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Abstract The complex anatomy and biology of craniofacial bones pose difficulties in their effective and precise reconstruction. Injectable hydrogels (IHs) with water-swollen networks are emerging as a shape-adaptive alternative for noninvasively rebuilding craniofacial bones. The advent of versatile nanomaterials (NMs) customizes IHs with strengthened mechanical properties and therapeutically favorable performance, presenting excellent contenders over traditional substitutes. Structurally, NM-reinforced IHs are energy dissipative and covalently crosslinked, providing the mechanics necessary to support craniofacial structures and physiological functions. Biofunctionally, incorporating unique NMs into IH expands a plethora of biological activities, including immunomodulatory, osteogenic, angiogenic, and antibacterial effects, further favoring controllable dynamic tissue regeneration. Mechanistically, NM-engineered IHs optimize the physical traits to direct cell responses, regulate intracellular signaling pathways, and control the release of biomolecules, collectively bestowing structure-induced features and multifunctionality. By encompassing state-of-the-art advances in NM-integrated IHs, this review offers a foundation for future clinical translation of craniofacial bone reconstruction.

The search for new green and efficient stabilizers is of great importance for the stabilization of nitrocellulose (NC). This is due to the shortcomings of traditional stabilizers, such as high toxicity. In this study, reduced polyaniline (r-PANI), which has a similar functional structure to diphenylamine (DPA) but is non-toxic, was prepared from PANI based on the action with N2H4 and NH3–H2O, and used for the first time as a potential stabilizer for NC. XPS, FTIR, Raman, and SEM were used to characterize the reduced chemical structure and surface morphology of r-PANI. In addition, the effect of r-PANI on the stabilization of NC was characterized using DSC, VST, isothermal TG, and MMC. Thermal weight loss was reduced by 83% and 68% and gas pressure release by 75% and 49% compared to pure NC and NC&3%DPA, respectively. FTIR and XPS were used to characterize the structural changes of r-PANI before and after reaction with NO2. The 1535 cm−1 and 1341 cm−1 of the FTIR and the 404.98 eV and 406.05 eV of the XPS showed that the –NO2 was generated by the absorption of NO2. Furthermore, the quantum chemical calculation showed that NO2 was directly immobilized on r-PANI by forming –NO2 in the neighboring position of the benzene ring.

Abstract This study conducted a comparison of the nutritional content and lipid composition of five different varieties of quinoa (QL-1, SJ-1, SJ-2, KL-1, and KL-2) from Qinghai Province, China. Each of the five varieties exhibited varying levels of essential nutrients, including crude protein, dietary fiber, and crude fat. The QL-1 variety has the highest concentration of phytic acid, measuring 1.66 g/100 g. A non-targeted lipomics analysis discovered a total of 16 lipid categories and 383 individual lipids in quinoa. Out of the several substances, glyceride had the highest concentration, exceeding 70%, with phospholipids coming next. The percentage of fatty acids and fatty acid esters was between 5 and 11%. The glycerides in all five kinds exhibited a similar composition, with unsaturated glycerides constituting over 99% of the total glycerides. Phospholipids constituted over 11% of the overall lipid content, with lecithin comprising more than 80% and cephalin ranging from 16.70 to 18.61%. The results establish a solid basis for the utilization of quinoa in processing, particularly in lipid processing. Graphical Abstract

ABSTRACT: Objectives: Herein, we detected one multidrug-resistant Aeromonas hydrophila strain K522 co-carrying two blaKPC-2 genes together with a novel chromosomal integrative and mobilizable element (IME) Tn7548 from China. To reveal the genetic characteristics of the novel reservoir of blaKPC-2 and IME in Aeromonas, a detailed genomic characterization of K522 was performed, and a phylogenetic analysis of Tn7412-related IMEs was carried out. Methods: Carbapenemases were detected by using the immunocolloidal gold technique and antimicrobial susceptibility was tested by using VITEK 2. The whole-genome sequences of K522 were analysed using phylogenetics, detailed dissection, and comparison. Results: Strain K522 carried a Tn7412-related chromosomal IME Tn7548 and three resistance plasmids pK522-A-KPC, pK522-B-KPC, and pK522-MOX. A phylogenetic tree of 82 Tn7412-related IMEs was constructed, and five families of IMEs were divided. These IMEs shared four key backbone genes: int, repC, and hipAB, and carried various profiles of antimicrobial resistance genes (ARGs). pK522-A-KPC and pK522-B-KPC carried blaKPC-2 and belonged to IncG and unclassified type plasmid, respectively. The blaKPC-2 regions of these two plasmids were the truncated version derived from Tn6296, resulting in the carbapenem resistance of K522. Conclusion: We first reported A. hydrophila harbouring a novel Tn7412-related IME Tn7548 together with two blaKPC-2 carrying plasmids and a MDR plasmid. Three of these four mobile genetic elements (MGEs) discovered in A. hydrophila K522 were novel. The emergence of novel MGEs carrying ARGs indicated the rapid evolution of the resistance gene vectors in A. hydrophila under selection pressure and would contribute to the further dissemination of various ARGs in Aeromonas.

ABSTRACT: The differences in lipids in duck eggs between the 2 rearing systems during storage have not been fully studied. Herein, we propose untargeted lipidomics combined with a random forest (RF) algorithm to identify potential marker lipids based on ultra-performance liquid chromatography‒mass spectrometry (UPLPC-MS/MS). A total of 106 and 16 differential lipids (DL) were screened in egg yolk and white, respectively. In yolk, metabolic pathway analysis of DLs revealed that glycerophospholipid metabolism and sphingolipid metabolism were the key metabolic pathways in the traditional free-range system (TFS) during storage, glycosylphosphatidylinositol-anchored biosynthesis and glyceride metabolism were the key pathways in the floor-rearing system (FRS). In egg white, the key pathway in both systems is the biosynthesis of unsaturated fatty acids. Combined with RF algorithm, 12 marker lipids were screened during storage. Therefore, this study elucidates the changes in lipids in duck eggs during storage in 2 rearing systems and provides new ideas for screening marker lipids during storage. This approach is highly important for evaluating the quality of egg and egg products and provides guidance for duck egg production.

