High-quality genome assembly enables prediction of allele-specific gene expression in hybrid poplar.

Poplar (Populus) is a well-established model system for tree genomics and molecular breeding, and hybrid poplar is widely used in forest plantations. However, distinguishing its diploid homologous chromosomes is difficult, complicating advanced functional studies on specific alleles. In this study, we applied a trio-binning design and PacBio high-fidelity long-read sequencing to obtain haplotype-phased telomere-to-telomere genome assemblies for the 2 parents of the well-studied F1 hybrid "84K" (Populus alba × Populus tremula var. glandulosa). Almost all chromosomes, including the telomeres and centromeres, were completely assembled for each haplotype subgenome apart from 2 small gaps on one chromosome. By incorporating information from these haplotype assemblies and extensive RNA-seq data, we analyzed gene expression patterns between the 2 subgenomes and alleles. Transcription bias at the subgenome level was not uncovered, but extensive-expression differences were detected between alleles. We developed machine-learning (ML) models to predict allele-specific expression (ASE) with high accuracy and identified underlying genome features most highly influencing ASE. One of our models with 15 predictor variables achieved 77% accuracy on the training set and 74% accuracy on the testing set. ML models identified gene body CHG methylation, sequence divergence, and transposon occupancy both upstream and downstream of alleles as important factors for ASE. Our haplotype-phased genome assemblies and ML strategy highlight an avenue for functional studies in Populus and provide additional tools for studying ASE and heterosis in hybrids.

Controlled Growth of Metal Atom Arrays on Graphdiyne for Seawater Oxidation.

Advanced atomic-level heterointerface engineering provides a promising method for the preparation of next-generation catalysts. Traditional carbon-based heterointerface catalytic performance rely heavily on the undetermined defects in complex and demanding preparation processes, rendering it impossible to control the catalytic performance. Here, we present a general method for the controlled growth of metal atom arrays on graphdiyne (GDY/IrCuOx), and we are surprised to find strong heterointerface strains during the growth. We successfully controlled the thickness of GDY to regulate the heterointerface metal atoms and achieved compressive strain at the interface. Experimental and density functional theory calculation results show that the unique incomplete charge transfer between GDY and metal atoms leads to the formation of strong interactions and significant heterointerface compressive strain between GDY and IrCuOx, which results in high oxidation performances with 1000 mA cm-2 at a low overpotential of 283 mV and long-term stability at large current densities in alkaline simulated seawater. We anticipate that this finding will contribute to construction of high-performance heterogeneous interface structures, leading to the development of new generation of GDY-based heterojunction catalysts in the field of catalysis for future promising performance.

Bio-Inspired Superhydrophilic Self-Assembled Coronavirus-Like Pt-WC/CNT for Hydrogen Evolution Reaction.

This study presents a novel approach to enhance the catalytic activity of composite materials by promoting active surface exposure and improving hydrogen transfer performance. Through a self-assembly route involving tailored gas-solid and galvanic replacement reactions, Pt-WC/CNT catalysts with superhydrophilicity and coronavirus-like structure are synthesized. These unique structural features contribute to a remarkable enhancement in the electrocatalytic performance of the hydrogen evolution reaction (HER). Notably, the Pt-WC/CNT catalyst exhibits an outstanding intrinsic activity and efficient bubble transfer properties, leading to a high turnover frequency of 34.97 H2·s-1 at an overpotential of 100 mV. This value is 4.8 times higher than that achieved by commercial Pt/C catalysts (7.30 H2·s-1), establishing Pt-WC/CNT as one of the most active catalysts reported to date. Moreover, the combination of gas-solid and galvanic replacement reactions in the synthesis process offers a scalable route for the production of Pt-loading controllable composite catalysts, thus challenging the dominance of commercial Pt/C catalysts.

A Multi-Interface Structure of Graphdiyne/Cobalt Oxides for Chlorine Production.

