AtPIP1;4 and AtPIP2;4 Cooperatively Mediate H2O2 Transport to Regulate Plant Growth and Disease Resistance.

The rapid production of hydrogen peroxide (H2O2) is a hallmark of plants' successful recognition of pathogen infection and plays a crucial role in innate immune signaling. Aquaporins (AQPs) are membrane channels that facilitate the transport of small molecular compounds across cell membranes. In plants, AQPs from the plasma membrane intrinsic protein (PIP) family are utilized for the transport of H2O2, thereby regulating various biological processes. Plants contain two PIP families, PIP1s and PIP2s. However, the specific functions and relationships between these subfamilies in plant growth and immunity remain largely unknown. In this study, we explore the synergistic role of AtPIP1;4 and AtPIP2;4 in regulating plant growth and disease resistance in Arabidopsis. We found that in plant cells treated with H2O2, AtPIP1;4 and AtPIP2;4 act as facilitators of H2O2 across membranes and the translocation of externally applied H2O2 from the apoplast to the cytoplasm. Moreover, AtPIP1;4 and AtPIP2;4 collaborate to transport bacterial pathogens and flg22-induced apoplastic H2O2 into the cytoplasm, leading to increased callose deposition and enhanced defense gene expression to strengthen immunity. These findings suggest that AtPIP1;4 and AtPIP2;4 cooperatively mediate H2O2 transport to regulate plant growth and immunity.

Nicotinamide deficiency promotes imidacloprid resistance via activation of ROS/CncC signaling pathway-mediated UGT detoxification in Nilaparvata lugens.

Metabolic alternation is a typical characteristic of insecticide resistance in insects. However, mechanisms underlying metabolic alternation and how altered metabolism in turn affects insecticide resistance are largely unknown. Here, we report that nicotinamide levels are decreased in the imidacloprid-resistant strain of Nilaparvata lugens, may due to reduced abundance of the symbiotic bacteria Arsenophonus. Importantly, the low levels of nicotinamide promote imidacloprid resistance via metabolic detoxification alternation, including elevations in UDP-glycosyltransferase enzymatic activity and enhancements in UGT386B2-mediated metabolism capability. Mechanistically, nicotinamide suppresses transcriptional regulatory activities of cap 'n' collar isoform C (CncC) and its partner small muscle aponeurosis fibromatosis isoform K (MafK) by scavenging the reactive oxygen species (ROS) and blocking the DNA binding domain of MafK. In imidacloprid-resistant N. lugens, nicotinamide deficiency re-activates the ROS/CncC signaling pathway to provoke UGT386B2 overexpression, thereby promoting imidacloprid detoxification. Thus, nicotinamide metabolism represents a promising target to counteract imidacloprid resistance in N. lugens.

Airborne antibiotic resistome and microbiome in pharmaceutical factories.

Antimicrobial resistance is considered to be one of the biggest public health problems, and airborne transmission is an important but under-appreciated pathway for the spread of antibiotic resistance genes (ARGs) in the environment. Previous research has shown pharmaceutical factories to be a major source of ARGs and antibiotic resistant bacteria (ARB) in the surrounding receiving water and soil environments. Pharmaceutical factories are hotspots of antibiotic resistance, but the atmospheric transmission and its environmental risk remain more concerns. Here, we conducted a metagenomic investigation into the airborne microbiome and resistome in three pharmaceutical factories in China. Soil (average: 38.45%) and wastewater (average: 28.53%) were major contributors of airborne resistome. ARGs (vanR/vanS, blaOXA, and CfxA) conferring resistance to critically important clinically used antibiotics were identified in the air samples. The wastewater treatment area had significantly higher relative abundances of ARGs (average: 0.64 copies/16S rRNA). Approximately 28.2% of the detected airborne ARGs were found to be associated with plasmids, and this increased to about 50% in the wastewater treatment area. We have compiled a list of high-risk airborne ARGs found in pharmaceutical factories. Moreover, A total of 1,043 viral operational taxonomic units were identified and linked to 47 family-group taxa. Different CRISPR-Cas immune systems have been identified in bacterial hosts in response to phage infection. Similarly, higher phage abundance (average: 2451.70 PPM) was found in the air of the wastewater treatment area. Our data provide insights into the antibiotic resistance gene profiles and microbiome (bacterial and non-bacterial) in pharmaceutical factories and reveal the potential role of horizontal transfer in the spread of airborne ARGs, with implications for human and animal health.

