Comparison of multiple preservation and digestion methods for determination of tungsten concentrations in environmental media using ICP-MS.

Tungsten is an emerging environmental pollutant. However, a proved robust method for preserving and determining the concentrations of tungsten in environmental media is still lacking. This study examined and compared the suitability of classic methods and previously reported tungsten-oriented methods on preserving dissolved tungsten and recovering tungsten from soil/sediment matrix. Tungsten concentrations in the water samples and digestates were then determined by inductively coupled plasma mass spectrometry. Our data showed that the tungsten-oriented HF and alkaline preservatives indeed successfully maintained the stability of dissolved tungsten. Even when preserved using HNO3 or HCl, dissolved tungsten concentrations did not notably change in most of our water samples over the course of ∼4 months. Using glass containers for storing water samples also did not produce much difference from using high-density polyethylene containers. Our data further suggested that the addition of HF in digestion was important for tungsten solubilization from soil/sediment matrix. The digestion methods with HNO3/HCl/HF and HNO3/HF/NH4OH/EDTA both yielded quantitative recoveries of tungsten from certified reference materials and known synthetic samples, while the other tested methods had limited recoveries. The methods validated by this study could be used to accurately determine tungsten concentrations in environmental media and thereby to assess the fate and potential risks of tungsten.

[Study on mechanism of inhibiting proliferation of head and neck cancer cells by citral, active ingredient of lemon essential oil].

To explore the active substances exerting anti-tumour effect in lemon essential oil and the molecular mechanism inhibiting the proliferation of head and neck cancer cells SCC15 and CAL33, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay(MTT) was utilized to identify the active component inhibiting the proliferation of head and neck cancer cells, namely citral. The IC_(50) of citral inhibiting the proliferation of head and neck cancer cells and normal cells were also determined. In addition, a 5-ethynyl-2'-deoxyuridine(EdU) staining assay was used to detect the effect of citral on the proliferation rate of head and neck cancer cells, and a colony formation assay was used to detect the effect of citral on tumor sphere formation of head and neck cancer cells in vitro. The cell cycle arrest and apoptosis induction of head and neck cancer cells by citral were evaluated by flow cytometry, and Western blot was used to detect the effect of citral on the expression levels of cell cycle-and apoptosis-related proteins in head and neck cancer cells. The findings indicated that citral could effectively inhibit the proliferation and growth of head and neck cancer cells, with anti-tumor activity, and its half inhibitory concentrations for CAL33 and SCC15 were 54.78 and 25.23 µg·mL~(-1), respectively. Furthermore, citral arrested cell cycle at G_2/M phase by down-regulating cell cycle-related proteins such as S-phase kinase associated protein 2(SKP2), C-MYC, cyclin dependent kinase 1(CDK1), and cyclin B. Moreover, citral increased the cysteinyl aspartate-specific proteinase-3(caspase-3), cysteinyl aspartate-specific proteinase-9(caspase-9), and cleaved poly ADP-ribose polymerase(PARP). It up-regulated the level of autophagy-related proteins including microtubule associated protein 1 light chain 3B(LC3B), sequestosome 1(P62/SQSTM1), autophagy effector protein Beclin1(Beclin1), and lysosome-associate membrane protein 1(LAMP1), suggesting that citral could effectively trigger cell apoptosis and cell autophagy in head and neck cancer cells. Furthermore, the dual-tagged plasmid system mCherry-GFP-LC3 was used, and it was found that citral impeded the fusion of autophagosomes and lysosomes, leading to autophagic flux blockage. Collectively, our findings reveal that the main active anti-proliferation component of lemon essential oil is citral, and this component has a significant inhibitory effect on head and neck cancer cells. Its underlying molecular mechanism is that citral induces apoptosis and autophagy by cell cycle arrest and ultimately inhibits cell proliferation.

Novel Palladium Hydride Surface Enabling Simultaneous Bacterial Killing and Osteogenic Formation through Proton Capturing and Activation of Antioxidant System in Immune Microenvironments.