A challenge facing the chlor-alkali process is the lack of electrocatalyst with high activity and selectivity for the efficient industrial production of chlorine. Herein the authors report a new electrocatalyst that can generate multi-interface structure by in situ growth of graphdiyne on the surface of cobalt oxides (GDY/Co3O4), which shows great potential in highly selective and efficient chlorine production. This result is due to the strong electron transfer and high density charge transport between GDY and Co3O4 and the interconversion of the mixed valence states of the Co atoms itself. These intrinsic characteristics efficiently enhance the conductivity of the catalyst, facilitate the reaction kinetics, and improve the overall catalytic selectivity and activity. Besides, the protective effect of the formed GDY layer is remarkable endowing the catalyst with excellent stability. The catalyst can selectively produce chlorine in low-concentration of NaCl aqueous solution at room temperature and pressure with the highest Faraday efficiency of 80.67% and an active chlorine yield rate of 184.40 mg h-1 cm-2, as well as superior long-term stability.

Interfacial Heat and Mass Transfer Effects on Secondary Hydrate Formation under Different Dissociation Conditions.

Secondary hydrate formation or hydrate reformation poses a serious threat to the oil and gas transportation safety and natural gas hydrate exploitation efficiency. The hydrate reformation behaviors in porous media have been widely studied in large simulators due to their importance in traditional industries and new energy resources. However, it is difficult to understand the interfacial effects of hydrate reformation on the surface and in micropores of the porous media via a basic experimental apparatus. In this work, in situ X-ray computed tomography (X-CT) technology is used to detect the period, distribution, volume, and morphology characteristics of secondary hydrate formation during hydrate dissociation under depressurization, thermal stimulation, and the combined conditions. It is found that the secondary hydrate formation is inevitable under any conditions of hydrate dissociation. The secondary hydrate morphology varies among porous, grain-enveloping, grain-cementing, granular, and patchy structures, which are closely correlated to the hydrate reformation region and gas/water saturated conditions during hydrate dissociation. Accordingly, we revealed that the interfacial superheating phenomenon before hydrate dissociation could provide a supercooling condition for hydrate reformation. The gas flow along the interface of pores and inside the liquid water, as well as gas accumulation in noninterconnected pores, would exaggerate the hydrate reformation by increasing the local pore pressure. Meanwhile, the hydrate reformation aggravates the nonuniform distribution of gas hydrates in pores. In order to avoid hydrate reformation during dissociation, we further compared hydrate reformation and dissociation behaviors under three hydrate dissociation conditions. It is revealed that the combination of thermal stimulation and depressurization is an effective method for hydrate dissociation by retarding secondary hydrate formation. This study provides visual evidence and an interaction mechanism between interfacial heat and mass transfer, as well as secondary hydrate formation behaviors, which can be favorable for future quantitative research on secondary hydrate formation in different scales under various dissociation conditions.

Prediction of Cytochrome P450 Inhibition Using a Deep Learning Approach and Substructure Pattern Recognition.

Cytochrome P450 (CYP) is a family of enzymes that are responsible for about 75% of all metabolic reactions. Among them, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 participate in the metabolism of most drugs and mediate many adverse drug reactions. Therefore, it is necessary to estimate the chemical inhibition of Cytochrome P450 enzymes in drug discovery and the food industry. In the past few decades, many computational models have been reported, and some provided good performance. However, there are still several issues that should be resolved for these models, such as single isoform, models with unbalanced performance, lack of structural characteristics analysis, and poor availability. In the present study, the deep learning models based on python using the Keras framework and TensorFlow were developed for the chemical inhibition of each CYP isoform. These models were established based on a large data set containing 85715 compounds extracted from the PubChem bioassay database. On external validation, the models provided good AUC values with 0.97, 0.94, 0.94, 0.96, and 0.94 for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. The models can be freely accessed on the Web server named CYPi-DNNpredictor (cypi.sapredictor.cn), and the codes for the model were made open source in the Supporting Information. In addition, we also analyzed the structural characteristics of chemicals with CYP450 inhibition and detected the structural alerts (SAs), which should be responsible for the inhibition. The SAs were also made available online, named CYPi-SAdetector (cypisa.sapredictor.cn). The models can be used as a powerful tool for the prediction of CYP450 inhibitors, and the SAs should provide useful information for the mechanisms of Cytochrome P450 inhibition.

Oral cancer detection and progression prediction using noninvasive cytology-based DNA ploidy approach.