Near-infrared PAINT localization microscopy via chromophore replenishment of phytochrome-derived fluorescent tag.

Bacterial phytochromes are attractive molecular templates for engineering fluorescent proteins (FPs) because their near-infrared (NIR) emission significantly extends the spectral coverage of GFP-like FPs. Existing phytochrome-based FPs covalently bind heme-derived tetrapyrrole chromophores and exhibit constitutive fluorescence. Here we introduce Rep-miRFP, an NIR imaging probe derived from bacterial phytochrome, which interacts non-covalently and reversibly with biliverdin chromophore. In Rep-miRFP, the photobleached non-covalent adduct can be replenished with fresh biliverdin, restoring fluorescence. By exploiting this chromophore renewal capability, we demonstrate NIR PAINT nanoscopy in mammalian cells using Rep-miRFP.

GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. METHODS: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. RESULTS: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. CONCLUSIONS: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

Screening and functional validation of the core detoxification genes conferring broad-spectrum response to insecticides in Spodoptera frugiperda.

BACKGROUND: Fall armyworm, Spodoptera frugiperda, a formidable agricultural pest, has developed resistance to various synthetic insecticides. However, how S. frugiperda utilizes its limited energy and resources to deal with various insecticides remains largely unexplored. RESULTS: We utilized transcriptome sequencing to decipher the broad-spectrum adaptation mechanism of S. frugiperda to eight insecticides with distinct modes-of-action. Analysis of the Venn diagram revealed that 1014 upregulated genes and 778 downregulated genes were present in S. frugiperda treated with at least five different insecticides, compared to the control group. Exposure to various insecticides led to the significant upregulation of eight cytochrome P450 monooxygenases (P450s), four UDP glucosyltransferases (UGTs), two glutathione-S-transferases (GSTs) and two ATP-binding cassette transporters (ABCs). Among them, the sfCYP340AD3 and sfCYP4G74 genes were demonstrated to respond to stress from six different insecticides in S. frugiperda, as evidenced by RNA interference and toxicity bioassays. Furthermore, homology modeling and molecular docking analyses showed that sfCYP340AD3 and sfCYP4G74 possess strong binding affinities to a variety of insecticides. CONCLUSION: Collectively, these findings showed that S. frugiperda utilizes a battery of core detoxification genes to cope with the exposure of synthetic insecticides. This study also sheds light on the identification of efficient insecticidal targets gene and the development of resistance management strategies in S. frugiperda, thereby facilitating the sustainable control of this serious pest. © 2024 Society of Chemical Industry.

Efficacy of transjugular intrahepatic portosystemic shunts in treating cirrhotic esophageal-gastric variceal bleeding.

BACKGROUND: Esophageal-gastric variceal bleeding (EGVB) represents a severe complication among patients with cirrhosis and often culminates in fatal outcomes. Interventional therapy, a rapidly developing treatment modality over the past few years, has found widespread application in clinical practice due to its minimally invasive characteristics. However, whether transjugular intrahepatic portosystemic shunt (TIPS) treatment has an impact on patient prognosis remains controversial. AIM: To probing the efficacy of TIPS for treating cirrhotic EGVB and its influence on the prognosis of patients afflicted by this disease. METHODS: A retrospective study was conducted on ninety-two patients presenting with cirrhotic EGVB who were admitted to our hospital between September 2020 and September 2022. Based on the different modes of treatment, the patients were assigned to the study group (TIPS received, n = 50) or the control group (percutaneous transhepatic varices embolization received, n = 42). Comparative analyses were performed between the two groups preoperatively and one month postoperatively for the following parameters: Varicosity status; hemodynamic parameters [portal vein flow velocity (PVV) and portal vein diameter (PVD); platelet count (PLT); red blood cell count; white blood cell count (WBC); and hepatic function [albumin (ALB), total bilirubin (TBIL), and aspartate transaminase (AST)]. The Generic Quality of Life Inventory-74 was utilized to assess quality of life in the two groups, and the 1-year postoperative rebleeding and survival rates were compared. RESULTS: Following surgical intervention, there was an improvement in the incidence of varicosity compared to the preoperative status in both cohorts. Notably, the study group exhibited more pronounced enhancements than did the control group (P < 0.05). PVV increased, and PVD decreased compared to the preoperative values, with the study cohort achieving better outcomes (P < 0.05). PLT and WBC counts were elevated postoperatively in the two groups, with the study cohort displaying higher PLT and WBC counts (P < 0.05). No differences were detected between the two groups in terms of serum ALB, TBIL, or AST levels either preoperatively or postoperatively (P < 0.05). Postoperative scores across all dimensions of life quality surpassed preoperative scores, with the study cohort achieving higher scores (P < 0.05). At 22.00%, the one-year postoperative rebleeding rate in the study cohort was significantly lower than that in the control group (42.86%; P < 0.05); conversely, no marked difference was observed in the 1-year postoperative survival rate between the two cohorts (P > 0.05). CONCLUSION: TIPS, which has demonstrated robust efficacy in managing cirrhotic EGVB, remarkably alleviates varicosity and improves hemodynamics in patients. This intervention not only results in a safer profile but also contributes significantly to a more favorable prognosis.

