Naringin as a natural candidate for anti-autoimmune hepatitis: Inhibitory potency and hepatoprotective mechanism.

BACKGROUND: Autoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood. PURPOSE: We aim to determine the role of naringin in AIH, exploring its targets and actions in this disease. METHODS: Network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms. RESULTS: Naringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1ß, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1ß, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1ß-naringin complexes. Naringin's hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1ß, IL-6, and TNF-α. CONCLUSION: Our data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.

Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg.

Endothelial cells are a heterogeneous population with various organ-specific and conserved functions that are critical to organ development, function, and regeneration. Here we report a Sox17-Erg direct reprogramming approach that uses cardiac fibroblasts to create differentiated endothelial cells that demonstrate endothelial-like molecular and physiological functions in vitro and in vivo. Injection of these induced endothelial cells into myocardial infarct sites after injury results in improved vascular perfusion of the scar region. Furthermore, we use genomic analyses to illustrate that Sox17-Erg reprogramming instructs cardiac fibroblasts toward an arterial-like identity. This results in a more efficient direct conversion of fibroblasts into endothelial-like cells when compared to traditional Etv2-based reprogramming. Overall, this Sox17-Erg direct reprogramming strategy offers a robust tool to generate endothelial cells both in vitro and in vivo, and has the potential to be used in repairing injured tissue.

Wastewater tiling amplicon sequencing in sentinel sites reveals longitudinal dynamics of SARS-CoV-2 variants prevalence.

The ongoing evolution of SARS-CoV-2 is a significant concern, especially with the decrease in clinical sequencing efforts, which impedes the ability of public health sectors to prepare for the emergence of new variants and potential COVID-19 outbreaks. Wastewater-based epidemiology (WBE) has been proposed as a surveillance program to detect and monitor the SARS-CoV-2 variants being transmitted in communities. However, research is limited in evaluating the effectiveness of wastewater collection at sentinel sites for monitoring disease prevalence and variant dynamics, especially in terms of inferring the epidemic patterns on a broader scale, such as at the state/province level. This study utilized a multiplexed tiling amplicon-based sequencing (ATOPlex) to track the longitudinal dynamics of variant of concern (VOC) in wastewater collected from municipalities in Queensland, Australia, spanning from 2020 to 2022. We demonstrated that wastewater epidemiology measured by ATOPlex exhibited a strong and consistent correlation with the number of daily confirmed cases. The VOC dynamics observed in wastewater closely aligned with the dynamic profile reported by clinical sequencing. Wastewater sequencing has the potential to provide early warning information for emerging variants. These findings suggest that WBE at sentinel sites, coupled with sensitive sequencing methods, provides a reliable and long-term disease surveillance strategy.

Appearance-based Gaze Estimation with Deep Learning: A Review and Benchmark.

Human gaze provides valuable information on human focus and intentions, making it a crucial area of research. Recently, deep learning has revolutionized appearance-based gaze estimation. However, due to the unique features of gaze estimation research, such as the unfair comparison between 2D gaze positions and 3D gaze vectors and the different pre-processing and post-processing methods, there is a lack of a definitive guideline for developing deep learning-based gaze estimation algorithms. In this paper, we present a systematic review of the appearance-based gaze estimation methods using deep learning. Firstly, we survey the existing gaze estimation algorithms along the typical gaze estimation pipeline: deep feature extraction, deep learning model design, personal calibration and platforms. Secondly, to fairly compare the performance of different approaches, we summarize the data pre-processing and post-processing methods, including face/eye detection, data rectification, 2D/3D gaze conversion and gaze origin conversion. Finally, we set up a comprehensive benchmark for deep learning-based gaze estimation. We characterize all the public datasets and provide the source code of typical gaze estimation algorithms. This paper serves not only as a reference to develop deep learning-based gaze estimation methods, but also a guideline for future gaze estimation research. The project web page can be found at https://phi-ai.buaa.edu.cn/Gazehub/.

Single-cell chromatin profiling reveals genetic programs activating proregenerative states in nonmyocyte cells.

