FoxK1 and FoxK2 cooperate with ORF45 to promote late lytic replication of Kaposi's sarcoma-associated herpesvirus.

Lytic replication is essential for persistent infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the mechanism involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV open reading frame 45 (ORF45) plays important roles in late transcription and translation. In the present study, we revealed that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production, and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently, FoxK1 and FoxK2 promote late viral gene expression to facilitate KSHV lytic replication.IMPORTANCEThe forkhead box proteins FoxK1 and FoxK2 can act as transcriptional inhibitors or activators to regulate several important processes, including aerobic glycolysis, metabolism, autophagy, and antiviral responses. However, the subversion and functions of FoxK1 and FoxK2 during KSHV infection and the pathogenesis of related diseases remain unknown. Here, we revealed that ORF45 binds to FoxK1 and FoxK2 and increases their transcriptional activity during KSHV lytic replication; consequently, FoxK1 and FoxK2 bind to late viral promoters and cooperate with ORF45 to promote late lytic gene expression. Our findings reveal two new ORF45 partners and a new function of ORF45 in which it utilizes FoxK1 and FoxK2 to promote transcription during late KSHV lytic replication.

Artificial trans-kingdom RNAi of FolRDR1 is a potential strategy to control tomato wilt disease.

Tomato is cultivated worldwide as a nutrient-rich vegetable crop. Tomato wilt disease caused by Fusarium oxysporum f.sp. Lycopersici (Fol) is one of the most serious fungal diseases posing threats to tomato production. Recently, the development of Spray-Induced Gene Silencing (SIGS) directs a novel plant disease management by generating an efficient and environmental friendly biocontrol agent. Here, we characterized that FolRDR1 (RNA-dependent RNA polymerase 1) mediated the pathogen invasion to the host plant tomato, and played as an essential regulator in pathogen development and pathogenicity. Our fluorescence tracing data further presented that effective uptakes of FolRDR1-dsRNAs were observed in both Fol and tomato tissues. Subsequently, exogenous application of FolRDR1-dsRNAs on pre-Fol-infected tomato leaves resulted in significant alleviation of tomato wilt disease symptoms. Particularly, FolRDR1-RNAi was highly specific without sequence off-target in related plants. Our results of pathogen gene-targeting RNAi have provided a new strategy for tomato wilt disease management by developing an environmentally-friendly biocontrol agent.

Safety and efficacy of an anti-human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Deciphering the Mechanisms of Photo-Enhanced Catalytic Activities in Plasmonic Pd-Au Heteromeric Nanozymes for Colorimetric Analysis.

The growing demand for highly active nanozymes in various fields has led to the development of several strategies to enhance their activity. Plasmonic enhancement, a strategy used in heterogenous catalysis, represents a promising strategy to boost the activity of nanozymes. Herein, Pd-Au heteromeric nanoparticles (Pd-Au dimers) with well-defined heterointerfaces have been explored as plasmonic nanozymes. As a model system, the Pd-Au dimers with integrated peroxidase (POD)-like activity and plasmonic activity are used to investigate the effect of plasmons on enhancing the activity of nanozymes under visible light irradiation. Mechanistic studies revealed that the generation of hot electron-hole pairs plays a dominant role in plasmonic effect, and it greatly enhances the decomposition of H2 O2 to the reactive oxygen species (ROS) intermediates (•OH, •O2 - and 1 O2 ), leading to elevated POD-like activity of the Pd-Au dimers. Finally, the Pd-Au dimers are applied in the plasmon-enhanced colorimetric method for the detection of alkaline phosphatase, exhibiting broad linear range and low detection limit. This study not only provides a straightforward approach for regulating nanozyme activity through plasmonic heterostructures but also sheds light on the mechanism of plasmon-enhanced catalysis of nanozymes.

The Peptide DHα-(4-pentenyl)-ANPQIR-NH2 Exhibits Antifibrotic Activity in Multiple Pulmonary Fibrosis Models Induced by Particulate and Soluble Chemical Fibrogenic Agents.

