Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception.

Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRα-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

Detection of organic dyes using Ag NPAs/SMP SERS substrate produced via sandpaper template-assisted lithography and liquid-liquid interface self-assembly.

Surface-enhanced Raman spectroscopy (SERS) is a highly sensitive and reliable fingerprinting technique. However, its analytical capability is closely related to the quality of a SERS substrate used for the analysis. In particular, conventional colloidal substrates possess disadvantages in terms of controllability, stability, and reproducibility, which limit their application. In order to address these issues, a simple, cost-effective, and efficient SERS substrate based on silver nanoparticle arrays (Ag NPAs) and sandpaper-molded polydimethylsiloxane (SMP) was proposed in this work. Successfully prepared via template lithography and liquid-liquid interface self-assembly (LLISA), the substrate can be applied to the specific detection of organic dyes in the environment. The substrate exhibited good SERS performance, and the limit of detection (LOD) of rhodamine 6G (R6G) was shown to be 10-7 M under the optimal conditions (1000 grit sandpaper) with a relative standard deviation (RSD) of 7.76%. Moreover, the SERS signal intensity was maintained at 60% of the initial intensity after the substrate was stored for 30 days. In addition, the Ag NPAs/SMP SERS substrate was also employed to detect crystal violet (CV) and methylene blue (MB) with the LODs of 10-6 M and 10-7 M, respectively. In summary, the Ag NPAs/SMP SERS substrate prepared in this study has great potential for the detection of organic dyes in ecological environments.

Substrate-embedded metal meshes for ITO-free organic light emitting diodes.

Organic light-emitting diodes (OLEDs) have great potential for use in large-area display and lighting applications, but their widespread adoption for large areas is hindered by the high cost and insufficient performance of indium tin oxide (ITO) anodes. In this study, we introduce an alternative anode material - a silver mesh embedded in glass - to facilitate production of large-area OLEDs. We present a facile, scalable manufacturing technique to create high aspect ratio micromeshes embedded in glass to provide the planar geometry needed for OLED layers. Our phosphorescent green OLEDs achieve a current efficiency of 51.4 cd/A at 1000 cd/m2 and reach a slightly higher external quantum efficiency compared to a standard ITO/glass reference sample. Notably, these advancements are achieved without any impact on the viewing angle of the OLEDs. These findings represent a promising advancement towards ITO-free, high-efficiency OLEDs for various high performance, large-area applications, such as lighting and displays.

Design of an Injectable Magnetic Hydrogel Based on the Tumor Microenvironment for Multimodal Synergistic Cancer Therapy.

Conventional tumor chemotherapy is limited by its low therapeutic efficacy and side effects, which severely hold back its further application. Drug delivery systems (DDSs) based on nanomaterials have attracted wide interest in cancer treatment; especially, the system can realize efficient synergistic therapies. Here, we designed a smart hydrogel drug delivery system with multiple responses to enhance the tumor treatment effect. By cross-linking oxidized hydroxypropyl cellulose with carboxymethyl chitosan, an injectable hydrogel was obtained, into which artesunate (ART), ferroferric oxide (Fe3O4) nanoparticles, and black phosphorus nanosheets (BPs) were preloaded. This DDS has multiple functions including magnetic targeting, pH sensitivity, chemodynamic therapy, and photothermal response. This nanoparticle-composited hydrogel not only preserved excellent rheological properties but also allowed for an accurate stable drug release at tumor sites and synergistic effects of multiple therapies. The in vitro and in vivo experiments revealed that this DDS could efficiently eliminate the HepG2 tumor with good biocompatibility. Taken together, this study clarifies the possible antitumor mechanism of this ART-loaded nanoparticle-composited hydrogel and provides a new strategy for synergistic photothermal-chemo-chemodynamic therapy.

Factors influencing the progression from prehypertension to hypertension among Chinese middle-aged and older adults: a 2-year longitudinal study.