Cardiac regeneration requires coordinated participation of multiple cell types whereby their communications result in transient activation of proregenerative cell states. Although the molecular characteristics and lineage origins of these activated cell states and their contribution to cardiac regeneration have been studied, the extracellular signaling and the intrinsic genetic program underlying the activation of the transient functional cell states remain largely unexplored. In this study, we delineated the chromatin landscapes of the noncardiomyocytes (nonCMs) of the regenerating heart at the single-cell level and inferred the cis-regulatory architectures and trans-acting factors that control cell type-specific gene expression programs. Moreover, further motif analysis and cell-specific genetic manipulations suggest that the macrophage-derived inflammatory signal tumor necrosis factor-α, acting via its downstream transcription factor complex activator protein-1, functions cooperatively with discrete transcription regulators to activate respective nonCM cell types critical for cardiac regeneration. Thus, our study defines the regulatory architectures and intercellular communication principles in zebrafish heart regeneration.

Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis.

Immunotherapy targeting PD-L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine-threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD-L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN-γ-mediated PD-L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti-PD-1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD-L1/PD-1 signaling and is a promising target for combined immunotherapy.

Epigenetic Regulation of Cardiomyocyte Maturation by Arginine Methyltransferase CARM1.

BACKGROUND: During the neonatal stage, the cardiomyocyte undergoes a constellation of molecular, cytoarchitectural, and functional changes known collectively as cardiomyocyte maturation to increase myocardial contractility and cardiac output. Despite the importance of cardiomyocyte maturation, the molecular mechanisms governing this critical process remain largely unexplored. METHODS: We leveraged an in vivo mosaic knockout system to characterize the role of Carm1, the founding member of protein arginine methyltransferase, in cardiomyocyte maturation. Using a battery of assays, including immunohistochemistry, immuno-electron microscopy imaging, and action potential recording, we assessed the effect of loss of Carm1 function on cardiomyocyte cell growth, myofibril expansion, T-tubule formation, and electrophysiological maturation. Genome-wide transcriptome profiling, H3R17me2a chromatin immunoprecipitation followed by sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing were used to investigate the mechanisms by which CARM1 (coactivator-associated arginine methyltransferase 1) regulates cardiomyocyte maturation. Finally, we interrogated the human syntenic region to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks for single-nucleotide polymorphisms associated with human heart diseases. RESULTS: We report that mosaic ablation of Carm1 disrupts multiple aspects of cardiomyocyte maturation cell autonomously, leading to reduced cardiomyocyte size and sarcomere thickness, severe loss and disorganization of T tubules, and compromised electrophysiological maturation. Genomics study demonstrates that CARM1 directly activates genes that underlie cardiomyocyte cytoarchitectural and electrophysiological maturation. Moreover, our study reveals significant enrichment of human heart disease-associated single-nucleotide polymorphisms in the human genomic region syntenic to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks. CONCLUSIONS: This study establishes a critical and multifaceted role for CARM1 in regulating cardiomyocyte maturation and demonstrates that deregulation of CARM1-dependent cardiomyocyte maturation gene expression may contribute to human heart diseases.

PnP-GA+: Plug-and-Play Domain Adaptation for Gaze Estimation Using Model Variants.

Appearance-based gaze estimation has garnered increasing attention in recent years. However, deep learning-based gaze estimation models still suffer from suboptimal performance when deployed in new domains, e.g., unseen environments or individuals. In our previous work, we took this challenge for the first time by introducing a plug-and-play method (PnP-GA) to adapt the gaze estimation model to new domains. The core concept of PnP-GA is to leverage the diversity brought by a group of model variants to enhance the adaptability to diverse environments. In this article, we propose the PnP-GA+ by extending our approach to explore the impact of assembling model variants using three additional perspectives: color space, data augmentation, and model structure. Moreover, we propose an intra-group attention module that dynamically optimizes pseudo-labeling during adaptation. Experimental results demonstrate that by directly plugging several existing gaze estimation networks into the PnP-GA+ framework, it outperforms state-of-the-art domain adaptation approaches on four standard gaze domain adaptation tasks on public datasets. Our method consistently enhances cross-domain performance, and its versatility is improved through various ways of assembling the model group.

cbPPGGAN: A Generic Enhancement Framework for Unpaired Pulse Waveforms in Camera-Based Photoplethysmography.