Interstitial lung diseases (ILDs) are a group of restrictive lung diseases characterized by interstitial inflammation and pulmonary fibrosis. The incidence of ILDs associated with exposure to multiple hazards such as inhaled particles, fibers, and ingested soluble chemicals is increasing yearly, and there are no ideal drugs currently available. Our previous research showed that the novel and low-toxicity peptide DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) had a strong antifibrotic effect on a bleomycin-induced murine model. Based on the druggability of DR3penA, we sought to investigate its effects on respirable particulate silicon dioxide (SiO2)- and soluble chemical paraquat (PQ)-induced pulmonary fibrosis in this study by using western blot, quantitative reverse-transcription polymerase chain reaction (RT-qPCR), immunofluorescence, H&E and Masson staining, immunohistochemistry, and serum biochemical assays. The results showed that DR3penA alleviated the extent of fibrosis by inhibiting the expression of fibronectin and collagen I and suppressed oxidative stress and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Further study revealed that DR3penA may mitigate pulmonary fibrosis by negatively regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and mitogen-activated protein kinase (MAPK) pathway. Unexpectedly, through the conversion of drug bioavailability under different routes of administration, DR3penA exerted antifibrotic effects equivalent to those of the positive control drug pirfenidone (PFD) at lower doses. In summary, DR3penA may be a promising lead compound for various fibrotic ILDs. SIGNIFICANCE STATEMENT: Our study verified that DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) exhibited positive antifibrotic activity in pulmonary fibrosis induced by silicon dioxide (SiO2) particles and soluble chemical paraquat (PQ) and demonstrated a low-dose advantage compared to the small-molecule drug pirfenidone (PFD). The peptide DR3penA can be further developed for the treatment of multiple fibrotic lung diseases.

Identification of macrophage driver genes in fibrosis caused by different heart diseases based on omics integration.

BACKGROUND: Myocardial fibrosis, a hallmark of heart disease, is closely associated with macrophages, yet the genetic pathophysiology remains incompletely understood. In this study, we utilized integrated single-cell transcriptomics and bulk RNA-seq analysis to investigate the relationship between macrophages and myocardial fibrosis across omics integration. METHODS: We examined and curated existing single-cell data from dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), myocardial infarction (MI), and heart failure (HF), and analyzed the integrated data using cell communication, transcription factor identification, high dimensional weighted gene co-expression network analysis (hdWGCNA), and functional enrichment to elucidate the drivers of macrophage polarization and the macrophage-to-myofibroblast transition (MMT). Additionally, we assessed the accuracy of single-cell data from the perspective of driving factors, cell typing, anti-fibrosis performance of left ventricular assist device (LVAD). Candidate drugs were screened using L1000FWD. RESULTS: All four heart diseases exhibit myocardial fibrosis, with only MI showing an increase in macrophage proportions. Macrophages participate in myocardial fibrosis through various fibrogenic molecules, especially evident in DCM and MI. Abnormal RNA metabolism and dysregulated transcription are significant drivers of macrophage-mediated fibrosis. Furthermore, profibrotic macrophages exhibit M1 polarization and increased MMT. In HF patients, those responding to LVAD therapy showed a significant decrease in driver gene expression, M1 polarization, and MMT. Drug repurposing identified cinobufagin as a potential therapeutic agent. CONCLUSION: Using integrated single-cell transcriptomics, we identified the drivers of macrophage-mediated myocardial fibrosis in four heart diseases and confirmed the therapeutic effect of LVAD on improving HF with single-cell accuracy, providing novel insights into the diagnosis and treatment of myocardial fibrosis.