Abstract Objective Autophagy‐related 5 (ATG5) facilitates the pathologic process of acute ischemic stroke (AIS) via multiple ways. This study aimed to identify the association of serum ATG5 with clinical outcomes in AIS patients. Methods Serum ATG5 from 280 AIS patients were detected at admission, Day (D)1, D3, D7, D30, and D90 after admission by enzyme‐linked immunosorbent assay. The median (interquartile range) follow‐up was 21.1 (5.9–43.9) months. Another 50 healthy controls (HCs) were also enrolled for serum ATG5 determination. Results ATG5 was elevated (p 2 and mRS ≤2 at D90, respectively. ATG5 at admission, D1, D3, D30, and D90 was elevated in AIS patients with mRS >2 versus those with mRS ≤2 (all p

Small molecule drugs play a pivotal role in the arsenal of anticancer pharmacological agents. Nonetheless, their small size poses a challenge when directly visualizing their localization, distribution, mechanism of action (MOA), and target engagement at the subcellular level in real time. We propose a strategy for developing triple-functioning drug beacons that seamlessly integrate therapeutically relevant bioactivity, precise subcellular localization, and direct visualization capabilities within a single molecular entity. As a proof of concept, we have meticulously designed and constructed a boronic acid fluorescence drug beacon using coumarin–hemicyanine (CHB). Our CHB design includes three pivotal features: a boronic acid moiety that binds both adenosine triphosphate (ATP) and adenosine diphosphate (ADP), thus depleting their levels and disrupting the energy supply within mitochondria; a positively charged component that targets the drug beacon to mitochondria; and a sizeable conjugated luminophore that emits fluorescence, facilitating the application of structured illumination microscopy (SIM). Our study indicates the exceptional responsiveness of our proof-of-concept drug beacon to ADP and ATP, its efficacy in inhibiting tumor growth, and its ability to facilitate the tracking of ADP and ATP distribution around the mitochondrial cristae. Furthermore, our investigation reveals that the micro-dynamics of CHB induce mitochondrial dysfunction by causing damage to the mitochondrial cristae and mitochondrial DNA. Altogether, our findings highlight the potential of SIM in conjunction with visual drug design as a potent tool for monitoring the in situ MOA of small molecule anticancer compounds. This approach represents a crucial advancement in addressing a current challenge within the field of small molecule drug discovery and validation.

ABSTRACTBackground: Peripheral T-cell lymphomas (PTCL) are an aggressive group of mature T-cell neoplasms, often associated with poor outcomes, in part, due to frequent relapsed/refractory disease. The objective of this study was to assess the prognostic impact of disease progression within 24 months (POD24) on overall survival (OS) for patients diagnosed with PTCL.Methods: A retrospective analysis was conducted on a cohort of patients with newly diagnosed PTCL who underwent chemotherapy at the Affiliated Hospital of Xuzhou Medical University between January 2010 and September 2021. Prognostic assessment was limited to patients who were evaluable for POD24.Results: Records were reviewed for 106 patients with PTCL, of whom 66 patients experienced POD24 (referred to as the POD24 group) and 40 patients did not experience POD24 (referred to as the no POD24 group). Significant differences were observed between the POD24 group and the no POD24 group in regard to clinical stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) levels, β2-microglobulin (β2-MG) levels, prealbumin and albumin levels. Patients in the POD24 group had a significant shorter median OS compared to the no POD24 group (11.9 months vs not reached, respectively; P

Background and Objectives: Diabetic cardiomyopathy (DCM) is a cardiac condition resulting from myocardial damage caused by diabetes mellitus (DM), currently lacking specific therapeutic interventions. Fuzhengkangfu decoction (FZK) plays an important role in the prevention and treatment of various cardiovascular diseases. However, the efficacy and potential mechanisms of FZK are not fully understood. This study aims to investigate the protective effect and mechanisms of FZK against DCM. Methodologies: Rats were given a high-calorie diet along with a low dosage of streptozotocin (STZ) to establish a rat model of DCM. The diabetic rats received FZK or normal saline subcutaneously for 12 weeks. Echocardiography was conducted to evaluate their heart function characteristics. Rat heart morphologies were assessed using Sirius Red staining and H&E staining. Transcriptome sequencing analysis and network pharmacology were used to reveal possible targets and mechanisms. Molecular docking was conducted to validate the association between the primary components of FZK and the essential target molecules. Finally, both in vitro and in vivo studies were conducted on the cardioprotective properties and mechanism of FZK. Results: According to the results of network pharmacology, FZK may prevent DCM by reducing oxidative stress and preventing apoptosis. Transcriptomics confirmed that FZK protected against DCM-induced myocardial fibrosis and remodelling, as predicted by network pharmacology, and suggested that FZK regulated the expression of oxidative stress and apoptosis-related proteins. Integrating network pharmacology and transcriptome analysis results revealed that the AGE-RAGE signalling pathway-associated MMP2, SLC2A1, NOX4, CCND1, and CYP1A1 might be key targets. Molecular docking showed that Poricoic acid A and 5-O-Methylvisammioside had the highest docking activities with these targets. We further conducted in vivo experiments, and the results showed that FZK significantly attenuated left ventricular remodelling, reduced myocardial fibrosis, and improved cardiac contractile function. And, our study demonstrated that FZK effectively reduced oxidative stress and apoptosis of cardiomyocytes. The data showed that Erk, NF-κB, and Caspase 3 phosphorylation was significantly inhibited, and Bcl-2/Bax was significantly increased after FZK treatment. In vitro, FZK significantly reduced AGEs-induced ROS increase and apoptosis in cardiomyocytes. Furthermore, FZK significantly inhibited the phosphorylation of Erk and NF-κB proteins and decreased the expression of MMP2. All the results confirmed that FZK inhibited the activation of the Erk/NF-κB pathway in AGE-RAGE signalling and alleviated oxidative stress and apoptosis of cardiomyocytes. In summary, we verified that FZK protects against DCM by inhibiting myocardial apoptotic remodelling through the suppression of the AGE-RAGE signalling pathway. Conclusion: In conclusion, our research indicates that FZK demonstrates anti-cardiac dysfunction properties by reducing oxidative stress and cardiomyocyte apoptosis through the AGE-RAGE pathway in DCM, showing potential for therapeutic use.