Camera-based photoplethysmography (cbP PG) is a non-contact technique that measures cardiac-related blood volume alterations in skin surface vessels through the analysis of facial videos. While traditional approaches can estimate heart rate (HR) under different illuminations, their accuracy can be affected by motion artifacts, leading to poor waveform fidelity and hindering further analysis of heart rate variability (HRV); deep learning-based approaches reconstruct high-quality pulse waveform, yet their performance significantly degrades under illumination variations. In this work, we aim to leverage the strength of these two methods and propose a framework that possesses favorable generalization capabilities while maintaining waveform fidelity. For this purpose, we propose the cbPPGGAN, an enhancement framework for cbPPG that enables the flexible incorporation of both unpaired and paired data sources in the training process. Based on the waveforms extracted by traditional approaches, the cbPPGGAN reconstructs high-quality waveforms that enable accurate HR estimation and HRV analysis. In addition, to address the lack of paired training data problems in real-world applications, we propose a cycle consistency loss that guarantees the time-frequency consistency before/after mapping. The method enhances the waveform quality of traditional POS approaches in different illumination tests (BH-rPPG) and cross-datasets (UBFC-rPPG) with mean absolute error (MAE) values of 1.34 bpm and 1.65 bpm, and average beat-to-beat (AVBB) values of 27.46 ms and 45.28 ms, respectively. Experimental results demonstrate that the cbPPGGAN enhances cbPPG signal quality and outperforms the state-of-the-art approaches in HR estimation and HRV analysis. The proposed framework opens a new pathway toward accurate HR estimation in an unconstrained environment.

Forkhead box F1 functions as a novel prognostic biomarker and induces caspase­dependent apoptosis in bladder cancer.

The downregulated expression of forkhead box F1 (FOXF1) has been found in many malignant tumors but no research was done in bladder cancer (BC). The present study aimed to investigate the prognostic value and antitumor effects of FOXF1 in patients with BC. Herein, a retrospectively recruited BC cohort and public datasets were utilized to identify the predictive ability of FOXF1 and determine its association with the clinical characteristics of BC patients. It was found that the expression level of FOXF1 was notably lower in BC tissues than in para­cancerous mucosae. Low FOXF1 expression was associated with unfavorable clinicopathological features and poor prognosis. Furthermore, in BC cells, the mRNA and protein expression levels of FOXF1 were examined using reverse transcription­quantitative PCR and western blot analysis. Cell viability was examined using Cell Counting Kit­8, EdU and clonogenic capacity assays. Cell apoptosis was detected using flow cytometry. The results revealed that the activation of FOXF1 impaired cell viability and induced apoptosis in BC. The antitumor effects of FOXF1 were also validated using animal models. Subsequently, caspase­3 was spotted as a downstream gene of FOXF1 by using RNA sequencing and protein­protein interaction analyses. FOXF1 inhibited proliferation and induced apoptosis of BC cells via caspase signaling pathway. The present study demonstrates the expression patterns, prognostic predictive ability and antitumor effects of FOXF1 in BC. FOXF1 is a favorable biomarker for predicting clinical outcomes in patients with BC and represents a potential therapeutic target.

Identification of indications for albumin administration in septic patients with liver cirrhosis.

BACKGROUND: Albumin infusion is the primary therapeutic strategy for septic patients with liver cirrhosis. Although recent studies have investigated the efficacy of albumin in the resuscitation stage of septic patients with liver cirrhosis, it remains unclear whether daily albumin administration can improve outcomes. Furthermore, the indications for initiating albumin therapy are not well defined. METHODS: Septic patients with liver cirrhosis were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV 2.0) database. Marginal structural Cox models were employed to investigate the association between daily albumin infusion and 28-day mortality. We also aimed to explore under what circumstances enrolled patients could benefit most from albumin administration, based on the clinical parameters collected on the day of albumin infusion, including serum albumin concentration, serum lactate concentration, mean arterial pressure (MAP), and vasopressor dosage. RESULTS: A total of 2265 patients were included in the final analysis, of whom 1093 (48.3%) had received albumin treatment at least once. The overall 28-day mortality was 29.6%. After marginal structural modeling, daily albumin infusion was associated with a reduced risk of 28-day death (hazard ratio, 0.76; 95% CI 0.61-0.94). We found that patients benefit most from albumin infusion when initiated on the day of serum albumin concentration between 2.5 and 3.0 g/dL, serum lactate concentration greater than or equal to 2 mmol/L, MAP less than 60 mmHg, or vasopressor dosage between 0.2 and 0.3 mcg/kg/min (norepinephrine equivalent, NEE). CONCLUSIONS: Albumin infusion is associated with a reduction in mortality in septic patients with liver cirrhosis under specific circumstances. Serum albumin concentration, serum lactate, MAP, and vasopressor dosage were found to be modifiers of treatment effectiveness and should be considered when deciding to initial albumin infusion.