A nomogram based on clinical factors and CT radiomics for predicting anti-MDA5+ DM complicated by RP-ILD.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) DM complicated by rapidly progressive interstitial lung disease (RP-ILD) has a high incidence and poor prognosis. The objective of this study was to establish a model for the prediction and early diagnosis of anti-MDA5+ DM-associated RP-ILD based on clinical manifestations and imaging features. METHODS: A total of 103 patients with anti-MDA5+ DM were included. The patients were randomly split into training and testing sets of 72 and 31 patients, respectively. After image analysis, we collected clinical, imaging and radiomics features from each patient. Feature selection was performed first with the minimum redundancy and maximum relevance algorithm and then with the best subset selection method. The final remaining features comprised the radscore. A clinical model and imaging model were then constructed with the selected independent risk factors for the prediction of non-RP-ILD and RP-ILD. We also combined these models in different ways and compared their predictive abilities. A nomogram was also established. The predictive performances of the models were assessed based on receiver operating characteristics curves, calibration curves, discriminability and clinical utility. RESULTS: The analyses showed that two clinical factors, dyspnoea (P = 0.000) and duration of illness in months (P = 0.001), and three radiomics features (P = 0.001, 0.044 and 0.008, separately) were independent predictors of non-RP-ILD and RP-ILD. However, no imaging features were significantly different between the two groups. The radiomics model built with the three radiomics features performed worse than the clinical model and showed areas under the curve (AUCs) of 0.805 and 0.754 in the training and test sets, respectively. The clinical model demonstrated a good predictive ability for RP-ILD in MDA5+ DM patients, with an AUC, sensitivity, specificity and accuracy of 0.954, 0.931, 0.837 and 0.847 in the training set and 0.890, 0.875, 0.800 and 0.774 in the testing set, respectively. The combination model built with clinical and radiomics features performed slightly better than the clinical model, with an AUC, sensitivity, specificity and accuracy of 0.994, 0.966, 0.977 and 0.931 in the training set and 0.890, 0.812, 1.000 and 0.839 in the testing set, respectively. The calibration curve and decision curve analyses showed satisfactory consistency and clinical utility of the nomogram. CONCLUSION: Our results suggest that the combination model built with clinical and radiomics features could reliably predict the occurrence of RP-ILD in MDA5+ DM patients.

The novel peptide DR4penA attenuates the bleomycin- and paraquat-induced pulmonary fibrosis by suppressing the TGF-ß/Smad signaling pathway.

Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR-NH2 ), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure-activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (α-(4-pentenyl)-Ala) into DR8 and screened the novel peptide DR4penA (DHNα-(4-pentenyl)-APQIR-NH2 ), which had higher anti-PF activity, higher antioxidant activity and a longer half-life than DR8. Notably, DR4penA attenuated bleomycin- and paraquat-induced PF, and the anti-PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF-ß/Smad pathway in TGF-ß1-induced A549 cells and paraquat-induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.

Comprehensive Analysis Identifies Hyaluronan Mediated Motility Receptor and Cell Division Cycle 25C as Potential Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, but its pathogenic mechanisms remain unclear. This study aimed to identify the potential biomarkers underlying the diagnosis and treatment of HNSCC. METHODS: Weighted gene co-expression network analysis (WGCNA) followed by pathway enrichment analysis, analysis of infiltrating immune cells, survival analysis, and methylation analysis were applied to identify the potential hub genes underlying the prognosis of HNSCC. The expression of hub genes was validated by immunofluorescence staining. RESULTS: A total of 10,274 differentially expressed genes (DEGs) were identified. Through WGCNA, the yellow module (R2 = 0.33, P = 2e-14) was confirmed to be the most significantly associated with the histological grade of HNSCC, and the "Cell Cycle" proved to be the most enriched signaling pathway. Based on the results of survival analysis and immune cell infiltration, 10 hub genes (HMMR, CENPK, AURKA, CDC25C, FEN1, CKS1B, MAJIN, PCLAF, SPC25, and STAG3) were identified. Eight of these (excluding MAJIN and STAG3) were confirmed by performing survival analysis using another dataset (GSE41613). Further, we identified 4 methylation loci in 3 hub genes (cg15122828 and cg20554926 in HMMR, cg12519992 in CDC25C, and cg2655739 in KIAA0101/PCLAF) as being significantly related to survival. Finally, we demonstrated the high mRNA and protein expression of HMMR and CDC25C in HNSCC patients. CONCLUSION: Two real hub genes (HMMR and CDC25C) and 3 methylation loci were identified that could potentially serve as prognostic and therapeutic targets for HNSCC, which is significant for studying the pathological mechanisms underlying HNSCC and for developing novel therapies for this disease.