BACKGROUND: Despite the oral cavity being readily accessible, oral cancer (OC) remains a significant burden. The objective of this study is to develop a DNA ploidy-based cytology test for early detection of high-risk oral lesions. METHODS: This retrospective study was conducted using 569 oral brushing samples collected from 95 normal and 474 clinically abnormal mucosa with biopsy diagnosis of reactive, low-grade or high-grade precancer or cancers. Brushing cells were processed to characterize DNA ploidy. A two-step DNA ploidy-based algorithm, the DNA ploidy oral cytology (DOC) test, was developed using a training set, and verified in test and validation sets to differentiate high-grade lesions (HGLs) from normal. The prognostic value of the test was evaluated by an independent outcome cohort, including progressed and non-progressing normal, reactive and low-grade lesions. Classification performance was assessed by accuracy, sensitivity, and specificity, while the prognostic value was evaluated by using the Cox proportional hazards analysis on 3-year progression-free survival (PFS). RESULTS: The developed DOC test exhibited high accuracy for detecting HGLs in the test and validation sets, with a sensitivity of 0.97 and 0.96, respectively. Its application to the Outcome cohort demonstrated significant prognostic value for 3-year PFS (log rank, p < 0.001). Multivariate analysis showed that high-grade pathology was the only variable explaining positive DOC test, not age, smoking, or lesional site. CONCLUSION: Clinical implementation of the DOC test could provide an effective screening method for detecting HGLs for biopsy and lesions at risk of progression.

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress.

Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

Understanding the Chemomechanical Function of the Silver-Carbon Interlayer in Sheet-type All-Solid-State Lithium-Metal Batteries.

All-solid-state batteries with lithium metal anodes hold great potential for high-energy battery applications. However, forming and maintaining stable solid-solid contact between the lithium anode and solid electrolyte remains a major challenge. One promising solution is the use of a silver-carbon (Ag-C) interlayer, but its chemomechanical properties and impact on interface stabilities need to be comprehensively explored. Here, we examine the function of Ag-C interlayers in addressing interfacial challenges using various cell configurations. Experiments show that the interlayer improves interfacial mechanical contact, leading to a uniform current distribution and suppressing lithium dendrite growth. Furthermore, the interlayer regulates lithium deposition in the presence of Ag particles via improved Li diffusivity. The sheet-type cells with the interlayer achieve a high energy density of 514.3 Wh L-1 and an average Coulombic efficiency of 99.97% over 500 cycles. This work provides insights into the benefits of using Ag-C interlayers for enhancing the performance of all-solid-state batteries.

Achieving Efficient CO2 Electrolysis to CO by Local Coordination Manipulation of Nickel Single-Atom Catalysts.

Selective electroreduction of CO2 to C1 feed gas provides an attractive avenue to store intermittent renewable energy. However, most of the CO2-to-CO catalysts are designed from the perspective of structural reconstruction, and it is challenging to precisely design a meaningful confining microenvironment for active sites on the support. Herein, we report a local sulfur doping method to precisely tune the electronic structure of an isolated asymmetric nickel-nitrogen-sulfur motif (Ni1-NSC). Our Ni1-NSC catalyst presents >99% faradaic efficiency for CO2-to-CO under a high current density of -320 mA cm-2. In situ attenuated total reflection surface-enhanced infrared absorption spectroscopy and differential electrochemical mass spectrometry indicated that the asymmetric sites show a significantly weaker binding strength of *CO and a lower kinetic overpotential for CO2-to-CO. Further theoretical analysis revealed that the enhanced CO2 reduction reaction performance of Ni1-NSC was mainly due to the effectively decreased intermediate activation energy.

Nuclear Binding Protein 2/Nesfatin-1 Affects Trophoblast Cell Fusion during Placental Development via the EGFR-PLCG1-CAMK4 Pathway.

Previous studies have shown that nuclear binding protein 2 (NUCB2) is expressed in the human placenta and increases with an increase in the syncytialization of trophoblast cells. This study aimed to investigate the role of NUCB2 in the differentiation and fusion of trophectoderm cells. In this study, the expression levels of NUCB2 and E-cadherin in the placentas of rats at different gestation stages were investigated. The results showed that there was an opposite trend between the expression of placental NUCB2 and E-cadherin in rat placentas in different trimesters. When primary human trophoblast (PHT) and BeWo cells were treated with high concentrations of Nesfatin-1, the trophoblast cell syncytialization was significantly inhibited. The effects of NUCB2 knockdown in BeWo cells and Forskolin-induced syncytialization were investigated. These cells showed a significantly decreased cell fusion rate. The mechanism underlying NUCB2-regulated trophoblast cell syncytialization was explored using RNA-Seq and the results indicated that the epidermal growth factor receptor (EGFR)-phospholipase C gamma 1 (PLCG1)-calmodulin-dependent protein kinase IV (CAMK4) pathway might be involved. The results suggested that the placental expression of NUCB2 plays an important role in the fusion of trophoblasts during differentiation via the EGFR-PLCG1-CAMK4 pathway.