ZNF692 promote proliferation through transcriptional repression of essential genes in clear cell renal carcinoma.

Transcription deregulation is recognized as a prominent hallmark of carcinogenesis. However, our understanding of the transcription factors implicated in the dysregulated transcription network of clear cell renal carcinoma (ccRCC) remains incomplete. In this study, we present evidence that ZNF692 drives tumorigenesis in ccRCC through the transcriptional repression of essential genes. We observed overexpression of ZNF692 in various cancers, including ccRCC, and found that the knockdown or knockout of ZNF692 suppressed the growth of ccRCC. Genome-wide binding site analysis using ChIP-seq revealed that ZNF692 regulates genes associated with cell growth, Wnt signaling, and immune response in ccRCC. Furthermore, motif enrichment analysis identified a specific motif (5'-GCRAGKGGAKAY-3') that is recognized and bound by ZNF692. Subsequent luciferase reporter assays demonstrated that ZNF692 transcriptionally represses the expression of IRF4 and FLT4 in a ZNF692 binding motif-dependent manner. Additionally, we observed MYC binding to the promoter regions of ZNF692 in most cancer types, driving ZNF692 overexpression specifically in ccRCC. Overall, our study sheds light on the functional significance of ZNF692 in ccRCC and provides valuable insights into its therapeutic potential as a target in cancer treatment.

Risk Factors and Disease Profile Associated with the Nucleic Acid Conversion Time of COVID-19 Patients Infected with the SARS-CoV-2 Omicron Variant in Fangcang Shelter Hospitals.

Purpose: This study aimed to determine the clinical profile connected to the nucleic acid conversion time of COVID-19 patients harboring the SARS-CoV-2 Omicron variant at the hospitals at the Fangcang shelter. Methods: We reported 39,584 COVID-19 patients who were hospitalized in Shanghai, China, between April 5 and May 5, 2022, and who had contracted the Omicron strain of SARS-CoV-2. Demographic data, medical and vaccination history, clinical symptoms, and NCT were reported for the patient. Results: The median age of the patients with COVID-19 included in this study was 45 (interquartile range [IQR]: 33-54), and 64.2% of them were male. The two most prevalent comorbidities among the patients were hypertension and diabetes. Additionally, we discovered that the percentage of unimmunized patients was negligible (13.2%). We found that male sex, age under 60, and other comorbidities including hypertension and diabetes are significant risk factors for extending NCT when we analyzed the risk variables for NCT. We discovered that vaccination with two or more doses can significantly reduce NCT. The analysis of the young (18-59 years) and older (60 years) populations produced the same outcomes. Conclusion: Our findings confirm that a full COVID-19 vaccine series or booster doses are highly recommended to significantly reduce NCT. In order to reduce NCT, it is also advised that elderly people who have no clear contraindications take vaccination shots.

Inhibition of BPHL inhibits proliferation in lung carcinoma cell lines.