Preparation of cellulose acetate based flexible separator and its application in zinc-air batteries.

Flexible solid-state zinc-air batteries as a wearable energy storage device with great potential, and their separators, which control ion permeability, inhibit zinc dendrite generation, and regulate catalytic active sites, have been developed as gel electrolyte separators with high retention of electrolyte uptake. However, the gel electrolyte separator still has problems such as poor affinity with the electrolyte and poor ionic conductivity, which limits its further application. In order to further improve the electrolyte absorption, ionic conductivity and mechanical strength of cellulose acetate(CA)/polyvinyl alcohol (PVA) nanofibers, TiO2was added to CA/PVA to increase the porosity, and glutaraldehyde (GA) was used to modify the CA/PVA/TiO2separator by acetal reaction with CA and PVA to make the molecules closely linked. The results shows that the optimal mass fractions of TiO2and GA were 2% and 5%, respectively. At this time, the porosity and absorption rate of the separator increased from 48% to 68.2% and 142.4% to 285.3%, respectively. The discharge capacity reached 179 mA cm-3, and the cycle stability rate was 89% after 7 stable constant current charge/discharge cycles.

Effect of apheresis plasma donation on plasma uric acid levels, the lipid profile, and major plasma proteins in plasma donors in China: A multicenter, prospective cohort study.

Abnormal plasma uric acid (UA) levels, the lipid profile, and plasma proteins in blood are associated with a range of adverse health outcomes. This multicenter, prospective cohort study aimed to determine the possible effects of multiple apheresis plasma donations on plasma UA levels, the lipid profile, and major proteins in plasma donors. Participants were enrolled from 1 April 2021 to 31 August 2022. When their plasma UA (men: >420 µmol/L, women: >360 µmol/L) and/or lipid levels (total cholesterol [TC]: ≥6.2 mmol/L, triglycerides [TGs]: ≥2.3 mmol/L, low-density lipoprotein cholesterol: ≥4.1 mmol/L, or high-density lipoprotein cholesterol [HDL-C]: <1.0 mmol/L) were abnormal at their first plasma donation, the enrolled participants were followed up until they had completed 10 plasma donations. A total of 11485 participants were enrolled, of whom 1861 met the inclusion criteria. During the study period, 320 donors completed 10 plasma donations. None of the participants took any corrective medicine for their abnormal index. The measured parameters were significantly different from the first to the tenth plasma donations (donors with asymptomatic hyperuricemia: UA, P < 0.001; donors with asymptomatic hyperlipidemia: HDL-C, P < 0.001; TC, P = 0.025; TGs, P < 0.001; apolipoprotein B, P = 0.025; all of the plasma donors, immunoglobulin G, P < 0.001). The levels of HDL-C, TC, and apolipoprotein B were increased, and the levels of UA, TGs, and immunoglobulin G were decreased over this time. However, immunoglobulin G levels were still in the normal range. Moreover, the changes in these parameters were closely associated with the frequency of plasma donation during the study period. Repeated apheresis plasma donations can reduce plasma UA and TG levels and increase HDL-C levels; and further evaluation of the clinical significance with a larger sample size is required.

Effect of different screen brightness and devices on online visual acuity test.

PURPOSE: This study aimed to study the difference in test results of online visual acuity (VA) test under different devices and screen brightness conditions and to compare online VA test with Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: Healthy volunteers with the best corrected VA of 0.0 LogMAR or higher were recruited. VAs under ETDRS were tested first, and then online VA test (the Stanford Acuity Test, StAT) visual acuities using iPad Air2 and Microsoft Surface pro4 under 50% and 100% screen brightness were performed. The VA results and the testing times were compared between different devices and screen brightness conditions. RESULTS: A total of 101 eyes were included in this study. The VA results measured by the StAT were better than those of ETDRS. The VA results measured at 100% screen brightness were better than those of 50% brightness (mean difference, 0.013 logMAR at most, less than 1 letter); the VA results measured by iPad Air2 were better than those of Surface pro4 (mean difference, -0.009 logMAR at most, less than 1 letter). Significantly less time was spent on VA testing under StAT than that under ETDRS. CONCLUSION: The impact of screen brightness and the device on the VA results generated by online VA tests was clinically insignificant. In addition, online VA tests are found to be reliable and more time efficient than ETDRS.