Screening and identification of miR-181a-5p in oral squamous cell carcinoma and functional verification in vivo and in vitro.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common malignant tumor associated with poor prognosis. MicroRNAs (miRNAs) play crucial regulatory roles in the cancer development. However, the role of miRNAs in OSCC development and progression is not well understood. METHODS: We sought to establish a dynamic Chinese hamster OSCC animal model, construct miRNA differential expression profiles of its occurrence and development, predict its targets, and perform functional analysis and validation in vitro. RESULTS: Using expression and functional analyses, the key candidate miRNA (miR-181a-5p) was selected for further functional research, and the expression of miR-181a-5p in OSCC tissues and cell lines was detected. Subsequently, transfection technology and a nude mouse tumorigenic model were used to explore potential molecular mechanisms. miR-181a-5p was significantly downregulated in human OSCC specimens and cell lines, and decreased miR-181a-5p expression was observed in multiple stages of the Chinese hamster OSCC animal model. Moreover, upregulated miR-181a-5p significantly inhibited OSCC cell proliferation, colony formation, invasion, and migration; blocked the cell cycle; and promoted apoptosis. BCL2 was identified as a target of miR-181a-5p. BCL2 may interact with apoptosis- (BAX), invasion- and migration- (TIMP1, MMP2, and MMP9), and cell cycle-related genes (KI67, E2F1, CYCLIND1, and CDK6) to further regulate biological behavior. Tumor xenograft analysis indicated that tumor growth was significantly inhibited in the high miR-181a-5p expression group. CONCLUSION: Our findings indicate that miR-181a-5p can be used as a potential biomarker and provide a novel animal model for mechanistic research on oral cancer.

Atorvastatin-induced tolerogenic dendritic cells improve cardiac remodeling by suppressing TLR-4/NF-κB activation after myocardial infarction.

OBJECTIVE: Myocardial infarction (MI) caused by ischemic cardiomyocyte necrosis induces inflammatory responses that strongly affect ventricular remodeling. Tolerogenic dendritic cells (tDCs) can suppress this effect on inflammatory responses. However, the precise role of atorvastatin-induced tDCs in ventricular remodeling after MI remains unclear. METHODS: To explore the effect of necrotic cardiomyocytes (SNC) and/or atorvastatin on DC function, the expression of CD40, CD80, CD86, and MHC-II was determined using flow cytometry. The protein levels of TLR-4/NF-κB-related molecules were evaluated using western blotting. The infarct area after MI was determined via 2,3,5-triphenyltetrazolium chloride staining. The TUNEL assay was employed to evaluate the apoptosis of cardiomyocytes in heart sections. Masson's trichrome method was used to determine the extent of fibrosis. RESULTS: Compared to the DCs co-cultured with PBS (control), cells co-cultured with Supernatant-IM or Supernatant-NH produced higher levels of inflammatory cytokines, including TNF-α, IL-1, IL-6, IL-12P40, and IL-8. This cytokine production was impaired by atorvastatin treatment. SNC treatment induced DC maturation and enhanced inflammatory cytokine secretion and oxidative stress through TLR-4/NF-κB pathway activation. Compared to that in the PBS-treated group, the left ventricular ejection fraction was significantly improved after tDC treatment. Additionally, compared to that in the PBS-treated group, tDC treatment reduced the left ventricular end-diastolic and end-systolic diameters in mice. Furthermore, treatment with tDCs improved the left ventricular systolic function, attenuated inflammatory cell infiltration, and reduced cardiomyocyte apoptosis, myocardial fibrosis, and infarct size compared to those in the control group. CONCLUSIONS: Adoptive transfer of atorvastatin-induced tDCs alleviated post-infarction cardiomyocyte apoptosis and myocardial fibrosis in association with decreased inflammatory cell infiltration and inhibited oxidative stress, likely by suppressing TLR-4/NF-κB activation after myocardial infarction.

Comprehensive physiological, transcriptomic, and metabolomic analysis of the key metabolic pathways in millet seedling adaptation to drought stress.

