CaSTH2 disables CaWRKY40 from activating pepper thermotolerance and immunity against Ralstonia solanacearum via physical interaction.

CaWRKY40 coordinately activates pepper immunity against Ralstonia solanacearum infection (RSI) and high temperature stress (HTS), forms positive feedback loops with other positive regulators and is promoted by CaWRKY27b/CaWRKY28 through physical interactions; however, whether and how it is regulated by negative regulators to function appropriately remain unclear. Herein, we provide evidence that CaWRKY40 is repressed by a SALT TOLERANCE HOMOLOG2 in pepper (CaSTH2). Our data from gene silencing and transient overexpression in pepper and epoptic overexpression in Nicotiana benthamiana plants showed that CaSTH2 acted as negative regulator in immunity against RSI and thermotolerance. Our data from BiFC, CoIP, pull down, and MST indicate that CaSTH2 interacted with CaWRKY40, by which CaWRKY40 was prevented from activating immunity or thermotolerance-related genes. It was also found that CaSTH2 repressed CaWRKY40 at least partially through blocking interaction of CaWRKY40 with CaWRKY27b/CaWRKY28, but not through directly repressing binding of CaWRKY40 to its target genes. The results of study provide new insight into the mechanisms underlying the coordination of pepper immunity and thermotolerance.

LINC00606 promotes glioblastoma progression through sponge miR-486-3p and interaction with ATP11B.

BACKGROUND: LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown. METHODS: The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay. RESULTS: We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein. CONCLUSIONS: Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM.

Pan-Genome Analysis of Wolbachia, Endosymbiont of Diaphorina citri, Reveals Independent Origin in Asia and North America.

Wolbachia, a group of Gram-negative symbiotic bacteria, infects nematodes and a wide range of arthropods. Diaphorina citri Kuwayama, the vector of Candidatus Liberibacter asiaticus (CLas) that causes citrus greening disease, is naturally infected with Wolbachia (wDi). However, the interaction between wDi and D. citri remains poorly understood. In this study, we performed a pan-genome analysis using 65 wDi genomes to gain a comprehensive understanding of wDi. Based on average nucleotide identity (ANI) analysis, we classified the wDi strains into Asia and North America strains. The ANI analysis, principal coordinates analysis (PCoA), and phylogenetic tree analysis supported that the D. citri in Florida did not originate from China. Furthermore, we found that a significant number of core genes were associated with metabolic pathways. Pathways such as thiamine metabolism, type I secretion system, biotin transport, and phospholipid transport were highly conserved across all analyzed wDi genomes. The variation analysis between Asia and North America wDi showed that there were 39,625 single-nucleotide polymorphisms (SNPs), 2153 indels, 10 inversions, 29 translocations, 65 duplications, 10 SV-based insertions, and 4 SV-based deletions. The SV-based insertions and deletions involved genes encoding transposase, phage tail tube protein, ankyrin repeat (ANK) protein, and group II intron-encoded protein. Pan-genome analysis of wDi contributes to our understanding of the geographical population of wDi, the origin of hosts of D. citri, and the interaction between wDi and its host, thus facilitating the development of strategies to control the insects and huanglongbing (HLB).

Application of online to offline teaching mode in the training of non-anesthesiology residents in the department of anesthesiology: a randomized, controlled trial.