Non-invasive geophysical methods for monitoring the shallow aquifer based on time-lapse electrical resistivity tomography, magnetic resonance sounding, and spontaneous potential methods.

The Ningdong coalfield has played a pivotal role in advancing local economic development and meeting national energy. Nevertheless, mining operations have engendered ecological challenges encompassing subterranean water depletion, land desertification, and ground subsidence, primarily stemming from the disruption of coal seam roof strata. Consequently, the local ecosystem has incurred substantial harm. Water-preserved coal mining presently constitutes the pivotal technology in mitigating this problem. The primary challenge of this technique lies in identifying critical aquifer layers and understanding the heights of water-conducting fracture zones. To obtain a precise comprehension of the seepage patterns within the upper coal seam aquifer during mining, delineate the extent of water-conducting fracture zones, non-invasive geophysical techniques such as time-lapse electrical resistivity tomography (TL-ERT), magnetic resonance sounding (MRS), and spontaneous potential (SP) have been employed to monitor alterations within the shallow coalfield's aquifer throughout the mining process in the Ningdong coalfield. By conducting meticulous examinations of fluctuations in resistivity, moisture content, and self-potential within the superjacent strata during coal seam extraction, the predominant underground water infiltration strata were ascertained, concurrently enabling the estimation of the development elevation of water-conducting fracture zones. This outcome furnishes a geophysical underpinning for endeavors concerning local water-preserved coal mining and ecological rehabilitation.

Calcium-induced upregulation of energy metabolism heats neurons during neural activity.

Cellular temperature affects every biochemical reaction, underscoring its critical role in cellular functions. In neurons, temperature not only modulates neurotransmission but is also a key determinant of neurodegenerative diseases. Considering that the brain consumes a disproportionately high amount of energy relative to its weight, neural circuits likely generate a lot of heat, which can increase cytosolic temperature. However, the changes in temperature within neurons and the mechanisms of heat generation during neural excitation remain unclear. In this study, we achieved simultaneous imaging of Ca2+ and temperature using the genetically encoded indicators, B-GECO and B-gTEMP. We then compared the spatiotemporal distributions of Ca2+ responses and temperature. Following neural excitation induced by veratridine, an activator of the voltage-gated Na+ channel, we observed an approximately 2 °C increase in cytosolic temperature occurring 30 s after the Ca2+ response. The temperature elevation was observed in the non-nuclear region, while Ca2+ increased throughout the cell body. Moreover, this temperature increase was suppressed under Ca2+-free conditions and by inhibitors of ATP synthesis. These results indicate that Ca2+-induced upregulation of energy metabolism serves as the heat source during neural excitation.

Role of HDL cholesterol in anthracycline-induced subclinical cardiotoxicity: a prospective observational study in patients with diffuse large B-cell lymphoma treated with R-CHOP.