BACKGROUND: This study aimed to investigate the proportion of prehypertension cases progressing to hypertension among Chinese middle-aged and elderly populations over a 2-year period and related influencing factors. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study, and 2,845 individuals who were ≥ 45 years old and prehypertensive at baseline were followed from 2013-2015. Structured questionnaires were administered, and blood pressure (BP) and anthropometric measurements were performed by trained personnel. Multiple logistic regression analysis was done to investigate factors associated with prehypertension progressing to hypertension. RESULTS: Over the 2-year follow-up, 28.5% experienced progression of prehypertension to hypertension; this occurred more frequently in men than women (29.7% vs. 27.1%). Among men, older age (55-64 years: adjusted odds ratio [aOR] = 1.414, 95% confidence interval [CI]:1.032-1.938; 65-74 years: aOR = 1.633, 95%CI: 1.132-2.355; ≥ 75 years: aOR = 2.974, 95%CI: 1.748-5.060), obesity (aOR = 1.634, 95%CI: 1.022-2.611), and number of chronic diseases (1: aOR = 1.366, 95%CI: 1.004-1.859; ≥ 2: aOR = 1.568, 95%CI: 1.134-2.169) were risk factors for progression to hypertension whereas being married/cohabiting (aOR = 0.642, 95% CI: 0.418-0.985) was a protective factor. Among women, risk factors included older age (55-64 years: aOR = 1.755, 95%CI: 1.256-2.450; 65-74 years: aOR = 2.430, 95%CI: 1.605-3.678; ≥ 75 years: aOR = 2.037, 95% CI: 1.038-3.995), married/cohabiting (aOR = 1.662, 95%CI: 1.052-2.626), obesity (aOR = 1.874, 95%CI: 1.229-2.857), and longer naps (≥ 30 and < 60 min: aOR = 1.682, 95%CI: 1.072-2.637; ≥ 60 min: aOR = 1.387, 95%CI: 1.019-1.889). CONCLUSIONS: Chinese middle-aged and elderly individuals experienced a risk of prehypertension progressing to hypertension over a 2-year period, although the influencing factors differed by sex; this should be considered in interventions.

Genomic insight into transmission mechanisms of carbapenem-producing Citrobacter spp. isolates between the WWTP and connecting rivers.

Carbapenem-resistant Enterobacteriaceae (CRE) poses major health risks worldwide. Most studies have focused on carbapenem resistance in Klebsiella pneumoniae and Escherichia coli; however, the occurrence and transmission of carbapenem-resistant Citrobacter spp. (CRCS) are poorly understood. In this study, we investigated the occurrence and potential transmission patterns of CRCS in different functional areas of an urban wastewater treatment plant (WWTP) and connecting rivers during one-year monitoring in Shandong Province, China. In total, 14 CRCS were detected in 376 environmental samples, including those from the WWTP inlet (n = 7), WWTP anaerobic tank (n = 2), and rivers (n = 5). Citrobacter braakii (n = 6) was the dominant subtype among 14 CRCS isolates, followed by Citrobacter freundii (n = 5), Citrobacter sedlakii (n = 2), and Citrobacter werkmanii (n = 1). All CRCS were resistant to imipenem, meropenem, ampicillin, amoxicillin/clavulanic acid, cefotaxime, ceftazidime, trimethoprim/sulfamethoxazole, and ciprofloxacin. Plasmid analysis showed that the blaKPC-2 gene was located on IncN and IncFII (Yp) plasmids, whereas the blaNDM gene was located on IncX3 and IncN2 plasmids. Clonal transmission of CRCS harboring carbapenem genes occurred between the WWTP and connecting rivers on a temporal or spatial scale. High genomic relatedness of NDM-5-producing C. sedlakii was identified between river water and WWTP aerosol, suggesting a potential exposure risk of CRCS for workers and surrounding residents near the WWTP. Furthermore, NDM-5-producing C. sedlakii isolated from rivers was related to C. sedlakii isolated from soil and well water in different regions of China, indicating that NDM-5-producing C. sedlakii may be widespread in China. These findings indicate that rare healthcare-associated pathogens such as CRCS can contribute to widespread carbapenem production in the environment; thus, CRCS should be continuously monitored.