Achieving bacterial killing and osteogenic formation on an implant surface rarely occurs. In this study, a novel surface design-a palladium hydride (PdHx) film that enables these two distinct features to coexist is introduced. The PdHx lattice captures protons in the extracellular microenvironment of bacteria, disrupting their normal metabolic activities, such as ATP synthesis, nutrient co-transport, and oxidative stress. This disruption leads to significant bacterial death, as evidenced by RNA sequence analysis. Additionally, the unique enzymatic activity and hydrogen-loading properties of PdHx activate the human antioxidant system, resulting in the rapid clearance of reactive oxygen species. This process reshapes the osteogenic immune microenvironment, promoting accelerated osteogenesis. These findings reveal that the downregulation of the NOD-like receptor signaling pathway is critical for activating immune cells toward M2 phenotype polarization. This novel surface design provides new strategies for modifying implant coatings to simultaneously prevent bacterial infection, reduce inflammation, and enhance tissue regeneration, making it a noteworthy contribution to the field of advanced materials.

Compound 225# inhibits the proliferation of human colorectal cancer cells by promoting cell cycle arrest and apoptosis induction.

Colorectal cancer (CRC) ranks as the second leading cause of cancer­related death worldwide due to its aggressive nature. After surgical resection, >50% of patients with CRC require adjuvant therapy. As a result, eradicating cancer cells with medications is a promising method to treat patients with CRC. In the present study, a novel compound was synthesized, which was termed compound 225#. The inhibitory activity of compound 225# against CRC was determined by MTT assay, EdU fluorescence labeling and colony formation assay; the effects of compound 225# on the cell cycle progression and apoptosis of CRC cells were detected by flow cytometry and western blotting; and the changes in autophagic flux after the administration of compound 225# were detected using the double fluorescence fusion protein mCherry­GFP­LC3B and western blotting. The results demonstrated that compound 225# exhibited antiproliferative properties, inhibiting the proliferation and expansion of CRC cell lines in a time­ and dose­dependent manner. Furthermore, compound 225# triggered G2/M cell cycle arrest by influencing the expression of cell cycle regulators, such as CDK1, cyclin A1 and cyclin B1, which is also closely related to the activation of DNA damage pathways. The cleavage of PARP and increased protein expression levels of PUMA suggested that apoptosis was triggered after treatment with compound 225#. Moreover, the increase in LC3­II expression and stimulation of autophagic flux indicated the activation of an autophagy pathway. Notably, compound 225# induced autophagy, which was associated with endoplasmic reticulum (ER) stress. In accordance with the in vitro findings, the in vivo results demonstrated that compound 225# effectively inhibited the growth of HCT116 tumors in mice without causing any changes in their body weight. Collectively, the present results demonstrated that compound 225# not only inhibited proliferation and promoted G2/M­phase cell cycle arrest and apoptosis, but also initiated cytoprotective autophagy in CRC cells by activating ER stress pathways. Taken together, these findings provide an experimental basis for the evaluation of compound 225# as a novel potential medication for CRC treatment.

Deciphering DOM-metal binding using EEM-PARAFAC: Mechanisms, challenges, and perspectives.

Dissolved organic matter (DOM) is a pivotal component of the biogeochemical cycles and can combine with metal ions through chelation or complexation. Understanding this process is crucial for tracing metal solubility, mobility, and bioavailability. Fluorescence excitation emission matrix (EEM) and parallel factor analysis (PARAFAC) has emerged as a popular tool in deciphering DOM-metal interactions. In this review, we primarily discuss the advantages of EEM-PARAFAC compared with other algorithms and its main limitations in studying DOM-metal binding, including restrictions in spectral considerations, mathematical assumptions, and experimental procedures, as well as how to overcome these constraints and shortcomings. We summarize the principles of EEM to uncover DOM-metal association, including why fluorescence gets quenched and some potential mechanisms that affect the accuracy of fluorescence quenching. Lastly, we review some significant and innovative research, including the application of 2D-COS in DOM-metal binding analysis, hoping to provide a fresh perspective for possible future hotspots of study. We argue the expansion of EEM applications to a broader range of areas related to natural organic matter. This extension would facilitate our exploration of the mobility and fate of metals in the environment.

Mechanical properties and energy damage evolution mechanism of fiber-reinforced cemented sulfur tailings backfill under uniaxial compression.