Objective: To explore the effect of applying the online to offline teaching mode in the training of non-anesthesiology residents in department of anesthesiology. Trial design: The randomized controlled trial was performed on non-anesthesiology residents from Affiliated Jiangning Hospital of Nanjing Medical University. Methods: All selected residents were randomly divided into the traditional teaching group (Group T) and the online to offline teaching group (Group O) by the random number table method. Traditional teaching mode was used in Group T, while the online to offline teaching mode was used in Group O. The training period lasted for two months. At the end of the training, theoretical and clinical skills were assessed for all residents, and students' satisfaction scores on teaching were investigated from the aspects of teaching mode, stimulating learning interest, improving learning process and teaching satisfaction. The teaching efficiency was compared and analyzed in the two groups. Results: In total, 39 cases in Group O and 38 cases in Group T were included in the statistical analysis. Compared with Group T, theory test scores, clinical skills test scores, and overall scores improved significantly in Group O (82.2 ± 8.1 vs. 91.3 ± 7.6; 85.1 ± 4.7 vs. 93.3 ± 5.4 and 83.4 ± 6.4 vs. 92.1 ± 6.7, respectively, p < 0.01). Compared with Group T, scores on teaching mode, stimulating learning interest, improving learning process and teaching satisfaction were higher in Group O (81.1 ± 6.9 vs. 93.7 ± 5.2; 83.6 ± 5.8 vs. 91.6 ± 6.4; 82.4 ± 5.3 vs. 90.9 ± 4.8 and 82.1 ± 5.9 vs. 92.1 ± 5.5, respectively, p < 0.01). Conclusion: The online to offline teaching mode can improve the level of professional theory and clinical skill operation, and teaching satisfaction of the non-anesthesiology residents in department of anesthesiology, thus improving the teaching effectiveness.

Open-Framework Vanadate as Efficient Ion Exchanger for Uranyl Removal.

The elimination of uranium from radioactive wastewater is crucial for the safe management and operation of environmental remediation. Here, we present a layered vanadate with high acid/base stability, [Me2NH2]V3O7, as an excellent ion exchanger capturing uranyl from highly complex aqueous solutions. The material possesses an indirect band gap, ferromagnetic characteristic and a flower-like morphology comprising parallel nanosheets. The layered structure of [Me2NH2]V3O7 is predominantly upheld by the H-bond interaction between anionic framework [V3O7]nn- and intercalated [Me2NH2]+. The [Me2NH2]+ within [Me2NH2]V3O7 can be readily exchanged with UO22+. [Me2NH2]V3O7 exhibits high exchange capacity (qm = 176.19 mg/g), fast kinetics (within 15 min), high removal efficiencies (>99%), and good selectivity against an excess of interfering ions. It also displays activity for UO22+ ion exchange over a wide pH range (2.00-7.12). More importantly, [Me2NH2]V3O7 has the capability to effectively remove low-concentration uranium, yielding a residual U concentration of 13 ppb, which falls below the EPA-defined acceptable limit of 30 ppb in typical drinking water. [Me2NH2]V3O7 can also efficiently separate UO22+ from Cs+ or Sr2+ achieving the highest separation factors (SFU/Cs of 589 and SFU/Sr of 227) to date. The BOMD and DFT calculations reveal that the driving force of ion exchange is dominated by the interaction between UO22+ and [V3O7]nn-, whereas the ion exchange rate is influenced by the mobility of UO22+ and [Me2NH2]+. Our experimental findings indicate that [Me2NH2]V3O7 can be considered as a promising uranium scavenger for environmental remediation. Additionally, the simulation results provide valuable mechanistic interpretations for ion exchange and serve as a reference for designing novel ion exchangers.

Interferon-induced polarization of M1 macrophages mediates antiviral activity against the hepatitis B virus via the hepcidin-ferroportin axis.

BACKGROUNDS & AIMS: Given its ability to inhibit HBV replication, Interferon alpha (IFN-α) treatment has been confirmed to be effective in managing Chronic Hepatitis B (CHB). However, its underlying mechanisms are incompletely understood. METHODS: Herein, we investigated the antiviral properties of IFN-α by introducing IFN-α expression plasmids into a well-established HBV Hydrodynamic Injection (HDI) mouse model and examined the impact of IFN-α or hepcidin treatment on macrophages derived from THP-1 cells. The cytokine profiles were analyzed using the cytometry microsphere microarray technology, and flow cytometry was used to analyze the polarization of macrophages. Additionally, the IL-6/JAK2/STAT3 signaling pathway and the hepcidin-ferroportin axis were analyzed to better understand the macrophage polarization mechanism. RESULTS: As evidenced by the suppression of HBV replication, injection of an IFN-α expression plasmid and supernatants of IFN-α-treated macrophages exerted anti-HBV effects. The IFN-α treatment up-regulated IL-6 in mice with HBV replication, as well as in IFN-α-treated HepG2 cells and macrophages. Furthermore, JAK2/STAT3 signaling and hepcidin expression was promoted, inducing iron accumulation via the hepcidin-ferroportin axis, which caused the polarization of M1 macrophages. Furthermore, under the effect of IFN-α, IL-6 silencing or blockade downregulated the JAK2/STAT3 signaling pathway and hepcidin, implying that increased hepcidin expression under IFN-α treatment was dependent on the IL-6/JAK2/STAT3 pathway. CONCLUSION: The IL-6/JAK2/STAT3 signaling pathway is activated by IFN-α which induces hepcidin expression. The resulting iron accumulation then induces the polarization of M1 macrophages via the hepcidin-ferroportin axis, yielding an immune response which exerts antiviral effects against HBV replication.