Abstract Despite recent advances in extrusion bioprinting of cell‐laden hydrogels, using naturally derived bioinks to biofabricate complex elastic tissues with both satisfying biological functionalities and superior mechanical properties is hitherto an unmet challenge. Here, we address this challenge with precisely designed biological tough hydrogel bioinks featuring a double‐network structure. The tough hydrogels consisted of energy‐dissipative dynamically crosslinked glycosaminoglycan hyaluronic acid (o‐nitrobenzyl‐grafted hyaluronic acid) and elastin through Schiff's base reaction, and free‐radically polymerized gelatin methacryloyl. The incorporation of elastin further improved the elasticity, stretchability (∼170% strain), and toughness (∼45 kJ m−3) of the hydrogels due to the random coiling structure. We used this novel class of hydrogel bioinks to bioprint several complex elastic tissues with good shape retention. Furthermore, in vitro and in vivo experiments also demonstrated that the existence of elastin in the biocompatible bioinks facilitated improved cell behaviors and biological functions of bioprinted tissues, such as cell spreading and phenotype maintenance as well as tissue regeneration. The results confirmed the potential of the elastin‐containing tough hydrogel bioinks for bioprinting of 3D complex elastic tissues with biological functionalities, which may find widespread applications in elastic tissue regeneration.

Separating fabrics stack using mechanical devices is considered a major obstacle to automation in garment processing due to their low density, low bending stiffness, and air permeability. To address this challenge, this paper discusses the feasibility of using a non-contact Bernoulli suction cup for automated separation and transfer of fabrics stack. First, a theoretical analysis of the non-contact separation mechanism was carried out and a calculation model for the separation process parameters was proposed. Subsequently, based on the calculation model, to improve the success rate of separation, a novel gradual descent separation method was proposed by analyzing the variations of suction force of Bernoulli suction cup with process parameters. To address the problem of fabric instability and falling during non-contact transfer, a visual control method that uses machine vision technology to regulate the suction force was also introduced. Finally, the above methods were integrated to create a non-contact automatic fabrics stack separation and transfer system. The results show the following: (1) The deviation between the results of the calculation model and the measured results is 6.9%; (2) The success rate of stack separation using the gradual descent method is 96%; (3) The improved visual detector achieved a recognition accuracy of 0.982 for the sagging deformation of the fabric piece. The visual control suction method can stabilize the fabric within 300 ms at a transfer speed of 800–1000 mm/s. The method for non-contact automatic separation and transfer of fabrics stack proposed in this paper provides new ideas for related research and industrial applications.

Abstract Background and aims Severe acute pancreatitis (SAP) is potentially lethal. Considering the role of inflammation in the progression of acute pancreatitis (AP), this study aims to develop a model based on inflammatory indexes for identifying the presence of SAP. Methods Overall, 253 patients with AP who were consecutively admitted between July 2018 and November 2020 were screened, of whom 60 had SAP. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), systemic inflammation response index (SIRI), platelet-to-albumin ratio (PAR), C-reactive protein-to-albumin ratio (CAR), C-reactive protein-to-lymphocyte ratio (CLR), and triglyceride glucose (TyG) index were calculated. Multivariate logistic regression analyses were performed to identify independent risk factors of SAP. Then, inflammation-based models were established. Receiver operating characteristics (ROC) curve analyses were performed. Area under ROC curve (AUROC) was calculated. Results Diabetes mellitus, fatty liver, high white blood cell count (WBC), C-reactive protein (CRP), red blood cell distribution width (RDW), procalcitonin (PCT), SII, NLR, NPR, CAR, CLR, and TyG index, and a low LMR were significantly associated with SAP. Considering the collinearity among these variables, 10 multivariate logistic regression analyses were separately performed. Finally, four independent inflammation-based models were established. Of them, the best one, which was calculated as follows: 1.204*fatty liver (yes = 1; no = 0) + 0.419*PCT + 0.005*CLR - 2.629, had an AUROC of 0.795 with a specificity of 73.4% and a sensitivity of 71.7%. Conclusion The inflammation-based model consisting of fatty liver, PCT, and CLR has a good diagnostic performance for SAP.

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of malignant liver tumor with poor prognosis. In this study, we investigated the expression of transforming growth factor beta regulator 4 (TBRG4) in HCC and its effects on the proliferation, invasion, and metastasis of HCC cells, and analyzed the possible molecular mechanisms. Method Downloading the expression and clinical information of HCC samples in the TCGA database, analyzing the expression differences of TBRG4 by bioinformatics methods, analyzing the clinical relevance and prognostic significance. Performing GO, KEGG and GSEA enrichment analysis on the TBRG4-related gene set in patient HCC tissues. Applying cell counting, scratch test and Transwell experiment to study the biological function of TBRG4 in HCC. Mitochondrial membrane potential, apoptosis and ROS levels were evaluated to assess cell iron death. Western blot, RT-PCR, laser confocal microscopy and co-immunoprecipitation were used to detect and analyze the downstream signaling pathways and interacting molecules of TBRG4. Results Bioinformatics analysis revealed that TBRG4 was abnormally highly expressed in HCC tumor tissues and was associated with poor prognosis and metastasis in HCC patients. GO and KEGG functional enrichment analysis showed that TBRG4 was related to oxidative stress and NADH dehydrogenase (ubiquinone) activity. GSEA enrichment analysis showed that TBRG4 was associated with Beta catenin independent wnt signaling and B cell receptor. Functional experiments confirmed that knocking down TBRG4 could inhibit the proliferation, migration, and invasion of HCC cells. Mechanistically, TBRG4 inhibited the function of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. In addition, interference with TBRG4 expression could reduce the mitochondrial membrane potential and accumulate ROS in HCC cells, leading to increased ferroptosis. Co-IP analysis showed that TBRG4 specifically bound to Beclin1. Conclusion TBRG4 is highly expressed in HCC tumor tissues and is associated with poor prognosis. It may regulate the proliferation, invasion, and metastasis of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. TBRG4 may interact with Beclin1 to regulate the ferroptosis of HCC cells.