This paper studies mechanical properties and energy damage evolution of fiber-reinforced cemented sulfur tailings (CSTB) backfill. The effects of fiber length and fiber content on the stress, toughness and failure properties of the CSTB were systematically revealed. In addition, the energy index evolution law was studied, and the energy damage evolution mechanism of CSTB was revealed. The results show that the deformation failure of fiber-reinforced CSTB mainly goes through four stages: initial crack compaction, linear elastic deformation, yield failure and post-peak failure. The peak stress and residual stress of the CSTB firstly increase and then decrease with the increase of fiber content and the addition of fiber can promote the change from brittle failure to ductile failure of the CSTB. Adding appropriate amount of fiber can improve the toughness of CSTB, and the influence degree of fiber length on the toughness index of CSTB is 6mm>12mm>3mm. The total strain energy increases linearly along the variation of fiber content, while the elastic strain energy and dissipated energy increase exponentially at the peak stress point. In the process of CSTB deformation and failure, "gentle-linear growth-slow growth-rapid decline" is for elastic strain energy, while "gentle-slow growth-rapid growth-linear growth" is for dissipation energy. The damage and failure of CSTB mainly experienced four stages: initial damage, slow growth of damage, accelerated damage and damage failure, and the damage evolution curve also showed the changing characteristics of "gentle-slow growth-rapid growth-linear growth". The CSTB without added fiber showed obvious "Y-type" and "linear-type" shear failure characteristics and the phenomenon of shear cracks penetrating the backfill appeared. No big shear crack occur when it is damaged, showing that the fiber addition restrain the crack growth and improve the overall crack resistance of the CSTB. Hydration products are obviously distributed on the surface of the fiber, which indicates that the fiber will be evenly dispersed in the CSTB and form a certain bonding force with the cement-tailings matrix, thus improving the overall mechanical properties of the CSTB.

Experimental study on time-dependent rheological properties and mechanical performance of cemented fine tailings backfill mixed with polypropylene fiber.

By preparing fine tailings slurry with different mass concentration and fiber content, the rheological parameters of slurry with different fiber content and curing time were tested. In addition, the influence law of fiber content and curing time on compressive strength was analyzed through the prepared fine tailings backfill samples, and the microstructure characteristics of fine tailings backfill were further studied. The results show that when the fiber content is 0.2 ~ 1.2%, the yield stress and plastic viscosity of the slurry increase with the increase of fiber content, and the thixotropy of the slurry also shows the same change characteristics. The bridge effect of fiber makes it easier for forming network structure, which increase the slurry rheology. When the curing time ranges from 0 h to 2.5 h, the increasing of curing time leads to the increasing trend of rheological parameters, and also increases the thixotropy of slurry. However, the increase of rheological parameters will continuously decrease when the curing time exceeds 1 h, indicating that the influence of curing time on yield stress and thixotropy will gradually weaken with the continuous extension of curing time. When the curing age increases from 3 to 56 days, the compressive strength of the fine tailings backfill increases with the curing age, but the increasing range of compressive strength decreases gradually. When the fiber content ranges from 0.2 to 1.2%, the compressive strength of backfill increases first and then decreases with the increase of fiber content, and reaches the maximum value when the fiber content is 0.6%. The extension of curing time reduces the generation of large-scale pore structure, which promotes the formation of more compact microstructure of backfill.

Population Genetic Analysis of Paris polyphylla var. yunnanensis Based on cpDNA Fragments.

Paris polyphylla var. yunnanensis is a well-known medicinal plant that is mainly distributed in Southwest China; however, its genetic diversity and biodiversity processes are poorly understood. In this study, the sequences of cpDNA trnL-trnF fragments of 15 wild populations and 17 cultivated populations of P. polyphylla var. yunnanensis were amplified, sequenced, and aligned to study the population genetics of this species. Genetic diversity was analyzed based on nucleotide diversity, haplotype diversity, Watterson diversity, population-level diversity, and species-level genetic diversity. Genetic structure and genetic differentiation were explored using haplotype distribution maps and genetic distance matrices. A total of 15 haplotypes were identified in the 32 populations of P. polyphylla var. yunnanensis. Five unique haplotypes were identified from the fourteen haplotypes of the cultivated populations, while only one unique haplotype was identified from the ten haplotypes of the wild populations. The haplotype richness and genetic diversity of the cultivated populations were higher than those of the wild populations (HT = 0.900 vs. 0.861). In addition, there were no statistically significant correlations between geographic distance and genetic distance in the cultivated populations (r = 0.16, p > 0.05), whereas there was a significant correlation between geographical distance and genetic structure in the wild populations (r = 0.32, p > 0.05), indicating that there was a geographical and genetic connection between the wild populations. There was only 2.5% genetic variation between the wild populations and cultivated populations, indicating no obvious genetic differentiation between the wild and cultivated populations. Overall, the genetic background of the cultivated populations was complex, and it was hypothesized that the unique haplotypes and higher diversity of the cultivated populations were caused by the mixed provenance of the cultivated populations.