GPNMB Expression Associates with Inferior Prognosis in Patients with Small Cell Lung Cancer.

Purpose: Small cell lung cancer (SCLC) is widely recognized for its propensity for early and frequent metastases, which contribute to its status as a refractory malignancy. While the high expression of GPNMB in SCLC is well-documented, the precise correlation between GPNMB expression and the prognosis of SCLC remains undetermined. Methods: HTG Edge-seq was used to screen the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes (LN). The plasma concentration of GPNMB was measured using enzyme-linked immunosorbent assay (ELISA). The relationship between GPNMB concentration and clinical characteristics, as well as overall survival (OS) was assessed. One-to-one propensity score matching (PSM) was performed to reduce bias from confounding factors between groups. The invasive, migratory, proliferative, and apoptotic abilities of SCLC cells were evaluated using migration and matrigel invasion assays, CCK8 assay and flow cytometry respectively. Results: GPNMB exhibited a significant up-regulation in LN compared to primary SCLC lesions as determined by HTG Edge-seq. Furthermore, patients with extensive disease demonstrated a significantly elevated plasma GPNMB concentration compared to those with local disease (P = 0.043). Additionally, patients with a high baseline plasma GPNMB level exhibited a shorter OS (10.32 vs. 16.10 months, P = 0.0299). Following PSM analysis, the statistical significance of the difference between the two groups persisted (9.43 vs. 15.27 months, P = 0.0146). Notably, both univariate and multivariate analyses confirmed that higher expression of GPNMB served as an independent biomarker for OS before PSM (P = 0.033, HR = 2.304) and after PSM (P = 0.003, HR = 6.190). Additionally, our study revealed that the inhibition of GPNMB expression through the use of siRNA effectively diminished the metastatic and proliferative capabilities of SCLC. Furthermore, this inhibition resulted in an enhanced ability to induce apoptosis. Conclusions: In light of our findings, it can be inferred that the expression of GPNMB is linked to metastasis and an unfavorable prognosis, thus suggesting its potential as a novel therapeutic target in the treatment of SCLC.

Supramolecular Nanofibers Ameliorate Bleomycin-Induced Pulmonary Fibrosis by Restoring Autophagy.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease, with limited therapeutic options available. Impaired autophagy resulting from aberrant TRB3/p62 protein-protein interactions (PPIs) contributes to the progression of IPF. Restoration of autophagy by modulating the TRB3/p62 PPIs has rarely been reported for the treatment of IPF. Herein, peptide nanofibers are developed that specifically bind to TRB3 protein and explored their potential as a therapeutic approach for IPF. By conjugating with the self-assembling fragment (Ac-GFFY), a TRB3-binding peptide motif A2 allows for the formation of nanofibers with a stable α-helix secondary structure. The resulting peptide (Ac-GFFY-A2) nanofibers exhibit specific high-affinity binding to TRB3 protein in saline buffer and better capacity of cellular uptake to A2 peptide. Furthermore, the TRB3-targeting peptide nanofibers efficiently interfere with the aberrant TRB3/p62 PPIs in activated fibroblasts and fibrotic lung tissue of mice, thereby restoring autophagy dysfunction. The TRB3-targeting peptide nanofibers inhibit myofibroblast differentiation, collagen production, and fibroblast migration in vitro is demonstrated, as well as bleomycin-induced pulmonary fibrosis in vivo. This study provides a supramolecular method to modulate PPIs and highlights a promising strategy for treating IPF diseases by restoring autophagy.