In present study, cassava starch (CS) and konjac gum (KGM) were used as the raw materials, and critical melting combined with freeze-thawing (CMFT) was employed as the main treatment for the preparation of CS/KGM composites. The study aimed to investigate the effects of CMFT on the physicochemical and structural properties of CS/KGM composites. The results demonstrated that CMFT effectively facilitated the release of soluble starches, which significantly increased the interaction sites with KGM. The prepared composite had a significantly increased thermal stability (significantly decreased water solubility and swelling power), in which the onset melting temperature of the CS/KGM composite after CMFT was increased significantly from 64.13 ℃ (native) to 69.73 ℃ (0.7% KGM, P

The change in laser output power caused by the temperature change of the pulse laser fuze drive circuit directly affects the detection distance and accuracy. In order to achieve accurate distance determination of the pulse laser fuze, it is necessary to study the influence of temperature changes on the output characteristics of the pulse laser fuze drive circuit. In this paper, we study the changes in peak power caused by changes in component parameters such as resistors, capacitors, and laser diodes in the pulse laser drive circuit, which is caused by typical temperature gradients in the transient state. Based on Simulink software, a simulation model of pulsed laser drive circuit is built, and based on the theory of RLC loop equation and laser rate equation, the temperature-dependent gain coefficients are introduced to obtain the laser output characteristics corresponding to typical temperature. As a main result, we found that the laser output power decreases by about 10% during the temperature change from -50°C to 50°C. A hardware test platform is built to verify that the error is no more than 1%. The above study provides a reliable method for the design of the temperature model of the pulsed laser fuze drive circuit.

Abstract Type I interferon (IFN-I) plays crucial roles in the regulation of inflammation and it is associated with various inflammatory diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and periodontitis, impacting people's health and quality of life. It is well-established that IFN-Is affect immune responses and inflammatory factors by regulating some signaling. However, currently, there is no comprehensive overview of the crucial regulatory role of IFN-I in distinctive pathways as well as associated inflammatory diseases. This review aims to provide a narrative of the involvement of IFN-I in different signaling pathways, mainly mediating the related key factors with specific targets in the pathways and signaling cascades to influence the progression of inflammatory diseases. As such, we suggested that IFN-Is induce inflammatory regulation through the stimulation of certain factors in signaling pathways, which displays possible efficient treatment methods and provides a reference for the precise control of inflammatory diseases.

Tin-based Babbitt alloys are a widely used bearing bushing material which have good comprehensive properties. However, problems such as high-temperature softening and insufficient bearing capacity occur during their use, so the optimization of tin-based Babbitt alloys has become a research hotspot. In this paper, ZChSnSb11-6 alloy was mainly prepared by the gravity casting method, and different amounts of Zn were added to the alloy (the mass fraction values were 0 wt.%, 0.05 wt.%, 0.1 wt.%, 0.15 wt.%, and 0.2 wt.%, respectively). Through the hardness test, the tensile test, the friction and wear test, and the microstructure observation of the prepared alloy, the influence of Zn on the organization and properties of the ZChSnSb11-6 alloy was analyzed. The results show that the size of the SnSb hard phase changed with the increasing content of Zn. The size of the hard phase of the SnSb tended to increase first and then decrease, and the number of phase particles increased first and then decreased, resulting in changes in performance. Through comparison, it was learned that the addition of Zn can effectively improve the hardness, tensile strength, yield strength, and wear resistance of the alloy, but the elongation rate was reduced. When the Zn content was 0.1 wt.%, the hardness value of the alloy reached the maximum value, 25.82 HB, which increased by 7.3% when compared with the sample without Zn. The hardness of the Zn, 0.15 wt.%, is close to that of the Zn, 0.1 wt.%. Compared to the sample without Zn, the tensile strength and elongation of the alloy were maximized at a Zn content of 0.15 wt.%. Compared to the sample without the Zn, the tensile strength was increased by 21.29%, and the elongation rate was increased by 46%. An analysis showed that the alloy has good comprehensive mechanical properties when the Zn content is 0.15 wt.%.

The Siberian Scoter (Melanitta stejnegeri) is a medium sea duck distinct from M. deglandi due to the absence of hybridization and differences in morphological characteristics. However, knowledge of its phylogenetic relationships within Anseriformes is limited due to a lack of molecular data. In this study, the complete mitogenome of M. stejnegeri was firstly sequenced, then annotated and used to reconstruct the phylogenetic relationships of 76 Anseriformes species. The complete mitogenome of M. stejnegeri is 16,631 bp and encodes 37 typical genes: 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and 1 non-coding control region. Its mitogenome organization is similar to that of other Anseriformes species. The phylogenetic relationships within the genus Melanitta are initially clarified, with M. americana at the base. M. stejnegeri and M. deglandi are sister groups, clustering with M. fusca and M. perspicillata in order. Phylogenetic analysis suggests that Mareca falcata and M. strepera are sister groups, differing from previous studies. Results firstly indicate that Clangula hyemalis and Somateria mollissima are sister groups, suggesting a potentially skewed phylogenetic relationship may have been overlooked in earlier analyses relying solely on mitochondrial genomes. Our results provide new mitogenome data to support further phylogenetic and taxonomic studies of Anseriformes.