OBJECTIVES: Anthracycline-induced cardiotoxicity is a debilitating cardiac dysfunction for which there are no effective treatments, making early prevention of anthracycline-induced subclinical cardiotoxicity (AISC) crucial. High-density lipoprotein cholesterol (HDL-C) plays a role in cardioprotection, but its impact on AISC remains unclear. Our study aims to elucidate the protective capacity of HDL-C in AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab). DESIGN: Prospective observational study. SETTING: Conducted in China from September 2020 to September 2022. PARTICIPANTS: 70 chemotherapy-naïve patients newly diagnosed with DLBCL who were scheduled to receive the standard dose of R-CHOP; 60 participants included in a case-control study (DOI: 10.1186/s12885-022-10085-6). PRIMARY OUTCOME MEASURES: Serum biomarkers, 2D speckle tracking echocardiography and conventional echocardiography were measured at baseline, at the end of the third and sixth cycles of R-CHOP and 6 and 12 months after chemotherapy. RESULTS: 24 patients experienced AISC, while 10 did not. 36 patients were lost to follow-up and death. Cox regression analysis showed that higher levels of HDL-C were associated with a significantly lower risk of AISC (unadjusted HR=0.24, 95% CI 0.09 to 0.67, p=0.006; adjusted HR=0.27, 95% CI 0.09 to 0.79, p=0.017). Patients without AISC had a more stable and higher HDL-C level during the follow-up period. HDL-C levels significantly decreased from the end of the third cycle of chemotherapy to the end of the sixth cycle of chemotherapy in all patients (p=0.034), and particularly in the AISC group (p=0.003). The highest level of HDL-C was significantly higher in patients without AISC than in those with AISC (1.52±0.49 vs 1.22±0.29, p=0.034). CONCLUSIONS: Our study suggests that higher HDL-C levels may associate with lower AISC risk in patients with DLBCL treated with R-CHOP. HDL-C could be a cardioprotective target, but further research is needed to confirm its benefits and limitations. STUDY REGISTRATION NUMBER: Study registration number: ChiCTR2100054721.

LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA.

Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.

The RING-Type Domain-Containing Protein GNL44 Is Essential for Grain Size and Quality in Rice (Oryza sativa L.).

Grain size in rice (Oryza sativa L.) shapes yield and quality, but the underlying molecular mechanism is not fully understood. We functionally characterized GRAIN NUMBER AND LARGE GRAIN SIZE 44 (GNL44), encoding a RING-type protein that localizes to the cytoplasm. The gnl44 mutant has fewer but enlarged grains compared to the wild type. GNL44 is mainly expressed in panicles and developing grains. Grain chalkiness was higher in the gnl44 mutant than in the wild type, short-chain amylopectin content was lower, middle-chain amylopectin content was higher, and appearance quality was worse. The amylose content and gel consistency of gnl44 were lower, and protein content was higher compared to the wild type. Rapid Visco Analyzer results showed that the texture of cooked gnl44 rice changed, and that the taste value of gnl44 was lower, making the eating and cooking quality of gnl44 worse than that of the wild type. We used gnl44, qgl3, and gs3 monogenic and two-gene near-isogenic lines to study the effects of different combinations of genes affecting grain size on rice quality-related traits. Our results revealed additive effects for these three genes on grain quality. These findings enrich the genetic resources available for rice breeders.

Effects of methionine deficiency on B7H3-DAP12-CAR-T cells in the treatment of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is a subtype of lung cancer for which precision therapy is lacking. Chimeric antigen receptor T-cells (CAR-T) have the potential to eliminate cancer cells by targeting specific antigens. However, the tumor microenvironment (TME), characterized by abnormal metabolism could inhibit CAR-T function. Therefore, the aim of this study was to improve CAR-T efficacy in solid TME by investigating the effects of amino acid metabolism. We found that B7H3 was highly expressed in LUSC and developed DAP12-CAR-T targeting B7H3 based on our previous findings. When co-cultured with B7H3-overexpressing LUSC cells, B7H3-DAP12-CAR-T showed significant cell killing effects and released cytokines including IFN-γ and IL-2. However, LUSC cells consumed methionine (Met) in a competitive manner to induce a Met deficiency. CAR-T showed suppressed cell killing capacity, reduced cytokine release and less central memory T phenotype in medium with lower Met, while the exhaustion markers were up-regulated. Furthermore, the gene NKG7, responsible for T cell cytotoxicity, was downregulated in CAR-T cells at low Met concentration due to a decrease in m5C modification. NKG7 overexpression could partially restore the cytotoxicity of CAR-T in low Met. In addition, the anti-tumor efficacy of CAR-T was significantly enhanced when co-cultured with SLC7A5 knockdown LUSC cells at low Met concentration. In conclusion, B7H3 is a prospective target for LUSC, and B7H3-DAP12-CAR-T cells are promising for LUSC treatment. Maintaining Met levels in CAR-T may help overcome TME suppression and improve its clinical application potential.