Surface nanostructuring of alkali-aluminosilicate Gorilla display glass substrates using a maskless process.

This paper reports on the formation of moth-eye nanopillar structures on surfaces of alkali-aluminosilicate Gorilla glass substrates using a self-masking plasma etching method. Surface and cross-section chemical compositions studies were carried out to study the formation of the nanostructures. CFxinduced polymers were shown to be the self-masking material during plasma etching. The nanostructures enhance transmission at wavelengths over 525 nm may be utilized for fluid-induced switchable haze. Additional functionalities associated with nanostructures may be realized such as self-cleaning, anti-fogging, and stain-resistance.

Effects of endovascular and surface cooling on resuscitation in patients with cardiac arrest and a comparison of effectiveness, stability, and safety: a systematic review and meta-analysis.

OBJECTIVES: This study conducted a meta-analysis to assess the effectiveness, stability, and safety of mild therapeutic hypothermia (TH) induced by endovascular cooling (EC) and surface cooling (SC) and its effect on ICU, survival rate, and neurological function integrity in adult CA patients. METHODS: We developed inclusion criteria, intervention protocols, results, and data collection. The results included outcomes during target temperature management as well as ICU stay, survival rate, and neurological functional integrity. The characteristics of the included population and each study were analyzed. RESULTS: Four thousand nine hundred thirteen participants met the inclusion criteria. Those receiving EC had a better cooling efficiency (cooling rates MD = 0.31[0.13, 0.50], p < 0.01; induced cooling times MD = - 90.45[- 167.57, - 13.33], p = 0.02; patients achieving the target temperature RR = 1.60[1.19, 2.15], p < 0.01) and thermal stability during the maintenance phase (maintenance time MD = 2.35[1.22, 3.48], p < 0.01; temperature fluctuation MD = - 0.68[- 1.03, - 0.33], p < 0.01; overcooling RR = 0.33[0.23, 0.49], p < 0.01). There were no differences in ICU survival rate (RR = 1.22[0.98, 1.52], p = 0.07, I2 = 0%) and hospital survival rate (RR = 1.02 [0.96, 1.09], p = 0.46, I2 = 0%), but EC reduced the length of stay in ICU (MD = - 1.83[- 3.45, - 0.21], p = 0.03, I2 = 49%) and improved outcome of favorable neurological function at discharge (RR = 1.15[1.04, 1.28], p < 0.01, I2 = 0%). EC may delay the hypothermia initiation time, and there was no significant difference between the two cooling methods in the time from the start of patients' cardiac arrest to achieve the target temperature (MD = - 46.64[- 175.86, 82.58]). EC was superior to non-ArcticSun in terms of cooling efficiency. Although there was no statistical difference in ICU survival rate, ICU length of stay, and hospitalization survival rate, in comparison to non-ArcticSun, EC improved rates of neurologically intact survival (RR = 1.16 [1.01, 1.35], p = 0.04, I2 = 0%). CONCLUSIONS: Among adult patients receiving cardiopulmonary resuscitation, although there is no significant difference between the two cooling methods in the time from the start of cardiac arrest to achieve the target temperature, the faster cooling rate and more stable cooling process in EC shorten patients' ICU hospitalization time and help more patients obtain good neurological prognosis compared with patients receiving SC. Meanwhile, although EC has no significant difference in patient outcomes compared with ArcticSun, EC has improved rates of neurologically intact survival.

Effect of gga-miR-155 on cell proliferation, apoptosis and invasion of Marek's disease virus (MDV) transformed cell line MSB1 by targeting RORA.