Nattokinase (NK) and red yeast rice (RYR) are both indicated for their potential in cardiovascular disease prevention and management, but their combined effects especially in coronary artery disease (CAD) are scarcely examined. This 90-day randomized, double-blind trial aims to investigate the effect of NK and RYR supplementations on cardiometabolic parameters in patients with stable CAD. 178 CAD patients were randomized to four groups: NK + RYR, NK, RYR, and placebo. No adverse effects due to the interventions were reported. In comparisons across groups, NK + RYR showed the maximum effect in reducing triglyceride (−0.39 mmol), total cholesterol (−0.66 mmol/L), diastolic blood pressure (−7.39 mmHg), and increase in high-density lipoprotein cholesterol (0.195 mmol/L) than other groups (all p for multiple groups comparison

Urinary tract infections (UTIs) represent a significant challenge in clinical practice, with recurrent forms (rUTIs) posing a continual threat to patient health. Escherichia coli (E. coli) is the primary culprit in a vast majority of UTIs, both community-acquired and hospital-acquired, underscoring its clinical importance. Among different mediators of pathogenesis, toxin-antitoxin (TA) systems are emerging as the most prominent. The type II TA system, prevalent in prokaryotes, emerges as a critical player in stress response, biofilm formation, and cell dormancy. ccdAB, the first identified type II TA module, is renowned for maintaining plasmid stability. This paper aims to unravel the physiological role of the ccdAB in rUTIs caused by E. coli, delving into bacterial characteristics crucial for understanding and managing this disease. We investigated UPEC-induced rUTIs, examining changes in type II TA distribution and number, phylogenetic distribution, and Multi-Locus Sequence Typing (MLST) using polymerase chain reaction (PCR). Furthermore, our findings revealed that the induction of ccdB expression in E. coli BL21 (DE3) inhibited bacterial growth, observed that the expression of both ccdAB and ccdB in E. coli BL21 (DE3) led to an increase in biofilm formation, and confirmed that ccdAB plays a role in the development of persistent bacteria in urinary tract infections. Our findings could pave the way for novel therapeutic approaches targeting these systems, potentially reducing the prevalence of rUTIs. Through this investigation, we hope to contribute significantly to the global effort to combat the persistent challenge of rUTIs.

IntroductionPrevious research has linked vaginal bacteria to polycystic ovary syndrome (PCOS) and obesity in women, yet the specific disparities in vaginal microbiota between these conditions remain unclear.MethodsIn this study, we aimed to elucidate the contribution of dysregulated vaginal microbiota to PCOS and obesity by analyzing the vaginal microbiota in reproductive-aged women with and without PCOS, as well as obese and non-obese women, using shotgun sequencing.ResultsSwab specimens were collected from four groups of subjects: PCOS and obese, PCOS and non-obese, non-PCOS and obese, and non-PCOS and non-obese. A total of 333 bacteria and 24 viruses/phages were identified to the species level. Clustering analysis revealed that non-PCOS and non-obese individuals exhibit a similar “healthy” vaginal microbiome, while both obesity and PCOS were associated with microbial dysbiosis. Significant differences in abundance were observed for 26 bacterial species and 6 phages/viruses between groups. Notably, pathobionts such as Streptococcus pyogenes, Leptospira santarosai, Citrobacter amalonaticus, Listeria ivanovii, and Clostridium perfringens were significantly less abundant or absent in the non-PCOS and non-obese group. Furthermore, the abundance of Lactobacillus, Pseudomonas bacteria, and their corresponding phages exhibited positive correlations. Lactobacillus bacteria, lactobacillus phage, and pseudomonas phage/virus were identified as indicators of a healthy vaginal microbiome. Importantly, the differentially enriched bacteria in the PCOS and obesity groups were distinct.DiscussionThis study confirms that PCOS and obesity are associated with differing enrichment of bacteria and viruses/phages, with both conditions linked to microbial dysbiosis. Moreover, our findings suggest that vaginal phage diversity is associated with a healthy vaginal microbiota, while dysbiosis is associated with a decrease in phages alongside increased bacterial diversity.

Abstract Autophagy-related gene (ATG) 5 regulates blood lipids, chronic inflammation, CD4+ T-cell differentiation, and neuronal death and is involved in post-stroke cognitive impairment. This study aimed to explore the correlation of serum ATG5 with CD4+ T cells and cognition impairment in stroke patients. Peripheral blood was collected from 180 stroke patients for serum ATG5 and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cell detection via enzyme-linked immunosorbent assays and flow cytometry. The Mini-Mental State Examination (MMSE) scale was completed at enrollment, year (Y)1, Y2, and Y3 in stroke patients. Serum ATG5 was also measured in 50 healthy controls (HCs). Serum ATG5 was elevated in stroke patients compared to HCs (P0.050). Serum ATG5 (P=0.037), Th1 cells (P=0.022), Th17 cells (P=0.002), and Th17/Treg ratio (P=0.018) were elevated in stroke patients with MMSE score-identified cognition impairment vs those without cognition impairment, whereas Th2 cells, Th1/Th2 ratio, and Treg cells were not different between them (all P>0.050). Importantly, serum ATG5 was negatively linked with MMSE score at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), and Y3 (P=0.001); moreover, it was positively related to 2-year (P=0.024) and 3-year (P=0.012) MMSE score decline in stroke patients. Serum ATG5 was positively correlated with Th2 and Th17 cells and estimated cognitive function decline in stroke patients.

Abstract Recent findings have shown that fatty acid metabolism is profoundly involved in ferroptosis. However, the role of cholesterol in this process remains incompletely understood. In this work, we show that modulating cholesterol levels changes vulnerability of cells to ferroptosis. Cholesterol alters metabolic flux of the mevalonate pathway by promoting Squalene Epoxidase (SQLE) degradation, a rate limiting step in cholesterol biosynthesis, thereby increasing both CoQ10 and squalene levels. Importantly, whereas inactivation of Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), the branch point of cholesterol biosynthesis pathway, exhibits minimal effect on ferroptosis, simultaneous inhibition of both CoQ10 and squalene biosynthesis completely abrogates the effect of cholesterol. Mouse models of ischemia-reperfusion and doxorubicin induced hepatoxicity confirm the protective role of cholesterol in ferroptosis. Our study elucidates a potential role of ferroptosis in diseases related to dysregulation of cholesterol metabolism and suggests a possible therapeutic target that involves ferroptotic cell death.

Abstract. Background:. Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC). Methods:. We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays. Results:. The abundance of fecal Veillonella parvula (V. parvula) decreased significantly after BBR administration (P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect. Conclusion:. BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula, thereby blocking the development of colorectal tumors. Trial Registraion:. ClinicalTrials.gov, No. NCT02226185.