Potential dynamic corneal response parameters for myopia: relationships between axial length with whole eye movement at the first and second applanations and the highest concavity.

PURPOSE: To investigate the correlation between whole eye movement (WEM) parameters measured using Corvis ST and axial length (AL) to explore whether AL affects WEMs. METHODS: This single-center, cross-sectional study included data from healthy subjects and patients preparing for refractive surgery at the Qingdao Eye Hospital of Shandong First Medical University. Data were collected from July 2021 to April 2022. We first determined the correlations of WEMs at the time of corneal first applanation (A1_WEM), highest concavity (HC_WEM), and second applanation (A2_WEM), as well as the maximum value of WEM (WEM_Max) with AL. Subsequently, we established a series of regression models to analyze the relationships between different WEM values and AL. RESULTS: AL was negatively correlated with HC_WEM, A2_WEM, and WEM_Max (r = - 0.28, - 0.23, and - 0.22, respectively; P < 0.001). The correlation between AL and A1_WEM was not significant (P = 0.77). According to the adjusted regression models, AL was negatively associated with HC_WEM (Model 2: ß = -7.39, P < 0.001) and WEM_Max (Model 4: ß = -3.52, P = 0.02), while the associations of AL with A1_WEM (Model 1: P = 0.61) and A2_WEM (Model 3: P = 0.23) were not significant. CONCLUSIONS: AL is an independent negative influencing factor for HC_WEM. WEM is a potentially useful parameter that reflects the biomechanical properties of the eye behind the cornea in myopia.

Comparatively analysing the postoperative optical performance of different intraocular lenses: a prospective observational study.

BACKGROUND: Postoperative performance, including best corrected distance visual acuity (BCDVA) and optical metrics (from the OQAS and iTrace devices), was compared among 4 different intraocular lenses (IOLs). METHODS: This prospective observational study included 104 eyes from 104 subjects who underwent cataract surgery combined with implantation of 4 different IOLs: monofocal (Mon) IOLs, segmental refractive (SegRef) IOLs, diffractive (Dif) IOLs and extended depth of focus (EDoF) IOLs. Postoperative BCDVA and optical metrics were collected at the 6th month. The OQAS optical metrics included the objective scattering index (OSI), Strehl ratio (SR), modulation transfer function (MTF) cut-off frequency, and predicted visual acuity (PVA); the iTrace optical metrics included blur/double vision, glare/halo, starburst, mixed focus, night myopia, and night hyperopia. RESULTS: There was no significant difference in BCDVA among the 4 groups (P = 0.059; power = 70.3%). Differences were observed in all OQAS optical metrics among the groups (all P < 0.001). Overall, Mon IOLs and EDoF IOLs exhibited better performance than Dif IOLs and SegRef IOLs. Starburst was the only iTrace optical metric that differed among the groups (P < 0.001): SegRef IOLs caused more starbursts than Mon IOLs (P = 0.001), Dif IOLs (P = 0.006) and EDoF IOLs (P < 0.001). Spearman rank correlation analysis was used to determine the relationships among the iTrace optical metrics, OQAS optical metrics and BCDVA: starburst was negatively correlated with BCDVA, PVA at contrasts of 100% and 20%, OSI, and MTF cut-off frequency (all P ≤ 0.001); mixed focus was positively correlated with BCDVA, PVA at contrasts of 100% and 20%, OSI, and MTF cut-off frequency (all P ≤ 0.001). CONCLUSIONS: Postoperative BCDVA and optical metrics varied among the different IOLs, which should be taken into account in the selection and management of IOLs for cataract patients. TRIAL REGISTRATION: This study was approved by the First Affiliated Hospital of Guangzhou Medical University Ethical Review Board (No. 50 2022).

SCAPE: a mixture model revealing single-cell polyadenylation diversity and cellular dynamics during cell differentiation and reprogramming.