Disorder effects on flatbands in moiré superlattices.

Plenty of exotic phenomena in moiré superlattices arise from the emergence of flatbands, but their significance could be diminished by structural disorders that will significantly alter flatbands. Thus, unveiling the effects of disorder on moiré flatbands is crucial. In this work, we explore the disorder effects on two sets of flatbands in silicon-based mismatched moiré superlattices, where the level of disorder is controlled by varying the magnitude of random perturbations of the locations of silicon strips. The results reveal that, after ensemble averaging, the average spectral positions of the four flatbands exhibit stability despite variations in the degree of disorder. However, the δ-like density of states (DOS) related to flatbands in the perfect superlattice evolves into a finite-width envelope of high DOS. By increasing the level of disorder, the width of the DOS envelope increases accordingly. Particularly, we observe a fascinating contrast: the width of bandgap flatbands saturates after initial growth, while the width of dispersive-band-crossed flatbands exhibits a linear increase versus the disorder. This unveils fundamental differences in how flatbands respond to structural imperfections, offering crucial insights into their perturbation characteristics within moiré superlattices. Our work offers new perspectives on flatbands in partially disordered moiré superlattices.

Biomimetic gradient scaffolds for the tissue engineering and regeneration of rotator cuff enthesis.

Rotator cuff tear is one of the most common musculoskeletal disorders, which often results in recurrent shoulder pain and limited movement. Enthesis is a structurally complex and functionally critical interface connecting tendon and bone that plays an essential role in maintaining integrity of the shoulder joint. Despite the availability of advanced surgical procedures for rotator cuff repair, there is a high rate of failure following surgery due to suboptimal enthesis healing and regeneration. Novel strategies based on tissue engineering are gaining popularity in improving tendon-bone interface (TBI) regeneration. Through incorporating physical and biochemical cues into scaffold design which mimics the structure and composition of native enthesis is advantageous to guide specific differentiation of seeding cells and facilitate the formation of functional tissues. In this review, we summarize the current state of research in enthesis tissue engineering highlighting the development and application of biomimetic scaffolds that replicate the gradient TBI. We also discuss the latest techniques for fabricating potential translatable scaffolds such as 3D bioprinting and microfluidic device. While preclinical studies have demonstrated encouraging results of biomimetic gradient scaffolds, the translation of these findings into clinical applications necessitates a comprehensive understanding of their safety and long-term efficacy.

Global trends in pharmacovigilance-related events: a 30-year analysis from the 2019 global burden of disease study.

BACKGROUND: Establishing effective pharmacovigilance systems globally is challenging due to the need for comprehensive epidemiological data on pharmacovigilance-related events, particularly in countries at different stages of development. AIM: This study aimed to determine magnitude and drivers of change in the global and regional burden of pharmacovigilance-related events from 1990 to 2019, analyzing variations between age groups and sex, providing data support for policymakers to adjust their pharmacovigilance policies. METHOD: Pharmacovigilance-related events were defined as Adverse Effects of Medical Treatment (AEMT) and Drug Use Disorders (DUD) in the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Time trend analysis utilized joinpoint regression, age-period-cohort model, and decomposition method. Disease burden was measured in incidence, deaths, and disability-adjusted life years (DALYs). RESULTS: The global burden of pharmacovigilance-related events remained high, driven predominantly by population growth. Children and older adults were identified as particularly susceptible groups. Across various regions and periods of the socio-demographic index (SDI), the risk of death from AEMT showed a decreasing trend. In contrast, the incidence of AEMT and both the incidence and death rates from DUD showed a stable or worsening trend. Significant regional disparities in the burden of these diseases were noted between different SDI levels. CONCLUSION: The study underscores the critical need for robust pharmacovigilance systems worldwide. The observed trends in the burden of pharmacovigilance-related events offer a clear direction for countries to refine and strengthen their pharmacovigilance policies and practices.