Abstract Objective The purpose of this study is to re-sensitive bacteria to carbapenemases and reduce the transmission of the bla KPC−2 gene by curing the bla KPC−2-harboring plasmid of carbapenem-resistant using the CRISPR-Cas9 system. Methods The single guide RNA (sgRNA) specifically targeted to the bla KPC−2 gene was designed and cloned into plasmid pCas9. The recombinant plasmid pCas9-sgRNA(bla KPC−2) was transformed into Escherichia coli (E.coli) carrying pET24-bla KPC−2. The elimination efficiency in strains was evaluated by polymerase chain reaction (PCR) and quantitative real-time PCR (qPCR). Susceptibility testing was performed by broth microdilution assay and by E-test strips (bioMérieux, France) to detect changes in bacterial drug resistance phenotype after drug resistance plasmid clearance. Results In the present study, we constructed a specific prokaryotic CRISPR-Cas9 system plasmid targeting cleavage of the bla KPC−2 gene. PCR and qPCR results indicated that prokaryotic CRISPR-Cas9 plasmid transforming drug-resistant bacteria can efficiently clear bla KPC−2-harboring plasmids. In addition, the drug susceptibility test results showed that the bacterial resistance to imipenem was significantly reduced and allowed the resistant model bacteria to restore susceptibility to antibiotics after the bla KPC−2-containing drug-resistant plasmid was specifically cleaved by the CRISPR-Cas system. Conclusion In conclusion, our study demonstrated that the one plasmid-mediated CRISPR-Cas9 system can be used as a novel tool to remove resistance plasmids and re-sensitize the recipient bacteria to antibiotics. This strategy provided a great potential to counteract the ever-worsening spread of the bla KPC−2 gene among bacterial pathogens and laid the foundation for subsequent research using the CRISPR-Cas9 system as adjuvant antibiotic therapy.

Abstract Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway.

Sailing speed is a critical factor affecting the ship’s energy consumption and operating costs for a voyage. Inland waterways present a complex navigation environment due to their narrow channels, numerous curved segments, and significant variations in water depth and flow speed. This paper constructs a model of a ship’s energy consumption based on an analysis of ship resistance and the energy transfer relationship of ships. The K-means clustering algorithm is introduced to divide the Yangtze River waterway into multiple segments based on the similarity of navigation environments. Considering the constraints of the ship’s main engine and the desired arrival time, a multi-objective particle swarm optimization (MOPSO) algorithm, improved with cosine decreasing inertial weight and Gaussian random mutation, is employed to optimize segmented navigation speeds to achieve different goals. Finally, four cases are studied with a fully electric ship navigating the reaches of the Yangtze River. The results indicate that the optimized speed can reduce ship energy consumption by up to 6.18% and significantly reduce ship energy consumption and operational costs under different conditions.

Strategies aimed at defining, discovering, and developing alternatives to traditional antibiotics will underlie the development of sustainable agricultural systems. Among such strategies, antimicrobial peptides (AMPs) with broad-spectrum antimicrobial activity and multifaceted mechanisms of action are recognized as ideal alternatives in the post-antibiotic era. In particular, AMPs derived from microbes with active metabolisms that can adapt to a variety of extreme environments have long been sought after. Consequently, this review summarizes information on naturally occurring AMPs, including their biological activity, antimicrobial mechanisms, and the preparation of microbial-derived AMPs; it also outlines their applications and the challenges presented by their use in the agroindustry. By dissecting the research results on microbial-derived AMPs of previous generations, this study contributes valuable knowledge on the exploration and realization of the applications of AMPs in sustainable agriculture.

Abstract Background Weight management has been an important component of the service in obstetric care offered to pregnant women. Current gestational weight gain recommendations were primarily for the general obstetric population, raising concern about the applicability to women with gestational diabetes mellitus (GDM). We aimed to assess the difference in weight progression and adherence to the recommended gestational weight gain targets between women with gestational diabetes mellitus (GDM) and women with normal glucose tolerance (NGT). Methods This was a hospital-based retrospective study of 56,616 pregnant women (9,430 GDM women and 47,186 NGT women) from Guangzhou between 2017 and 2021. The average change in weight progression was estimated based on serial weight measurements throughout pregnancy, using a mixed effects model with a random intercept to account for repeated measures of the same individual. Results Women with GDM gained less weight (12.07 [SD 5.20] kg) than women with NGT (14.04 [SD 5.04] kg) throughout pregnancy. Before OGTT, a small difference was observed in the average change in weight progression between the two groups (GDM, 0.44 kg/week vs. NGT, 0.45 kg/week, p

Abstract Excessive reactive oxygen species (ROS) can induce oxidative damage to cell membranes and biomolecules, leading to various chronic diseases. Therefore, the exploration of effective natural antioxidants that can replace traditional synthetic antioxidants to reduce excess free radicals without side effects is important. Herein, the antioxidant peptide (Lateolabrax japonicus protein hydrolysates; LPH) was obtained from bass (L. japonicus) by an optimal enzymatic hydrolysis process. The protective effect of LPH on the Caco‐2 cell oxidative stress model and the potential antioxidant signaling pathways were explored. The results showed that LPH was rich in hydrophobic amino acids, and the IC50 for 2,2‐diphenyl‐1‐picrylhydrazyl radical scavenging activity was 0.9667 mg/mL. Furthermore, the LPH treatment reduced cellular ROS levels and lipid peroxidation while increasing antioxidant enzyme activity in a dose‐dependent manner (p

Animal experiments have played a significant role in advancing scientific knowledge and enhancing people's quality of life. In order to better understand the opinions and knowledge of veterinary students in the domain of laboratory animal welfare and to explore and advance the teaching methods used in animal ethics education, a questionnaire was designed and used to conduct a survey among undergraduate and postgraduate students majoring in veterinary medicine. The survey encompassed various topics, such as students' level of knowledge about animal welfare, their perspectives on laboratory animals, their proficiency with animal experiments, and their opinions on teaching methods and content. The respondents were a total of 150 undergraduate students and 148 graduate students. The survey results indicated that most students expressed a strong sense of responsibility for the safeguarding of the welfare of experimental animals. However, there were a few students who lacked compassion for animals. Additionally, there was a general lack of basic theoretical knowledge of animal ethics and an inadequate grasp of experimental techniques among current students. Furthermore, most of the participants expressed a strong sense of responsibility to advocate for animal welfare. Although a substantial number of students were unaware of the existence of agencies for the supervision of work involving laboratory animals, they supported teaching and supervision in the domain of animal welfare and were open to various teaching methods and topics of content. In conclusion, targeted training and education regarding laboratory animal welfare and ethics should be conducted in the future to address the specific needs of students. This study provides a foundation for future animal welfare education and will help to improve the professional skills and humanistic qualities of veterinary students.