An integrated analysis identifies six molecular subtypes of pancreatic ductal adenocarcinoma revealing cellular and molecular landscape.

Pancreatic ductal adenocarcinoma (PDA) has been found to have a high mortality rate. Despite continuous efforts, current histopathological classification is insufficient to guide individualized therapies of PDA. We first define the molecular subtypes of PDA (MSOP) based on a meta-cohort of 845 samples from 11 PDA datasets. We then performed functional analyses involving immunity, fibrosis and metabolism. We recognized six molecular subtypes with different survival statistics and molecular composition. The squamous basal-like (SBL) subtype had a poor prognosis and high infiltration of ENO1+ (Enolase 1)/ADM+ (Adrenomedullin) cancer-associated fibroblasts (CAFs). The immune mesenchymal-like (IML) subtype and the normal mesenchymal-like (NML) subtype were characterized by genes associated with extracellular matrix (ECM) activities and immune responses, having favorable prognoses. IML was featured by elevated exhausted immune signaling and inflammatory CAFs infiltration, whereas NML was featured with myofibroblastic CAFs infiltration. The exocrine-like (EL) subtype was high in exocrine signals, while the pure classical-like (PCL) subtype lacked immunocytes infiltration. The quiescent-like (QL) subtype had diminished metabolic signaling and high infiltration of NK cells. SBL, IML and NML were enriched in innate anti-PD-1 resistance signatures. In sum, this MSOP depicts a vivid cell-to-molecular atlas of the tumor microenvironment of PDA and might facilitate to design a precise combination of therapies that target immunity, metabolism and stroma.

Surface defect engineered-Mg-based implants enable the dual functions of superhydrophobic and synergetic photothermal/chemodynamic therapy.

Promoting metallic magnesium (Mg)-based implants to treat bone diseases in clinics, such as osteosarcoma and bacterial infection, remains a challenging topic. Herein, an iron hydroxide-based composite coating with a two-stage nanosheet-like structure was fabricated on Mg alloy, and this was followed by a thermal reduction treatment to break some of the surface Fe-OH bonds. The coating demonstrated three positive changes in properties due to the defects. First, the removal of -OH made the coating superhydrophobic, and it had self-cleaning and antifouling properties. This is beneficial for keeping the implants clean and for anti-corrosion before implantation into the human body. Furthermore, the superhydrophobicity could be removed by immersing the implant in a 75% ethanol solution, to further facilitate biological action during service. Second, the color of the coating changed from yellow to brown-black, leading to an increase in the light absorption, which resulted in an excellent photothermal effect. Third, the defects increased the Fe2+ content in the coating and highly improved peroxidase activity. Thus, the defect coating exhibited synergistic photothermal/chemodynamic therapeutic effects for bacteria and tumors. Moreover, the coating substantially enhanced the anti-corrosion and biocompatibility of the Mg alloys. Therefore, this study offers a novel multi-functional Mg-based implant for osteosarcoma therapy.

Effect of Preliminary Treatment by Pulsed Electric Fields and Blanching on the Quality of Fried Sweet Potato Chips.

The effects of pulsed electric fields (PEF) and blanching pretreatments on frying kinetics, oil content, color, texture, acrylamide (AA) content, and microstructure have been investigated in this paper. The total PEF pretreatment duration was tPEF = 0.2 s with an intensity of E = 1 kV/cm; blanching was studied at 85 °C for 5 min. The results demonstrated that pretreatment significantly reduced the moisture ratio and oil content by 25% and 40.33%, respectively. The total color change ΔE value of the pretreated samples was lower than that of the untreated samples. In addition, pretreatment increased the hardness of the sample after frying, and the AA content in the fried samples pretreated with PEF + blanching was reduced by approximately 46.10% (638 µg/kg). Finally, fried sweet potato chips obtained by the combined pretreatment exhibited a smoother and flatter cross-sectional microstructure.

