mechanisms underlying its toxicity remain unclear. With the goal of learning how T-2 affects reproduction in animals, we utilized primary porcine ovarian granulosa cells (pGCs) as a carrier in vitro and constructed concentration models for analyzing cell morphology and RNA-sequencing (RNA-seq). Our findings showed that T-2 could influence pGCs morphology, induce cell cycle arrest, and promote apoptosis in a dose-dependent manner. The results of RNA-seq analyses indicated that a total of 8216 genes exhibited significant differential expression (DEG) following T-2 treatment, of which 4812 were observed to be down-regulated and 3404 were up-regulated. The DEGs following T-2 toxin treatment of pGCs had a notable impact on many metabolic pathways such as PI3K-Akt, Ras, MAPK, and apoptosis, which in turn altered important physiological processes. Gene set enrichment analysis (GSEA) indicated that the differences in the harmful effects of T-2 might be caused by the varying control of cellular processes and the pathway responsible for steroid metabolism. These results present further insights regarding the mechanism of T-2 action on sow reproductive toxicity, enhance our understanding of T-2 reproductive toxicological effects, and lay a theoretical foundation for the judicious prevention of T-2-induced reproductive toxicity.

Comparative Analysis of the Ovary Transcriptome among Wanyue Black and Yorkshire Gilts Using RNA-Seq.

Pubertal genetic variations between the indigenous Chinese Wanyue Black pig breed and the imported Yorkshire breed significantly impact their reproductive capacity. In order to identify the differentially expressed genes, gene networks, and metabolic pathways in ovary transcriptome of gilts, the serum hormone levels were analyzed by ELISA, and RNA-seq was performed to analyze ovarian genes. Our results reveal higher estradiol (E2) levels in Wanyue black gilts compared to Yorkshire gilts, while Yorkshire gilts exhibit elevated progesterone (P4) and GnRH levels. We identified a total of 154 differentially expressed genes (DEGs), with 87 up-regulated and 67 down-regulated genes in the Wanyue black gilts ovaries compared to the Yorkshire gilts. GO enrichment analysis unveiled the participation of DEGs in processes such as "Reproduction", "Reproductive system development", and "Ovarian follicle development". Moreover, KEGG enrichment analysis revealed the involvement of DEGs in multiple signaling pathways associated with hormone biosynthesis and puberty, encompassing "Steroid hormone biosynthesis", "Estrogen signaling pathway", and "Prolactin signaling pathway". The subsequent bioinformatics analysis identified nine functional genes that potentially contribute to the disparity in ovaries between Wanyue black gilts and Yorkshire gilts. This study offers significant insights into the endocrine and genetic aspects of pubertal development in gilts.

Development of an Imidazopyridazine-Based MNK1/2 Inhibitor for the Treatment of Lymphoma.

The mitogen-activated protein kinase-interacting protein kinases (MNKs) are the only kinases known to phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at Ser209, which plays a significant role in cap-dependent translation. Dysregulation of the MNK/eIF4E axis has been found in various solid tumors and hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). Herein, structure-activity relationship studies and docking models determined that 20j exhibits excellent MNK1/2 inhibitory activity, stability, and hERG safety. 20j exhibits strong and broad antiproliferative activity against different cancer cell lines, especially GCB-DLBCL DOHH2. 20j suppresses the phosphorylation of eIF4E in Hela cells (IC50 = 90.5 nM) and downregulates the phosphorylation of eIF4E and 4E-BP1 in A549 cells. In vivo studies first revealed that ibrutinib enhances the antitumor effect of 20j without side effects in a DOHH2 xenograft model. This study provided a solid foundation for the future development of a MNK inhibitor for GCB-DLBCL treatment.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects.

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.

MOFs-Derived Strategy and Ternary Alloys Regulation in Flower-Like Magnetic-Carbon Microspheres with Broadband Electromagnetic Wave Absorption.

Broadband electromagnetic (EM) wave absorption materials play an important role in military stealth and health protection. Herein, metal-organic frameworks (MOFs)-derived magnetic-carbon CoNiM@C (M = Cu, Zn, Fe, Mn) microspheres are fabricated, which exhibit flower-like nano-microstructure with tunable EM response capacity. Based on the MOFs-derived CoNi@C microsphere, the adjacent third element is introduced into magnetic CoNi alloy to enhance EM wave absorption performance. In term of broadband absorption, the order of efficient absorption bandwidth (EAB) value is Mn > Fe = Zn > Cu in the CoNiM@C microspheres. Therefore, MOFs-derived flower-like CoNiMn@C microspheres hold outstanding broadband absorption and the EAB can reach up to 5.8 GHz (covering 12.2-18 GHz at 2.0 mm thickness). Besides, off-axis electron holography and computational simulations are applied to elucidate the inherent dielectric dissipation and magnetic loss. Rich heterointerfaces in CoNiMn@C promote the aggregation of the negative/positive charges at the contacting region, forming interfacial polarization. The graphitized carbon layer catalyzed by the magnetic CoNiMn core offered the electron mobility path, boosting the conductive loss. Equally importantly, magnetic coupling is observed in the CoNiMn@C to strengthen the magnetic responding behaviors. This study provides a new guide to build broadband EM absorption by regulating the ternary magnetic alloy.

Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.

The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.