Alternative polyadenylation increases transcript diversities at the 3' end, regulating biological processes including cell differentiation, embryonic development and cancer progression. Here, we present a Bayesian method SCAPE, which enables de novo identification and quantification of polyadenylation (pA) sites at single-cell level by utilizing insert size information. We demonstrated its accuracy and robustness and identified 31 558 sites from 36 mouse organs, 43.8% (13 807) of which were novel. We illustrated that APA isoforms were associated with miRNAs binding and regulated in tissue-, cell type-and tumor-specific manners where no difference was found at gene expression level, providing an extra layer of information for cell clustering. Furthermore, we found genome-wide dynamic changes of APA usage during erythropoiesis and induced pluripotent stem cell (iPSC) differentiation, suggesting APA contributes to the functional flexibility and diversity of single cells. We expect SCAPE to aid the analyses of cellular dynamics and diversities in health and disease.

Phthalate exposure and subfecundity in preconception couples: A nested case-control study.

BACKGROUND: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples. METHODS: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples' exposure to PAEs on subfecundity. RESULTS: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10-5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36-6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38-2.26, p<0.001), male (aOR=1.58, 95% CI: 1.20-2.08, p=0.001), and couple (aOR=2.39, 95% CI: 1.61-3.52, p<0.001). The BKMR model found a positive combined effect of mixed exposure to PAEs on the risk of subfecundity. CONCLUSIONS: PAEs increase the risk of subfecundity in preconception couples. Our research reinforced the need of monitoring PAE exposure for the purpose of improving human reproductive health.

Overexpression of a nuclear receptor HR96 contributes to spirodiclofen susceptibility in Panonychus citri (McGregor).

The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.

Melatonin activates Nrf2/HO-1 signalling pathway to antagonizes oxidative stress-induced injury via melatonin receptor 1 (MT1) in cryopreserved mice ovarian tissue.

Our previous research has shown that melatonin (MLT) can reduce cryopreserved ovarian damage in mice. Yet, the molecular mechanism of MLT protection is still unclear. Some studies have shown that melatonin receptor 1 (MT1) is very important for animal reproductive system. To evaluate whether MLT exerts its protective effect on cryopreserved mice ovarian tissue via MT1, we added antagonist of MT1/MT2 (Luzindor) or antagonist of MT2 (4P-PDOT) to the freezing solution, followed by cryopreservation and thawing of ovarian tissue. The levels of total superoxide dismutase (T-SOD), catalase (CAT), nitric oxide (NO) and malondialdehyde (MDA) were detected. Besides, by using RT-PCR and Western blotting, the expression of Bcl-2, Bax and Nrf2/HO-1 signalling pathway-related proteins was detected. These findings demonstrated that compared with the melatonin group, the addition of Luzindor increased apoptosis, NO and MDA activities, decreased CAT and T-SOD activities and inhibited Nrf2/HO-1 signalling pathway. In conclusion, melatonin can play a protective role in cryopreserved ovarian tissue of mice through MT1 receptor.

Small Things Make a Big Difference: Conductive Cross-Linking Sodium Alginate@MXene Binder Enables High-Volumetric-Capacity and High-Mass-Loading Li-S Battery.

Binders are crucial for maintaining the integrity of an electrode, and there is a growing need for integrating multiple desirable properties into the binder for high-energy batteries, yet significant challenges remain. Here, we successfully synthesized a new binder by cross-linking sodium alginate (SA) with MXene materials (Ti3C2Tx). Besides the improved adhesion and mechanical properties, the integrated SA@Ti3C2Tx binder demonstrates much improved electronic conductivity, which enables ruling out the fluffy conductive additive from the electrode component with enhanced volumetric capacity. When SA@Ti3C2Tx is used to fabricate sulfur (S) cathodes, the conductive-additive-free electrode demonstrates extremely high capacity (1422 mAh cm-3/24.5 mAh cm-2) under an S loading of 17.2 mg cm-2 for Li-S batteries. Impressively, the SA@Ti3C2Tx binder shows remarkable feasibility in other battery systems such as Na-S and LiFePO4 batteries. The proposed strategy of constructing a cross-linking conductive binder opens new possibilities for designing high-mass-loading electrodes with high volumetric capacity.