Analog soil organo-ferrihydrite composites as suitable amendments for cadmium and arsenic stabilization in co-contaminated soils.

Remediation of CdAs co-contaminated soils has long been considered a difficult problem to solve, as Cd and As have distinctly different metallic characters. Amending contaminated soils with traditional single passivation materials may not always work well in the stabilization of both Cd and As. Here, we reported that analog soil organo-ferrihydrite composites made with either living or non-living organics (bacterial cells or humic acid) could achieve stabilization of both Cd and As in contaminated soils. BCR and Wenzel sequential extractions showed that organo-ferrihydrite, particularly at 1 wt% loading, shifted liable Cd and As to more stable phases. Organo-ferrihydrite amendments significantly (p < 0.05) increased soil urease, alkaline phosphatase and catalase enzyme activities. With organo-ferrihydrite amendments, the bioavailable fraction of Cd decreased to 35.3 % compared with the control (65.1 %), while the bioavailable As declined from 29.4 % to 12.4%. Soil pH, microbial community abundance and diversity were almost unaffected by organo-ferrihydrite. Ferrihydrite and organo fractions both contributed to direct Cd-binding, while the organo fraction probably maintained the Fe-bound As via lowering ferrihydrite phase transformation. Compared to pure ferrihydrite, organo-ferrihydrite composites performed better not only in reducing liable Cd and As, but also in maintaining soil quality and ecosystem functions. This study demonstrates the applications of organo-ferrihydrite composites in eco-friendly remediation of CdAs contaminated soils, and provides a new direction in selecting appropriate soil amendments.

Transmission mechanisms of antibiotic resistance genes in arsenic-contaminated soil under sulfamethoxazole stress.

Numerous studies have revealed the spread mechanism of antibiotic resistance genes (ARGs) in single antibiotic-contaminated soils. However, the comprehensive impacts of heavy metals and antibiotics on ARGs and the underlying mechanisms are still unknown. Here, high-throughput quantitative PCR and high-throughput sequencing were used to investigate changes in ARGs and bacterial communities under various sulfamethoxazole (SMX) regimes (0, 1, 10, 50 mg kg-1) in arsenic (As) contaminated soils. The study found that the abundances of ARGs, mobile genetic elements (MGEs), and heavy metal resistance genes (HMRGs) significantly increased in the soil fortified at 10 and 50 mg kg-1 SMX concentrations. The ARGs abundance increased with the increase in the MGEs abundance. Many significant positive correlations between various ARGs subtypes and HMRGs subtypes were found. These results indicate that the HMRGs and MGEs positively contributed to the enrichment of ARGs in As-contaminated soils under SMX stress. Meanwhile, the abundance of copiotrophic (Actinobacteriota) reduced and oligotrophic (Gemmatimonadota) increased, indicating that the life history strategy of the community changed. In addition, Gemmatimonadota was positively correlated to ARGs, HMRGs, and MGEs, suggesting that Gemmatimonadota, which can cope with As and SMX stress, was the host for resistance genes in the soil. Finally, the study found that MGEs play a determinant role in ARGs proliferation due to the direct utilization of HGT, and the indirect effect for ARGs spread under a co-selection mechanism of ARGs and HMRGs, while the bacterial community showed indirect influences by altering environmental factors to act on MGEs. Collectively, this study revealed new insights into the mechanisms of resistance gene transmission under combined SMX and As contamination in soil ecosystems.

Multiple mechanisms collectively mediate tungsten homeostasis and resistance in Citrobacter sp. Lzp2.

Tungsten (W) is an emerging contaminant, and current knowledge on W resistance profiles of microorganisms remains scarce and fragmentary. This study aimed to explore the physiological responses of bacteria under W stress and to resolve genes and metabolic pathways involved in W resistance using a transcriptome expression profiling assay. The results showed that the bacterium Citrobacter sp. Lzp2, screened from W-contaminated soil, could tolerate hundreds of mM W(VI) with a 50% inhibiting concentration of ∼110 mM. To cope with W stress, Citrobacter sp. Lzp2 secreted large amounts of proteins through the type VI secretory system (T6SS) to chelate W oxoanions via carboxylic groups in extracellular polymeric substances (EPS), and could transport cytosolic W outside via the multidrug efflux pumps (mdtABC and acrD). Intracellular W is probably bound by chaperone proteins and metal-binding pterin (tungstopterin) through the sulfur relay system. We propose that tetrathionate respiration is a new metabolic pathway for cellular W detoxification likely producing thio-tungstate. We conclude that multiple mechanisms collectively mediate W homeostasis and resistance in Citrobacter sp. Lzp2. Our results have important implications not only for understanding the intricate regulatory network of W homeostasis in microbes but also for bio-recovery and bioremediation of W in contaminated environments.