Objective: A meta-analysis is conducted to evaluate the effectiveness and safety of bevacizumab in hereditary hemorrhagic telangiectasia (HHT) epistaxis.Method: Two researchers search PubMed, EMBASE and Web of Science databases from their inception until September 3th, 2023. The literature is read and screened, and valid data extracted, collated and analyzed. Its quality is then assessed using the Cochrane risk assessment scale. This study uses Endnote 9.3 software for literature management and RevMan 5.3.1 software for evaluation.Results: A total of 7 documents met the requirements, including a total of 359 patients, and the literature quality evaluation was grade B. The Meta-analysis results showed that:Bevacizumab reduces the Epistaxis Severity Score (ESS) in patients with HHT epistaxis compared with the control [WMD = −0.22,95%CI (−0.38, −0.05), p = 0.01]. However, there is no significant effect on duration of epistaxis [WMD = −15.59, 95%CI (−70.41,39.23), p = 0.58] and number of epistaxes [WMD = −1.27,95%CI (−10.23,7.70), p = 0.78] in patients with HHT epistaxis. In terms of adverse effects, there is no significant difference between the bevacizumab group and control group [OR = 1.36, 95% CI (0.54, 3.44), p = 0.52].Conclusion: Bevacizumab is superior to the control group in the treatment of HHT epistaxis, and adverse reactions are not further increased in the bevacizumab group than in the control group, suggesting that bevacizumab has clinical value in the treatment of HHT epistaxis.

AbstractIntroduction Blood bone metabolic biomarkers are noninvasive indices for evaluating metabolic bone diseases. We investigated the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients and analyzed the effects of parathyroidectomy (PTX) on the above indices.Methods In this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) patients with PTX, were enrolled. Moreover, a prospective study was conducted in which 28 PTX patients were followed up. The degree of anemia was classified as mild, moderate, or severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83 g/L and 102 g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23), and α-klotho, were tested.Results The mean estimated glomerular filtration rate (eGFR) in CKD patients was 25.7 ± 36.0 ml/min/1.73 m2, and 84.10% of CKD patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86 ± 5.99 g/L, 92.71 ± 5.96 g/L, and 67.38 ± 10.56 g/L, respectively. CKD patients had higher adjusted Ca, P, alkaline phosphatase (ALP), iPTH, and FGF23 levels and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH, and α-klotho levels were associated with Hb levels in CKD patients. Blood adjusted Ca, P, and iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH, and FGF23 levels were ameliorated, while α-klotho levels were increased.Conclusions Blood adjusted Ca, P, iPTH, and α-klotho levels were correlated with Hb levels in CKD patients. Correction of bone metabolic disorders may be a therapeutic strategy for anemia treatment.

ABSTRACTNeutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the underlying mechanisms whereby neutrophils regulate IELs to inhibit intestinal inflammation are still not completely understood. Here, we found that depletion of neutrophils (especially CD177+ subset) caused expansion of colitogenic TCRγδ+CD8αα+ IELs, increased intestinal inflammation, and dysbiosis after dextran sulfate sodium exposure or Citrobacter rodentium infection in mice. scRNA-seq analysis revealed a pyroptosis-related gene signature and hyperresponsiveness to microbiota in TCRγδ+CD8αα+ IELs from colitic Cd177−/− mice. Microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), as well as fumarate-producing microbiotas, decreased in the feces of colitic Cd177−/− mice. Elimination of dysbiosis by antibiotics treatment or co-housing procedure and DMF supplementation restrained TCRγδ+CD8αα+ IEL activation. Consistently, DMF significantly alleviated intestinal mucosal inflammation in mice through restricting gasdermin D (GSDMD)-induced pyroptosis of TCRγδ+CD8αα+ IELs. Therefore, our data reveal that neutrophils inhibit intestinal inflammation by promoting microbiota-derived DMF to regulate TCRγδ+CD8αα+ IEL activation in a GSDMD-mediated pyroptosis-dependent manner, and that DMF may serve as a therapeutic target for the management of intestinal inflammation.

Objective: A liquid chromatography-tandem mass spectrometry coupled with immunoaffinity column clean-up method was established for the determination of 8 mycotoxins in aquatic products. Methods: The samples were extracted with acetonitrile water (84:16, V:V), and purified by multifunctional immunoaffinity columns. The chromatographic column was Agilent Proshell 120 SB·C18 column (2.1 mm×100 mm, 2.7 μm). Mobile phase was methanol and 5 mmol/L ammonium acetate (containing 0.1% formic acid), gradient elution. The flow rate was 0.4 mL/min, and the column temperature was 40 ℃. The electrospray was operated in both positive and negative mode at the same time, and the samples were detected by multiple reaction monitoring mode (MRM). Results: The linear relations of the eight mycotoxins were good within the concentration range of 1.0~50.0 ng/mL (R2>0.992). The limits of detection were between 0.05~0.50 μg/kg, and the limits of quantification were between 0.17~1.65 μg/kg. The average recoveries were 75.6%~106.3%, and the relative standard deviations (RSDs) were 3.5%~9.3%. Conclusion: The method is simple, sensitive and accurate for the rapid analysis of mycotoxin residues in aquatic products.