Recent Advances in Catalyst Design and Performance Optimization of Nanostructured Cathode Materials in Zinc-Air Batteries.

This review focuses on the advanced design and optimization of nanostructured zinc-air batteries (ZABs), with the aim of boosting their energy storage and conversion capabilities. The findings show that ZABs favor porous nanostructures owing to their large surface area, and this enhances the battery capacity, catalytic activity, and life cycle. In addition, the nanomaterials improve the electrical conductivity, ion transport, and overall battery stability, which crucially reduces dendrite growth on the zinc anodes and improves cycle life and energy efficiency. To obtain a superior performance, the importance of controlling the operational conditions and using custom nanostructural designs, optimal electrode materials, and carefully adjusted electrolytes is highlighted. In conclusion, porous nanostructures and nanoscale materials significantly boost the energy density, longevity, and efficiency of Zn-air batteries. It is suggested that future research should focus on the fundamental design principles of these materials to further enhance the battery performance and drive sustainable energy solutions.

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

BACKGROUND AND OBJECTIVES: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy. METHODS: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency. RESULTS: This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e-16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 µg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 µg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 µg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively. CONCLUSIONS: UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.

Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human Papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventative vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

Study on the regulation of trophoblast activity by abnormally expressed hsa_circ_0024838/miR-543/HIF1A in patients with gestational diabetes mellitus.

INTRODUCTION: This study aimed to screen circRNAs involved in gestational diabetes mellitus (GDM)-related macrosomia. One differentially expressed circRNA (DEC), hsa_circ_0024838, was further tested for its potential role and mechanism in trophoblasts. METHODS: DECs in GDM were selected through GSE182737 and GSE194119. The targets were predicted for DECs and microRNAs (miRNAs), to complete the construction of the circRNA-miRNA-gene network. Functional annotation and related biological pathway enrichment analysis were performed on the target genes of miRNAs in the network. Subsequently, the expression levels of hsa_circ_0024838, miR-543, and HIF1A mRNA were identified by real-time quantitative real-time PCR (RT-qPCR) in GDM patients. Trophoblast activity was assessed via CCK-8 assay, apoptosis assay, and Matrigel invasion assay. Finally, interactions between miR-543 and either hsa_circ_0024838 or HIF1A were confirmed using dual-luciferase reporter assays. RESULTS: A GDM-related circRNA-miRNA-genes interaction network was constructed, consisting of 35 circRNAs, 46 miRNAs, and 122 target genes. Functional enrichment revealed that the enriched pathways were involved in GDM. Hsa_circ_0024838 and HIF1A mRNA expression levels were upregulated in GDM, while miR-543 expression levels were downregulated. A significant positive correlation between hsa_circ_0024838 and newborn weight was observed. Both hsa_circ_0024838 and HIF1A possessed binding sites for miR-543. Overexpressing hsa_circ_0024838 in high-glucose (HG)-cultured trophoblasts can partially reverse HG-induced reduction in trophoblast cell proliferation/migration and increase apoptosis. But this reversal can be negated by co-transfection with miR-543 mimics. The effects of miR-543 can be counteracted by HIF1A. DISCUSSION: Hsa_circ_0024838 can regulate the expression of HIF1A by interacting with miR-543. This regulates the HIF1A signaling pathway and enhance vitality in trophoblast cells.

Development of an Automated Morphometric Approach to Assess Vascular Outcomes following Exposure to Environmental Chemicals in Zebrafish.