Background: Lung cancer is one of the most common human malignant tumors and the leading cause of cancer death worldwide. Biphenyl hydrolase-like (BPHL) is a gene encoding the human BPHL enzyme, a serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. However, the role of BPHL in lung cancer is still unknown. Methods: In this study, we assessed the effect BPHL knockdown on the proliferation, apoptosis, colony formation, metastasis, and cell cycle of cancer cells. BPHL knockdown NCI-H1299 and A549 cells demonstrated decreased proliferation, as measured by Celigo cell counting. The MTT assay results were consistent with Celigo cell counting. Caspase 3/7 activity increased significantly in the NCI-H1299 and A549 cells after shBPHL knockdown. Decreased colony formation in the NCI-H1299 and A54 cells after shBPHL knockdown, as measured by crystal violet staining. Transmigration assay using a Transwell demonstrated that there were significantly fewer migrating cells in the lower chamber in the BPHL knockdown NCI-H1299 and A549 cells. Cell cycle analysis by Propidium Iodide (PI) staining and fluorescence activated cell sorter (FACS). We also explored the effect of BPHL knockdown on tumor growth in a mouse model of tumor implantation in nude mice. Results: We found that the knockdown of BPHL gene expression by short hairpin RNA (shRNA) leads to a decrease in proliferation, colony formation, and metastasis and an increase in apoptosis in two lung adenocarcinoma (LUAD) cell lines in vitro. BPHL knockdown induces decreased tumor growth, colony formation, and metastasis; increased apoptosis; and altered cell cycle destruction. BPHL knockdown results in decreased tumor growth in vivo. Moreover, BPHL knockdown A549 cells demonstrated slower growth compared to control cells upon implantation in nude mice, confirming the in vitro findings. Conclusions: In this study, the data indicate that BPHL potentially promotes proliferation, inhibits apoptosis, and increases colony formation and metastasis in lung cancer. Overall, our study suggests that BPHL may be a gene that promotes tumor growth in lung cancer.

Forecast of policy-driven land use change and its impact on ecosystem services in China: A case study of the Yangtze River Economic Belt.

Land use change is an important factor affecting the performance of ecosystem services (ESs). Therefore, understanding the impact of land use change on ESs is of great significance for promoting the coordination of regional human-land relationships. In this study, random forest and cellular automata were used to simulate and predict the characteristics of land use change in the Yangtze River Economic Belt, and diversified land use evolution patterns were formed in combination with China's strategic development needs. The effects of habitat suitability on ESs were analyzed by using a multiscenario land use change model. The results demonstrated that the driving factors selected in this article had a good induction effect on the law of land use evolution, and the simulated land use change had high credibility. Under the mode of ecological protection and cultivated land protection, the expansion of construction land was greatly affected and was not conducive to social and economic development. Under the natural evolution mode, farmland was greatly encroached upon, and food security was greatly threatened. The regional coordination model had relative advantages, and all kinds of land use needs were met to a certain extent. The water production function of ESs was strong, but the carbon storage function was weak. The relationship between the habitat suitability index and ES changes under land use change revealed that there were significant differences in ES changes caused by ecological quality changes in mountainous and plain areas. This study provides a reference for promoting social and economic development and ecosystem integrity. Integr Environ Assess Manag 2023;19:1473-1484. © 2023 SETAC.

Effects of hydrocortisone combined with vitamin C and vitamin B1 versus hydrocortisone alone on microcirculation in septic shock patients: A pilot study.

OBJECTIVE: To investigate the effects of hydrocortisone combined with vitamin C and vitamin B1 versus hydrocortisone on sublingual microcirculation in septic shock patients. METHODS: This pilot study enrolled septic shock patients admitted to the ICU of a tertiary teaching hospital from February 2019 to January 2020. We randomly assigned the enrolled patients to the treatment group (hydrocortisone combined with vitamin C and vitamin B1 added to standard care) and the control group (hydrocortisone alone added to standard care) in a 1 : 1 ratio. The primary outcome was perfused small vascular density (sPVD) monitored by a sublingual microcirculation imaging system at 24 hours after treatment. RESULTS: Twelve patients in the treatment group and ten in the control group completed the study. The baseline characteristics were comparable between the groups. No statistically significant difference was found in the sPVD between the groups at baseline. The sPVD in the treatment group was significantly higher than that in the control group at 4 hours after treatment (mean difference, 7.042; 95% CI, 2.227-11.857; P = 0.009) and 24 hours after treatment (mean difference, 7.075; 95% CI, 2.390-11.759; P = 0.008). CONCLUSIONS: Compared with hydrocortisone, hydrocortisone combined with vitamin C and vitamin B1 significantly improves microcirculation in septic shock patients.