BACKGROUND: Marek's disease (MD) is caused by the oncogenic Marek's disease virus (MDV), and is a highly contagious avian infection with a complex underlying pathology that involves lymphoproliferative neoplasm formation. MicroRNAs (miRNAs) act as oncogenes or tumor suppressors in most cancers. The gga-miR-155 is downregulated in the MDV-infected chicken tissues or lymphocyte lines, although its exact role in tumorigenesis remains unclear. The aim of this study was to analyze the effects of gga-miR-155 on the proliferation, apoptosis and invasiveness of an MDV-transformed lymphocyte line MSB1 and elucidate the underlying mechanisms. RESULTS: The expression level of gga-miR-155 was manipulated in MSB1 cells using specific mimics and inhibitors. While overexpression of gga-miR-155 increased proliferation, decreased the proportion of G1 phase cells relative to that in S and G2 phases, reduced apoptosis rates and increased invasiveness. However, its downregulation had the opposite effects. Furthermore, gga-miR-155 directly targeted the RORA gene and downregulated its expression in the MSB1 cells. CONCLUSION: The gga-miR-155 promotes the proliferation and invasiveness of the MDV-transformed lymphocyte line MSB1 and inhibits apoptosis by targeting the RORA gene.

Recent advances and potential applications of human pluripotent stem cell-derived pancreatic ß cells.

Diabetes mellitus is characterized by chronic high blood glucose levels resulted from deficiency and/or dysfunction of insulin-producing pancreatic ß cells. Generation of large amounts of functional pancreatic ß cells is critical for the study of pancreatic biology and treatment of diabetes. Recent advances in directed differentiation of pancreatic ß-like cells from human pluripotent stem cells (hPSCs) can provide patient-specific and disease-relevant target cells. With the improved differentiation protocols, it is now possible to generate large amounts of functional human pancreatic ß-like cells that can response to high level of glucose both in vitro and in vivo. Combined with precise genomic editing, biomedical engineering, high throughput profiling, bioinformatics, and high throughput genetic and chemical screening, these hPSC-derived pancreatic ß-like cells will hold great potentials in disease modeling, drug discovery, and cell-based therapies. In this review, we summarize the recent progress in human pancreatic ß-like cells derived from hPSCs and discuss their potential applications.

The pelvic radius technique in the assessment of spinopelvic sagittal alignment of degenerative spondylolisthesis and lumbar spinal stenosis.

BACKGROUND: Degenerative spondylolisthesis (DS) and lumbar spinal stenosis (LSS) are the most common degenerative spinal diseases. The evaluating of spinopelvic sagittal alignment of the two diseases using pelvic radius (PR) technique have not been reported. The purpose of this study was to use PR measurement technique to compare the differences in spinopelvic sagittal alignment between DS and LSS. METHODS: A total of 145 patients with DS or LSS were retrospectively reviewed. Seventy patients with DS (DS group) and 75 age-matched patients with LSS (LSS group) were enrolled. Spinopelvic parameters including pelvic angle (PA), regional lumbopelvic lordosis (PR-L1, PR-L2, PR-L3, PR-L4 and PR-L5), total lumbopelvic lordosis (PR-T12), pelvic morphology (PR-S1), sagittal vertical axis from the C7 plumb line (SVA), lumbar lordosis (LL), thoracic kyphosis (TK), L4 slope and L5 slope were assessed in the two groups. Several parameters of DS and LSS group were compared with the normal population (NP). RESULTS: The PR-L4, PR-L5 and PR-S1 in the DS group were significantly smaller than those in the LSS group. There was no difference in PR-T12 between the DS group and NP (p > 0.05), while PR-T12 of the LSS group were significantly lower (p < 0.01). Degree of correlations among spinopelvic parameters differed between the two groups. PR-T12 of the DS group was more strongly correlated with PA (r = -0.829, p < 0.001) than with LL (r = 0.664, p < 0.001), TK (r = 0.582, p < 0.001). PR-T12 of the LSS group was more strongly correlated with LL (r = 0.854, p < 0.001), TK (r = 0.616, p < 0.001) than with PA (r = -0.582, p < 0.001). CONCLUSIONS: PR-L4 and PR-L5 may be the predisposing factors for DS development. Spinopelvic morphology differed in patients with DS and LSS compared to NP. The compensatory mechanisms to maintain spinopelvic sagittal alignment in DS and LSS patients may be different.