BACKGROUND: Disruptions in vascular formation attributable to chemical insults is a pivotal risk factor or potential etiology of developmental defects and various disease settings. Among the thousands of chemicals threatening human health, the highly concerning groups prevalent in the environment and detected in biological monitoring in the general population ought to be prioritized because of their high exposure risks. However, the impacts of a large number of environmental chemicals on vasculature are far from understood. The angioarchitecture complexity and technical limitations make it challenging to analyze the entire vasculature efficiently and identify subtle changes through a high-throughput in vivo assay. OBJECTIVES: We aimed to develop an automated morphometric approach for the vascular profile and assess the vascular morphology of health-concerning environmental chemicals. METHODS: High-resolution images of the entire vasculature in Tg(fli1a:eGFP) zebrafish were collected using a high-content imaging platform. We established a deep learning-based quantitative framework, ECA-ResXUnet, combined with MATLAB to segment the vascular networks and extract features. Vessel scores based on the rates of morphological changes were calculated to rank vascular toxicity. Potential biomarkers were identified by vessel-endothelium-gene-disease integrative analysis. RESULTS: Whole-trunk blood vessels and the cerebral vasculature in larvae exposed to 150 representative chemicals were automatically segmented as comparable to human-level accuracy, with sensitivity and specificity of 95.56% and 95.81%, respectively. Chemical treatments led to heterogeneous vascular patterns manifested by 31 architecture indexes, and the common cardinal vein (CCV) was the most affected vessel. The antipsychotic medicine haloperidol, flame retardant 2,2-bis(chloromethyl)trimethylenebis[bis(2-chloroethyl) phosphate], and tert-butylphenyl diphenyl phosphate ranked as the top three in vessel scores. Pesticides accounted for the largest group, with a vessel score of ≥1, characterized by a remarkable inhibition of subintestinal venous plexus and delayed development of CCV. Multiple-concentration evaluation of nine per- and polyfluoroalkyl substances (PFAS) indicated a low-concentration effect on vascular impairment and a positive association between carbon chain length and benchmark concentration. Target vessel-directed single-cell RNA sequencing of fli1a+ cells from larvae treated with λ-cyhalothrin, perfluorohexanesulfonic acid, or benzylbutyl phthalate, along with vessel-endothelium-gene-disease integrative analysis, uncovered potential associations with vascular disorders and identified biomarker candidates. DISCUSSION: This study provides a novel paradigm for phenotype-driven screenings of vascular-disrupting chemicals by converging morphological and transcriptomic profiles at a high-resolution level, serving as a powerful tool for large-scale toxicity tests. Our approach and the high-quality morphometric data facilitate the precise evaluation of vascular effects caused by environmental chemicals. https://doi.org/10.1289/EHP13214.

Prognostic value of pulmonary hypertension with a nomogram in acute myocardial infarction patients with reduced left ventricular function.

Background: Pulmonary hypertension (PH) is a common prognostic factor for acute myocardial infarction (AMI) and its impact may increase when combined with reduced left ventricular function. Methods: This retrospective cohort study enrolled AMI patients with reduced left ventricular function at the First Affiliated Hospital of Xi'an Jiaotong University from January 2018 to January 2022. Basing on the systolic pulmonary artery pressure assessed by echocardiogram, patients were assigned to the PH group and control group. Propensity score matching (PSM) in sex, age and Killip classification was used to match patients between two groups. The primary outcome was defined as 1-year mortality rate, which were obtained from medical records and phone calls. Results: After the PSM, a total of 504 patients were enrolled, with 252 in both groups. No significant difference of the adjusted factors was observed between the two groups. The 1-year mortality rate was significantly higher in the PH group compared with the control group (15.5% vs. 5.3%, P < 0.001). In the cox regression analysis, PH (HR: 2.068, 95% CI: 1.028-4.161, P = 0.042) was identified as an independent risk factor, alongside left ventricular ejection fraction (HR: 0.948; 95% CI: 0.919-0.979; P < 0.001), creatine kinase-MB isoenzymes (HR: 1.002; 95% CI: 1.000-1.003; P = 0.010) and pro-brain natriuretic peptide (HR: 1.000; 95% CI: 1.000-1.000; P = 0.018) for the 1-year mortality in AMI patients with reduced left ventricular function. A nomogram was established using the above factors to predict the 1-year mortality risks in these patients. Conclusion: AMI patients with reduced left ventricular function showed higher 1-year mortality rate when concomitant with PH. Four independent risk factors, including PH, were identified and used to establish a nomogram to predict the 1-year mortality risks in these patients. Clinical Trialsgov ID: NCT06186713.