Black soybean meal was used as raw material to prepare lactic acid beverage with antioxidant activity through lactic acid bacteria fermentation. Single factor and response surface methodology were used to optimize the fermentation process of lactic acid bacteria. The effects of the solid-liquid ratio, inoculation quantity, fermentation temperature, and fermentation time on the fermentation process were investigated with DPPH radical scavenging ratio as an index. The DPPH radical scavenging experiment, OH radical scavenging experiment, ABTS radical scavenging experiment, and lipid peroxidation inhibition experiment were tested to assess the antioxidant effect of fermented products. The results showed that Streptococcus thermophilus was the best fermentation strain, and the optimum fermentation processes were solid-liquid ratio 1:5 g/mL, inoculation quantity 5%, fermentation temperature 37.6 ℃, and fermentation time 36 h, respectively. Under the optimal fermentation conditions, the DPPH radical scavenging ratio was 71.56%. The semi-inhibitory concentrations of DPPH, OH and ABTS free radicals in the fermentation products of black soybean meal were 2.43, 1.30 and 0.37 mg/mL, respectively, and the lipid peroxidation was effectively inhibited, indicating that the fermentation products had good antioxidant activity in vitro. The sensory evaluation and suspension stability of beverage were 90.21 and 96.8%, respectively. This study provides a new idea for the development of functional foods with black soybean meal as raw material, and also provides a reference for the further development of agricultural by-products.

Background: After the adjustment of COVID-19 epidemic policy, mainland China experienced two consecutive waves of Omicron variants within a seven-month period. In Guangzhou city, as one of the most populous regions, the viral infection characteristics, molecular epidemiology, and the dynamic of population immunity are still elusive. Methods: We launched a prospective cohort study in the Guangdong Provincial CDC from December 2022 to July 2023. Fifty participants who received the same vaccination regimen and had no previous infection were recruited. Results: 90% of individuals were infected with Omicron BA.5* variants within three weeks in the first wave. Thirteen cases (28.26%) experienced infection with XBB.1* variants, occurring from 14 weeks to 21 weeks after the first wave. BA.5* infections exhibited higher viral loads in nasopharyngeal sites compared to oropharyngeal sites. Compared to BA.5* infections, the XBB.1* infections had significantly milder clinical symptoms, lower viral loads, and shorter durations of virus positivity. The infection with the BA.5* variant elicited varying levels of neutralizing antibodies against XBB.1* among different individuals, even with similar levels of BA.5* antibodies. The level of neutralizing antibodies specific to XBB.1* determined the risk of reinfection. Conclusions: The rapid large-scale infections of the Omicron variants have quickly established herd immunity among the population in mainland China. In the future of the COVID-19 epidemic, a lower infection rate but a longer duration can be expected. Given the large population size and ongoing diversified herd immunity, it remains crucial to closely monitor the molecular epidemiology of SARS-CoV-2 for the emergence of new variants of concern in this region. Additionally, the timely evaluation of the immune status across different age groups is essential for informing future vaccination strategies and intervention policies.

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Periodontitis, a condition that results in periodontal attachment loss and alveolar bone resorption, contributes to the global burden of oral disease. The underlying mechanism of periodontitis involves the dysbiosis and dyshomeostasis between host and oral microbes, among which the macrophage is one of the major innate immune cell players, producing interferon β (IFNβ) in response to bacterial infection. The objective of this research was to examine the interaction of macrophages with periodontitis and the role and mechanism of IFNβ on macrophages. IFNβ has been shown to have the potential to induce the differentiation of M1 to M2 macrophages, which are stimulated by low levels of lipopolysaccharide (LPS). Additionally, IFNβ has been demonstrated to promote the production of ISG15 by macrophages, which leads to the inhibition of the innate immune response. Moreover, our investigation revealed that IFNβ has the potential to augment the secretion of ISG15 and its downstream cytokine, IL10, in LPS-stimulated macrophages. Single-cell analysis was conducted on the gingival tissues of patients with periodontitis, which revealed a higher proportion of macrophages in the periodontitis-diseased tissue and increased expression of IFNβ, ISG15, and IL10. Gene Set Enrichment Analysis indicated that bacterial infection was associated with upregulation of IFNβ, ISG15, and IL10. Notably, only IL10 has been linked to immunosuppression, indicating that the IFNβ-ISG15-IL10 axis might promote an anti-inflammatory response in periodontitis through IL10 expression. It is also found that macrophage phenotype transitions in periodontitis involve the release of higher levels of IFNβ, ISG15, and IL10 by the anti-inflammatory M2 macrophage phenotype compared to the pro-inflammatory M1 phenotype and myeloid-derived suppressor cells (MDSCs). This implies that the IFNβ-induced production of IL10 might be linked to the M2 macrophage phenotype. Furthermore, cell communication analysis demonstrated that IL10 can promote fibroblast proliferation in periodontal tissues via STAT3 signaling.

Abstract Dysfunction of podocytes has been regarded as an important early pathologic characteristic of diabetic kidney disease (DKD), but the regulatory role of long noncoding RNAs (lncRNAs) in this process remains largely unknown. Here, we performed RNA sequencing in kidney tissues isolated from DKD patients and nondiabetic renal cancer patients undergoing surgical resection and discovered that the novel lncRNA ENST00000436340 was upregulated in DKD patients and high glucose-induced podocytes, and we showed a significant correlation between ENST00000436340 and kidney injury. Gain- and loss-of-function experiments showed that silencing ENST00000436340 alleviated high glucose-induced podocyte injury and cytoskeleton rearrangement. Mechanistically, we showed that fat mass and obesity- associate gene (FTO)-mediated m6A induced the upregulation of ENST00000436340. ENST00000436340 interacted with polypyrimidine tract binding protein 1 (PTBP1) and augmented PTBP1 binding to RAB3B mRNA, promoted RAB3B mRNA degradation, and thereby caused cytoskeleton rearrangement and inhibition of GLUT4 translocation to the plasma membrane, leading to podocyte injury and DKD progression. Together, our results suggested that upregulation of ENST00000436340 could promote podocyte injury through PTBP1-dependent RAB3B regulation, thus suggesting a novel form of lncRNA-mediated epigenetic regulation of podocytes that contributes to the pathogenesis of DKD.