Optimized protocol for direct cardiac reprogramming in mice using Ascl1 and Mef2c.

Direct cardiac reprogramming refers to the conversion of fibroblasts into cardiomyocyte-like cells (iCMs) without going through an intermediate progenitor stage. Here, we present a protocol for direct cardiac reprogramming in mice using Ascl1 and Mef2c. We describe steps for isolating primary neonatal mouse cardiac fibroblast, preparing retrovirus encoding reprogramming factors, and efficient cardiac reprogramming with Ascl1 and Mef2c. The resulting iCMs display cardiomyocyte-like sarcomere structure, gene expression, and calcium flux. For complete details on the use and execution of this protocol, please refer to Wang et al. (2022).1.

Growth-regulating factor 15-mediated gene regulatory network enhances salt tolerance in poplar.

Soil salinity is an important determinant of crop productivity and triggers salt stress response pathways in plants. The salt stress response is controlled by transcriptional regulatory networks that maintain regulatory homeostasis through combinations of transcription factor (TF)-DNA and TF-TF interactions. We investigated the transcriptome of poplar 84 K (Populus alba × Populus glandulosa) under salt stress using samples collected at 4- or 6-h intervals within 2 days of salt stress treatment. We detected 24,973 differentially expressed genes, including 2,231 TFs that might be responsive to salt stress. To explore these interactions and targets of TFs in perennial woody plants, we combined gene regulatory networks, DNA affinity purification sequencing, yeast two-hybrid-sequencing, and multi-gene association approaches. Growth-regulating factor 15 (PagGRF15) and its target, high-affinity K+ transporter 6 (PagHAK6), were identified as an important regulatory module in the salt stress response. Overexpression of PagGRF15 and PagHAK6 in transgenic lines improved salt tolerance by enhancing Na+ transport and modulating H2O2 accumulation in poplar. Yeast two-hybrid assays identified more than 420 PagGRF15-interacting proteins, including ETHYLENE RESPONSE FACTOR TFs and a zinc finger protein (C2H2) that are produced in response to a variety of phytohormones and environmental signals and are likely involved in abiotic stress. Therefore, our findings demonstrate that PagGRF15 is a multifunctional TF involved in growth, development, and salt stress tolerance, highlighting the capability of a multifaceted approach in identifying regulatory nodes in plants.

Identifying high-risk phenotypes and associated harms of delayed time-to-antibiotics in patients with ICU onset sepsis: A retrospective cohort study.

PURPOSE: To identify phenotypes of Intensive Care Unit (ICU) onset sepsis and its associated harms of delayed time-to-antibiotics. MATERIALS AND METHODS: The Medical Information Mart for Intensive Care IV (MIMIC-IV) database was employed to identify patients with ICU onset sepsis. The primary exposure was time-to-antibiotics, as measured from sepsis recognition to first antibiotic administered. Latent profile analysis (LPA) was used to identify phenotypes of sepsis based on individual organ failure score derived from Sequential Organ Failure Assessment (SOFA). Interactions between phenotypes and time-to-antibiotics on 28-day mortality were explored. RESULTS: 6246 patients were enrolled in final analysis. The overall 28-day mortality was 12.7%. Delayed time-to-antibiotics was associated with increased 28-day mortality in patients with ICU onset sepsis (HR 1.12, 95% CI 1.08-1.18). Four phenotypes of sepsis were identified: phenotype 1 was characterized by respiratory dysfunction, phenotype 2 was characterized by cardiovascular dysfunction, phenotype 3 was characterized by multiple organ dysfunction, and phenotype 4 was characterized by neurological dysfunction. The adjusted HR of 28-day mortality was 1.16 (95% CI 1.08-1.25) in phenotype 1, and 1.06 (95% CI 1.00-1.13) in phenotype 2, while no significant interaction was observed. CONCLUSIONS: Septic patients with respiratory or cardiovascular dysfunction were associated with harms of delayed time-to-antibiotics.

Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions.

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio-nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio-nano interactions and pave the way forward in the development of more effective cancer nanomedicines.