Improving metabolic efficiency of the reverse beta-oxidation cycle by balancing redox cofactor requirement.

Previous studies have made many exciting achievements on pushing the functional reversal of beta-oxidation cycle (r-BOX) to more widespread adoption for synthesis of a wide variety of fuels and chemicals. However, the redox cofactor requirement for the efficient operation of r-BOX remains unclear. In this work, the metabolic efficiency of r-BOX for medium-chain fatty acid (C6-C10, MCFA) production was optimized by redox cofactor engineering. Stoichiometric analysis of the r-BOX pathway and further experimental examination identified NADH as a crucial determinant of r-BOX process yield. Furthermore, the introduction of formate dehydrogenase from Candida boidinii using fermentative inhibitor byproduct formate as a redox NADH sink improved MCFA titer from initial 1.2g/L to 3.1g/L. Moreover, coupling of increasing the supply of acetyl-CoA with NADH to achieve fermentative redox balance enabled product synthesis at maximum titers. To this end, the acetate re-assimilation pathway was further optimized to increase acetyl-CoA availability associated with the new supply of NADH. It was found that the acetyl-CoA synthetase activity and intracellular ATP levels constrained the activity of acetate re-assimilation pathway, and 4.7g/L of MCFA titer was finally achieved after alleviating these two limiting factors. To the best of our knowledge, this represented the highest titer reported to date. These results demonstrated that the key constraint of r-BOX was redox imbalance and redox engineering could further unleash the lipogenic potential of this cycle. The redox engineering strategies could be applied to acetyl-CoA-derived products or other bio-products requiring multiple redox cofactors for biosynthesis.

MicroRNA expression profile of human periodontal ligament cells under the influence of Porphyromonas gingivalis LPS.

Periodontitis is a chronic inflammatory disease which is caused by bacterial infection and leads to the destruction of periodontal tissues and resorption of alveolar bone. Thus, special attention should be paid to the mechanism under lipopolysaccharide (LPS)-induced periodontitis because LPS is the major cause of periodontitis. However, to date, miRNA expression in the LPS-induced periodontitis has not been well characterized. In this study, we investigated miRNA expression patterns in LPS-treated periodontal ligament cells (PDLCs). Through miRNA array and differential analysis, 22 up-regulated miRNAs and 28 down-regulated miRNAs in LPS-treated PDLCs were identified. Seven randomly selected up-regulated (miR-21-5p, 498, 548a-5p) and down-regulated (miR-495-3p, 539-5p, 34c-3p and 7a-2-3p) miRNAs were examined by qRT-PCR, and the results proved the accuracy of the miRNA array. Moreover, targets of these deregulated miRNAs were analysed using the miRWalk database. Database for Annotation, Visualization and Integration Discovery software were performed to analyse the Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway of differential expression miRNAs, and the results shown that Toll-like receptor signalling pathway, cAMP signalling pathway, transforming growth factor-beta signalling pathway, mitogen-activated protein kinase (MAPK) signalling pathway and other pathways were involved in the molecular mechanisms underlying LPS-induced periodontitis. In conclusion, this study provides clues for enhancing our understanding of the mechanisms and roles of miRNAs as key regulators of LPS-induced periodontitis.

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling.

AIM: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. METHODS: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg(-1)·d(-1)) for 4 weeks. Another group was treated with LPS (50 µg·kg(-1)·d(-1), sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. RESULTS: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. CONCLUSION: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

Electrical Stimulations Generated by P(VDF-TrFE) Films Enhance Adhesion Forces and Odontogenic Differentiation of Dental Pulp Stem Cells (DPSCs).