Silicon and Zinc Fertilizer Application Improves Grain Quality and Aroma in the japonica Rice Variety Nanjing 46.

This study examined how silicon and zinc fertilizers affect the quality and aroma of Nanjing 46. We applied nine different fertilizer treatments, one involving soil topdressing at the top fourth leaf-age stage and one involving foliar spraying during the booting stage of the silicon and zinc fertilizers. We tested the effects of the nine treatments on grain quality and aroma. Silicon and zinc fertilizers significantly affected the brown rice rate, milled rice rate, head rice rate, amylose content, gel consistency, RVA characteristic value, taste value, and aroma but did not affect the chalky grain rate, chalkiness, protein content, rice appearance, hardness, stickiness, balance, peak time, or pasting temperature. Silicon fertilizer decreased the rate of brown rice and milled rice, whereas zinc fertilizer increased the rate of brown rice and milled rice. Silicon and zinc fertilizers improved the head rice rate. Compared to silicon fertilizer, the impact of zinc fertilizer on increasing the head rice rate was more pronounced. Although the effects of silicon and zinc fertilizers on the amylose content and RVA characteristic value varied depending on the treatment, their application could lower the amylose content, increase gel consistency, improve breakdown viscosity, decrease setback viscosity, increase aroma, and improve the taste value of rice.

Characterization and functional analysis of UDP-glycosyltransferases reveal their contribution to phytochemical flavone tolerance in Spodoptera litura.

Efficient detoxification is the key factor for phytophagous insect to adapt to phytochemicals. However, the role of uridine diphosphate (UDP)-glycosyltransferases (UGTs) in insect anti-defense to phytochemical flavone is largely unknown. In this study, 52 UGT genes were identified in Spodoptera litura and they presented evident gene duplication. UGT played a crucial part in larval tolerance to flavone because the enzyme activity and transcriptional level of 77 % UGT members were remarkably upregulated by flavone administration and suppression of UGT enzyme activity and gene expressions significantly increased larval susceptibility to flavone. Bacteria coexpressing UGTs had high survival rates under flavone treatment and flavone was dramatically metabolized by UGT recombinant cells, which indicated the involvement of UGTs in flavone detoxification. What's more, ecdysone pathway was activated by flavone. Topical application of 20-hydroxyecdysone highly upregulated UGT enzyme activity and more than half of UGT expressions. The effects were opposite when ecdysone receptor (EcR) and ultraspiracle (USP)-mediated ecdysone signaling pathway was inhibited. Furtherly, promoter reporter assays of 5 UGT genes showed that their transcription activities were notably increased by cotransfection with EcR and USP. In consequence, this study suggested that UGTs were involved in flavone detoxification and their transcriptional expressions were regulated by ecdysone pathway.

ENPP1 inhibits the transcription activity of the hepatitis B virus pregenomic promoter by upregulating the acetylation of LMNB1.

Current therapies for hepatitis B virus (HBV) infection can slow disease progression but cannot cure the infection, as it is difficult to eliminate or permanently silence HBV covalently closed circular DNA (cccDNA). The interaction between host factors and cccDNA is essential for their formation, stability, and transcriptional activity. Here, we focused on the regulatory role of the host factor ENPP1 and its interacting transcription factor LMNB1 in HBV replication and transcription to better understand the network of host factors that regulate HBV, which may facilitate the development of new antiviral drugs. Overexpression of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in Huh7 cells decreased HBV pregenomic RNA (pgRNA) and hepatitis B core antigen (HBcAg) expression levels, whereas knockdown of ENPP1 increased them. A series of HBV promoter and mutant plasmids were constructed, and a luciferase reporter assay showed that overexpression of ENPP1 caused inhibition of the HBV promoter and its mutants. A DNA pull-down assay showed that lamin B1 (LMNB1), but not ENPP1, interacts directly with the HBV enhancer II/ basic core promoter (EnhII/BCP). ZDOCK and PyMOL software were used to predict the interaction of ENPP1 with LMNB1. Overexpression of LMNB1 inhibited the activity of the HBV promoter and its mutant. The acetylation levels at the amino acids 111K, 261K, and 483K of LMNB1 were reduced compared to the control, and an LMNB1 acetylation mutant containing 111R, 261Q, 261R, 483Q, and 483R showed increased promoter activity. In summary, ENPP1 together with LMNB1 increased the acetylation level at 111K and 261K, and LMNB1 inhibited the activity of HBV promoter and downregulated the expression of pregenomic RNA and HBcAg. Our follow-up studies will investigate the expression, clinical significance, and relevance of ENPP1 and LMNB1 in HBV patient tissues, explore the effect of LMNB1 on post-transcriptional progression, and examine whether ENPP1 can reduce cccDNA levels in the nucleus.