Drought is one of the leading environmental constraints that affect the growth and development of plants and, ultimately, their yield and quality. Foxtail millet (Setaria italica) is a natural stress-resistant plant and an ideal model for studying plant drought resistance. In this study, two varieties of foxtail millet with different levels of drought resistance were used as the experimental material. The soil weighing method was used to simulate drought stress, and the differences in growth, photosynthetic physiology, metabolite metabolism, and gene transcriptional expression under drought stress were compared and analyzed. We aimed to determine the physiological and key metabolic regulation pathways of the drought-tolerant millet in resistance to drought stress. The results showed that drought-tolerant millet exhibited relatively stable growth and photosynthetic parameters under drought stress while maintaining a relatively stable level of photosynthetic pigments. The metabolomic, transcriptomic, and gene co-expression network analysis confirmed that the key to adaptation to drought by millet was to enhance lignin metabolism, promote the metabolism of fatty acids to be transformed into cutin and wax, and improve ascorbic acid circulation. These findings provided new insights into the metabolic regulatory network of millet adaptation to drought stress.

Near-Field Radiative Heat Transfer Modulation with an Ultrahigh Dynamic Range through Mode Mismatching.

Modulating near-field radiative heat transfer (NFRHT) with a high dynamic range is challenging in nanoscale thermal science and engineering. Modulation depths [(maximum value - minimum value)/(maximum value + minimum value) × 100%] of ≈2% to ≈15.7% have been reported with matched modes, but breaking the constraint of mode matching theoretically allows for higher modulation depth. We demonstrate a modulation depth of ≈32.2% by a pair of graphene-covered SU8 heterostructures at a gap distance of ≈80 nm. Dissimilar Fermi levels tuned by bias voltages enable mismatched surface plasmon polaritons which improves the modulation. The modulation depth when switching from a matched mode to a mismatched mode is ≈4.4-fold compared to that when switching between matched modes. This work shows the importance of symmetry in polariton-mediated NFRHT and represents the largest modulation depth to date in a two-body system with fixed gap distance and temperature.

Concentrated Growth Factor (CGF): The Newest Platelet Concentrate and Its Application in Nasal Hyaluronic Acid Injection Complications.

BACKGROUND: Several cases of wounds caused by vascular compromise after facial cosmetic injection have been reported in recent years. How to promote wound healing, restore facial appearance, and avoid secondary injury in such patients have remained a clinical challenge. Our study was designed to assess the effect of concentrated growth factor (CGF) for repairing nasal wounds after nasal hyaluronic acid injection. METHODS: Six women with nasal wounds after hyaluronic acid injection were enrolled from June 2019 to June 2022. The average time of the first CGF treatment from admission was 2-4 days. CGF gel was prepared from each patient's blood by using a Medifuge™ system. After debridement of the wound, the prepared CGF gel was applied on the wound surface, and the wound dressing was fixed to stabilize the CGF gel. The CGF treatment interval was 3-4 days. RESULTS: The wound began to heal after the first CGF treatment. After 2-3 CGF treatments, the wound was almost completely healed. There was no deflection of the nasal columella, and nasal ventilation function was good. There was no obvious deformity in the appearance of the nose. After follow-up ranging from 2 months to 1 year, the appearance and function of the nose showed satisfactory recovery. CONCLUSIONS: CGF has great potential in promoting wound healing and restoring the appearance after complications from nasal hyaluronic acid injection. The preparation of CGF gel is simple, and the clinical application is convenient and safe. In future, more clinical trials are needed to further prove the efficacy and safety of CGF in the treatment of wounds secondary to cosmetic injection. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Boosting the Proton-coupled Electron Transfer via Fe-P Atomic Pair for Enhanced Electrochemical CO2 Reduction.

Single-atom catalysts exhibit superior CO2 -to-CO catalytic activity, but poor kinetics of proton-coupled electron transfer (PCET) steps still limit the overall performance toward the industrial scale. Here, we constructed a Fe-P atom paired catalyst onto nitrogen doped graphitic layer (Fe1 /PNG) to accelerate PCET step. Fe1 /PNG delivers an industrial CO current of 1 A with FECO over 90 % at 2.5 V in a membrane-electrode assembly, overperforming the CO current of Fe1 /NG by more than 300 %. We also decrypted the synergistic effects of the P atom in the Fe-P atom pair using operando techniques and density functional theory, revealing that the P atom provides additional adsorption sites for accelerating water dissociation, boosting the hydrogenation of CO2 , and enhancing the activity of CO2 reduction. This atom-pair catalytic strategy can modulate multiple reactants and intermediates to break through the inherent limitations of single-atom catalysts.