Biophysical and biochemical cues of biomaterials can regulate cell behaviors. Dental pulp stem cells (DPSCs) in pulp tissues can differentiate to odontoblast-like cells and secrete reparative dentin to form a barrier to protect the underlying pulp tissues and enable complete pulp healing. Promotion of the odontogenic differentiation of DPSCs is essential for dentin regeneration. The effects of the surface potentials of biomaterials on the adhesion and odontogenic differentiation of DPSCs remain unclear. Here, poly(vinylidene fluoride-trifluoro ethylene) (P(VDF-TrFE)) films with different surface potentials were prepared by the spin-coating technique and the contact poling method. The cytoskeletal organization of DPSCs grown on P(VDF-TrFE) films was studied by immunofluorescence staining. Using atomic force microscopy (AFM), the lateral detachment forces of DPSCs from P(VDF-TrFE) films were quantified. The effects of electrical stimulation generated from P(VDF-TrFE) films on odontogenic differentiation of DPSCs were evaluated in vitro and in vivo. The unpolarized, positively polarized, and negatively polarized films had surface potentials of -52.9, +902.4, and -502.2 mV, respectively. DPSCs on both negatively and positively polarized P(VDF-TrFE) films had larger cell areas and length-to-width ratios than those on the unpolarized films (P < 0.05). During the detachment of DPSCs from P(VDF-TrFE) films, the average magnitudes of the maximum detachment forces were 29.4, 72.1, and 53.9 nN for unpolarized, positively polarized, and negatively polarized groups, respectively (P < 0.05). The polarized films enhanced the mineralization activities and increased the expression levels of the odontogenic-related proteins of DPSCs compared to the unpolarized films (P < 0.05). The extracellular signal-regulated kinase (ERK) signaling pathway was involved in the odontogenic differentiation of DPSCs as induced by surface charge. In vivo, the polarized P(VDF-TrFE) films enhanced adhesion of DPSCs and promoted the odontogenic differentiation of DPSCs by electrical stimulation, demonstrating a potential application of electroactive biomaterials for reparative dentin formation in direct pulp capping.

Global diversity of airborne pathogenic bacteria and fungi from wastewater treatment plants.

Wastewater treatment plants (WWTPs) have been recognized as one of the major potential sources of the spread of airborne pathogenic microorganisms under the global pandemic of COVID-19. The differences in research regions, wastewater treatment processes, environmental conditions, and other aspects in the existing case studies have caused some confusion in the understanding of bioaerosol pollution characteristics. In this study, we integrated and analyzed data from field sampling and performed a systematic literature search to determine the abundance of airborne microorganisms in 13 countries and 37 cities across four continents (Asia, Europe, North America, and Africa). We analyzed the concentrations of bioaerosols, the core composition, global diversity, determinants, and potential risks of airborne pathogen communities in WWTPs. Our findings showed that the culturable bioaerosol concentrations of global WWTPs are 102-105 CFU/m3. Three core bacterial pathogens, namely Bacillus, Acinetobacter, and Pseudomonas, as well as two core fungal pathogens, Cladosporium and Aspergillus, were identified in the air across global WWTPs. WWTPs have unique core pathogenic communities and distinct continental divergence. The sources of airborne microorganisms (wastewater) and environmental variables (relative humidity and air contaminants) have impacts on the distribution of airborne pathogens. Potential health risks are associated with the core airborne pathogens in WWTPs. Our study showed the specificity, multifactorial influences, and potential pathogenicity of airborne pathogenic communities in WWTPs. Our findings can improve the understanding of the global diversity and biogeography of airborne pathogens in WWTPs, guiding risk assessment and control strategies for such pathogens. Furthermore, they provide a theoretical basis for safeguarding the health of WWTP workers and ensuring regional ecological security.

Exploration of altered miRNA expression and function in MSC-derived extracellular vesicles in response to hydatid antigen stimulation.