How multiple air pollutants affect hand, foot, and mouth disease incidence in children: assessing effect modification by geographical context in multicity of Sichuan, southwest China.

BACKGROUND: Several studies have suggested a significant association of hand, foot, and mouth disease (HFMD) with ambient air pollutants. Existing studies have characterized the role of air pollutants on HFMD using only risk ratio measures while ignoring the attributable burden. And whether the geographical context (i.e., diverse topographic features) could modulate the relationships is unclear. METHODS: Daily reported childhood HFMD counts, ambient air pollution, and meteorological data during 2015-2017 were collected for each of 21 cities in Sichuan Province. A multistage analysis was carried out in different populations based on geographical context to assess effect modification by topographic conditions. We first constructed a distributed lag nonlinear model (DLNM) for each city to describe the relationships with risk ratio measures. Then, we applied a multivariate meta-regression to estimate the pooled effects of multiple air pollutants on HFMD from the exposure and lagged dimensions. Finally, attributable risks measures were calculated to quantify HFMD burden by air pollution. RESULTS: Based on 207554 HFMD cases in Sichuan Province, significant associations of HFMD with ambient air pollutants were observed mainly at relatively high exposure ranges. The effects of ambient air pollutants on HFMD are most pronounced on lag0 or around lag7, with relative risks gradually approaching the reference line thereafter. The attributable risks of O3 were much greater than those of other air pollutants, particularly in basin and mountain regions. CONCLUSIONS: This study revealed significant pooled relationships between multiple air pollutants and HFMD incidence from both exposure and lag dimensions. However, the specific effects, including RRs and ARs, differ depending on the air pollution variable and geographical context. These findings provide local authorities with more evidence to determine key air pollutants and regions for devising and implementing targeted interventions.

Sirtuin 3 is required for the dexmedetomidine-mediated alleviation of inflammation and oxidative stress in nephritis.

INTRODUCTION: Although sirtuin 3 (SIRT3) is known to be involved in dexmedetomidine (DEX)-mediated alleviation of renal ischemia and reperfusion injury, the influence of the association between DEX and SIRT3 on nephritis development remains unclear. In this study, the role of SIRT3 in DEX-mediated amelioration of inflammation and oxidative stress in nephritis as well as the possible underlying mechanism were explored in vivo and in vitro. METHODS: An animal model of glomerulonephritis was generated by injecting mice with interferon-alpha (IFNα)-expressing adenoviruses, and periodic acid-Schiff staining was then used to reveal pathogenicity-related changes in the renal tissue. Additionally, human embryonic kidney cells (HEK293) and renal mesangial cells (RMCs) were treated with IFNα to establish cell models of inflammation in vitro. RESULTS: DEX administration alleviated glomerulonephritis in the animal model and upregulated SIRT3 expression in the renal tissue. SIRT3 knockdown inhibited the renoprotective effects of DEX against nephritis. IFNα induced inflammation, oxidative stress, and apoptosis in the RMCs and HEK293 cells and reduced their growth, as evidenced by the evaluation of cytokine levels (enzyme-linked immunosorbent assay), reactive oxygen species generation, catalase and superoxide dismutase activities, nuclear factor-erythroid factor 2-related factor 2/heme oxygenase-1 signal transduction, apoptotic cell proportion, and cell viability. In addition to promoting SIRT3 expression, DEX inhibited IFNα-induced inflammation, oxidative stress, and apoptosis in these cells and promoted their viability. SIRT3 knockdown partially reversed the beneficial effects of DEX on RMCs and HEK293 cells. CONCLUSIONS: Our results suggest that DEX exhibits renoprotective activity during nephritis progression, protecting renal cells against inflammatory injury by promoting SIRT3 expression.

Fourteen new 2-benzylbenzofuran glycosides with cardioprotective activity from Heterosmilax yunnanensis.

Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.