GALNT4 primes monocytes adhesion and transmigration by regulating O-Glycosylation of PSGL-1 in atherosclerosis.

Atherosclerosis is a major underlying cause of cardiovascular disease. Genome wide association studies have predicted that GalNAc-T4 (GALNT4), which responsible for initiating step of mucin-type O-glycosylation, plays a causal role in the susceptibility to cardiovascular diseases, whereas the precise mechanism remains obscure. Thus, we sought to determine the role and mechanism of GALNT4 in atherosclerosis. Firstly, we found the expression of GALNT4 and protein O-glycosylation were both increased in plaque as atherosclerosis progressed in ApoE-/- mice by immunohistochemistry. And the expression of GALNT4 was also increased in human monocytes treated with ACS (acute coronary syndrome) sera and subjected to LPS and ox-LDL in vitro. Moreover, silencing expression of GALNT4 by shRNA lentivirus alleviated atherosclerotic plaque formation and monocyte/macrophage infiltration in ApoE-/- mice. Functional investigations demonstrate that GALNT4 knockdown inhibited P-selectin-induced activation of ß2 integrin on the surface of monocytes, decreased monocytes adhesion under flow condition with P-selectin stimulation, as well as suppressed monocytes transmigration triggered by monocyte chemotactic protein- 1(MCP-1). In contrast, GALNT4 overexpression enhanced monocytes adhesion and transmigration. Furthermore, Vicia Villosa Lectin (VVL) pull down and PSGL-1 immunoprecipitation assays showed that GALNT4 overexpression increased O-Glycosylation of PSGL-1 and P-selectin induce phosphorylation of Akt/mTOR and IκBα/NFκB on monocytes. Conversely, knockdown of GALNT4 decreased VVL binding and attenuated the activation of Akt/mTOR and IκBα/NFκB. Additionally, mTOR inhibitor rapamycin blocked these effects of GALNT4 overexpression on monocytes. Collectively, GALNT4 catalyzed PSGL-1 O-glycosylation that involved in P-selectin induced monocytes adhesion and transmigration via Akt/mTOR and NFκB pathway. Thus, GALNT4 may be a potential therapeutic target for atherosclerosis.

ANKRD49 promotes the invasion and metastasis of lung adenocarcinoma via a P38/ATF-2 signalling pathway.

Lung adenocarcinoma (LUAD) is the most challenging neoplasm to treat in clinical practice. Ankyrin repeat domain 49 protein (ANKRD49) is highly expressed in several carcinomas; however, its pattern of expression and role in LUAD are not known. Tissue microarrays, immunohistochemistry, χ2 test, Spearman correlation analysis, Kaplan-Meier, log-rank test, and Cox's proportional hazard model were used to analyse the clinical cases. The effect of ANKRD49 on the LUAD was investigated using CCK-8, clonal formation, would healing, transwell assays, and nude mice experiment. Expressions of ANKRD49 and its associated downstream protein molecules were verified by real-time PCR, Western blot, immunohistochemistry, and/or immunofluorescence analyses. ANKRD49 expression was highly elevated in LUAD. The survival rate and Cox's modelling analysis indicated that there may be an independent prognostic indicator for LUAD patients. We also found that ANKRD49 promoted the invasion and migration in both in in vitro and in vivo assays, through upregulating matrix metalloproteinase (MMP)-2 and MMP-9 activities via the P38/ATF-2 signalling pathway Our findings suggest that ANKRD49 is a latent biomarker for evaluating LUAD prognosis and promotes the metastasis of A549 cells via upregulation of MMP-2 and MMP-9 in a P38/ATF-2 pathway-dependent manner.

Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia.

BACKGROUND & AIMS: The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized. METHODS: Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and non-parenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T-cell suppression in septic murine liver. RESULTS: We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T-cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone. CONCLUSIONS: Our study elucidates unanticipated aspects of the cellular and molecular effects of endotoxemia on liver cells at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection. LAY SUMMARY: The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation and demonstrated that the interactions of this subpopulation with recruited macrophages are pivotal in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.