Background: Hydatid disease is caused by Echinococcus parasites and can affect various tissues and organs in the body. The disease is characterized by the presence of hydatid cysts, which contain specific antigens that interact with the host's immune system. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can regulate immunity through the secretion of extracellular vesicles (EVs) containing microRNAs (miRNAs). Methods: In this study, hydatid antigens were isolated from sheep livers and mice peritoneal cavities. MSCs derived from mouse bone marrow were treated with different hydatid antigens, and EVs were isolated and characterized from the conditioned medium of MSCs. Small RNA library construction, miRNA target prediction, and differential expression analysis were conducted to identify differentially expressed miRNAs. Functional enrichment and network construction were performed to explore the biological functions of the target genes. Real-time PCR and Western blotting were used for miRNA and gene expression verification, while ELISA assays quantified TNF, IL-1, IL-6, IL-4, and IL-10 levels in cell supernatants. Results: The study successfully isolated hydatid antigens and characterized MSC-derived EVs, demonstrating the impact of antigen concentration on MSC viability. Key differentially expressed miRNAs, such as miR-146a and miR-9-5p, were identified, with functional analyses revealing significant pathways like Endocytosis and MAPK signaling associated with these miRNAs' target genes. The miRNA-HUB gene regulatory network identified crucial miRNAs and HUB genes, such as Traf1 and Tnf, indicating roles in immune modulation and osteogenic differentiation. Protein-protein interaction (PPI) network analysis highlighted central HUB genes like Akt1 and Bcl2. ALP activity assays confirmed the influence of antigens on osteogenic differentiation, with reduced ALP activity observed. Expression analysis validated altered miRNA and chemokine expression post-antigen stimulation, with ELISA analysis showing a significant reduction in CXCL1 expression in response to antigen exposure. Conclusion: This study provides insights into the role of MSC-derived EVs in regulating parasite immunity. The findings suggest that hydatid antigens can modulate the expression of miRNAs in MSC-derived EVs, leading to changes in chemokine expression and osteogenic capacity. These findings contribute to a better understanding of the immunomodulatory mechanisms involved in hydatid disease and provide potential therapeutic targets for the development of new treatment strategies.

The Distribution of Crystalline Lens Rise in High Myopia Population and Its Influence on Vault After Implanting Intraocular Collamer Lens.

INTRODUCTION: As a result of the insufficient ocular anatomical parameters used to customize implantable collamer lens (ICL), many patients still cannot achieve a suitable vault after ICL implantation surgery. This study analyzed the characteristics of a new anatomical parameter crystalline lens rise (CLR) in a population with high myopia and explored the influence of CLR on the vault after ICL implantation. METHODS: Patients (298 eyes) with high myopia who underwent ICL implantation were enrolled to study CLR characteristics. Postoperatively, patients (159 eyes) were divided into five groups according to the value of CLR (A, CLR ≤ - 150; B, - 150 < CLR ≤ 0; C, 0 < CLR < 150; D, 150 ≤ CLR < 300; E, CLR ≥ 300 µm), and to investigate the correlation between CLR and vault. RESULTS: In the 298 eyes, the CLR had a normal distribution (P = 0.35) and the mean CLR was 67.93 ± 150.66 µm. Ninety-nine eyes (33.22%) had a CLR ≤ 0 µm, of which 20 eyes (6.71%) had a CLR ≤ - 150 µm; 199 eyes (66.78%) had a CLR > 0 µm, of which 20 eyes (6.71%) had a CLR ≥ 300 µm. In 159 eyes, the CLR was negatively correlated with the vault at 1 day (R = - 0.497, P < 0.001), 3 months (R = - 0.505, P < 0.001), and 6 months (R = - 0.505, P < 0.001) postoperatively. At 6 months, the vault of group A was statistically significantly different compared to groups B-E (all P < 0.05), and that of group E was statistically significantly different compared to groups A-D (all P < 0.001). The remaining groups did not show statistically significant differences (all P > 0.05). CONCLUSION: The CLR had a normal distribution in the high myopia population, and 13.42% of the CLR values were extreme (CLR ≤ - 150 µm or CLR ≥ 300 µm). A larger ICL diameter than that recommended by the manufacturer should be considered when the CLR is ≥ 300 µm and a smaller ICL diameter should be considered when the CLR is ≤ - 150 µm.