Collaborative Design of MgO/FeOx Nanosheets on Titanium: Combining Therapy with Regeneration.

The repair of bone defects caused by osteosarcoma resection remains a clinical challenge because of the tumor recurrence and bacterial infection. Combining tumor and bacterial therapy with bone regeneration properties in bone implants is a promising strategy for the treatment of osteosarcoma. Here, a layer of MgO/FeOx nanosheet is constructed on the Ti implant to prevent tumor recurrence and bacterial infection, while simultaneously accelerating bone formation. This MgO/FeOx double metal oxide demonstrates good peroxidase activity to catalyze H2 O2 , which is rich in tumor microenvironment, to form reactive oxygen species (ROS), and shows good photothermal conversion capacity to produce photothermal effect, thus synergistically killing tumor cells and eliminating tumor tissue. In addition, it generates a local alkaline surface microenvironment to inhibit the energy metabolism of bacteria to enhance the photothermal antibacterial effect. Furthermore, benefiting from the generation of a Mg ion-containing alkaline microenvironment, this MgO/FeOx film can promote the osteogenic differentiation of osteoblast and angiogenesis of vascular endothelial cells in vitro as well as accelerated bone formation in vivo. This study proposes a multifunctional platform for integrating tumor and bacterial therapy and bone regeneration, which has good application prospects for the treatment of osteosarcoma.

The ignored risk: heavy metal pollution of medicine and food homologous substances.

A survey was conducted to investigate the effects of cadmium (Cd), arsenic (As), chromium (Cr), lead (Pb), and copper (Cu) in medicine and food homologous substances (MFHs) on human health. Nine common and typical MFHs (Dendrobium, Bulbus lilii, Poria, Semen nelumbinis, Radix puerariae, Gardenia jasminoides, Hordeum vulgare L, Semen coicis, and Ganoderma Karst) in the form of medicinal slices ready for decoction were purchased from pharmacies. Five among the MFHs (Dendrobium, Bulbus lilii, Poria, Semen nelumbinis, and Radix puerariae) were further obtained from a local field as raw materials for comparison. The results showed that raw materials of MFHs collected from the field had higher contents of heavy metal and greater health risks than medicinal slices purchased from pharmacy. Generally, the heavy metal residues in MFHs of different medicinal parts were different, and MFHs from roots or stems had significantly higher contents of heavy metals than those from fruits or seeds. Most importantly, the contents of Cd in Bulbus lilii and As in wild Poria from field were higher than the contents described in the Pharmacopoeia of the People's Republic of China (ChP). Non-carcinogenic and carcinogenic risk assessments revealed that Poria from field had larger non-carcinogenic and carcinogenic risks to human health; Bulbus lilii showed no non-carcinogenic risk but exhibited carcinogenic risks, whereas Cr showed carcinogenic risks in all samples. Given that MFHs are incorporated in regular foods, care should be taken to minimize health hazards caused by heavy metals to human. This study creates awareness on the safety issues associated with MFHs, and provides basic information for establishing the maximum allowable contents of medicinal and food substances in normal diets.

Exposure to Nanoplastic Particles Enhances Acinetobacter Survival, Biofilm Formation, and Serum Resistance.

The interaction between nanoplastics and bacteria remains still largely unclear. In this study, we determined the effect of nanopolystyrene particle (NP) on a bacterial pathogen of Acinetobacter johnsonii AC15. Scanning electron microscopy (SEM) analysis indicated the aggregation of NPs from 10 µg/L to 100 µg/L on surface of A. johnsonii AC15, suggesting that A. johnsonii AC15 acted as the vector for NPs. Exposure to 100−1000 µg/L NPs increased the growth and colony-forming unit (CFU) of A. johnsonii AC15. In addition, exposure to 100−1000 µg/L NPs enhanced the amount of formed biofilm of A. johnsonii AC15. Alterations in expressions of 3 survival-related (zigA, basD, and zur), 5 biofilm formation-related (ompA, bap, adeG, csuC, and csuD), and 3 serum resistance-related virulence genes (lpxC, lpxL, and pbpG) were observed after exposure to 1000 µg/L NPs. Moreover, both CFU and survival rate of A. johnsonii AC15 in normal human serum (NHS) were significantly increased by 1−1000 µg/L NPs, suggesting the enhancement in serum resistance of Acinetobacter pathogen by NPs. In the NHS, expressions of 3 survival-related (zigA, basD, and zur), 9 biofilm formation-related (ompA, bap, adeF, adeG, csuA/B, csuC, csuD, csuE, and hlyD), and 3 serum resistance-related virulence genes (lpxC, lpxL, and pbpG) were affected by 1000 µg/L NPs. Expressions of 1 survival-related (zigA), 5 biofilm formation-related (bap, adeG, csuC, csuD, and csuE), and 3 serum resistance-related virulence genes (lpxC, lpxL, and pbpG) were also altered by 10 µg/L NPs after the addition of NHS. Therefore, exposure to NPs in the range of µg/L has the potential to enhance bacterial virulence by increasing their growth, biofilm formation, and serum resistance.

Multi-omics analysis identifies rare variation in leptin/PPAR gene sets and hypermethylation of ABCG1 contribute to antipsychotics-induced metabolic syndromes.

Antipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations. By population-based omics analysis, we revealed that rare functional variants across in the leptin and peroxisome proliferator-activated receptors (PPARs) gene sets were imbalanced with rare functional variants across the APs-induced Mets and Non-Mets cohort. Besides, we discovered that APs-induced Mets are hypermethylated in ABCG1 (chr21:43642166-43642366, adjusted P < 0.05) than Non-Mets, and hypermethylation of this area was associated with higher TC (total cholesterol) and TG (triglycerides) levels in HepG2 cells. Candidate genes from omics studies were furtherly screened in C. elegans and 17 gene have been verified to associated with olanzapine (OLA) induced fat deposit. Among them, several genes were expressed differentially in Mets cohort and APs-induced in vitro/in vivo models compared to controls, demonstrating the validity of omics study. Overexpression one of the most significant gene, PTPN11, exhibited compromised glucose responses and insulin resistance. Pharmacologic inhibition of PTPN11 protected HepG2 cell from APs-induced insulin resistance. These findings provide important insights into our understanding of the mechanism of the APs-induced Mets.

Transient Receptor Potential Vanilloid-1 (TRPV1) Alleviates Hepatic Fibrosis via TGF-ß Signaling.

Hepatic fibrosis is a major global health problem and considered a leading cause of liver-related morbidity and mortality worldwide. Although previous studies have suggested that transient receptor potential vanilloid-1 (TRPV1) is protective against cardiac and renal fibrosis, its functional role in hepatic fibrosis has remained elusive. Herein, we characterize the effects of TRPV1 on carbon tetrachloride- (CCl4-) induced mice, in vitro transforming growth factor-ß- (TGF-ß-) treated hepatic stellate cells (HSCs), and human fibrosis specimens. Finally, our results demonstrated the significant TRPV1 downregulation in human liver fibrosis tissues. Knocking out TRPV1 significantly increased the expression of various hepatic fibrosis markers, while the expression of these biomarkers declined markedly in capsaicin-activated mice. Moreover, our study revealed that knocking down TRPV1 would enhance the promotive effect of TGF-ß on HSC proliferation, cell cycle, cell apoptosis, and ECM expression. Also, such promotive effect can be partially reversible by capsaicin, an exogenous activator of TRPV1. Collectively, the obtained data suggest that TRPV1 may alleviate CCl4-induced hepatic fibrosis and attenuate the effect of TGF-ß on HSC activation, proliferation, and apoptosis, which overall implies that targeting TRPV1 channel activity may be an effective therapeutic strategy for treating hepatic fibrosis.

miR143-3p-Mediated NRG-1-Dependent Mitochondrial Dysfunction Contributes to Olanzapine Resistance in Refractory Schizophrenia.

BACKGROUND: Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies. METHODS: Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS. RESULTS: Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection. CONCLUSIONS: Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency-induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency-induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS.