Coronaviral ORF6 protein mediates inter-organelle contacts and modulates host cell lipid flux for virus production.

Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance ß-oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria-LD and ER-LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER-LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.

Synergistic actions of three MYB transcription factors underpins the high accumulation of myricetin in Morella rubra.

Flavonols are health-promoting bioactive compounds important for human nutrition, health, and plant defense. The transcriptional regulation of kaempferol and quercetin biosynthesis has been studied extensively, while little is known about the regulatory mechanisms underlying myricetin biosynthesis, which has strong antioxidant, anticancer, antidiabetic, and anti-inflammatory activities. In this study, the flavonol-specific MrMYB12 in Morella rubra preferred activating the promoter of flavonol synthase 2 (MrFLS2) (6.4-fold) rather than MrFLS1 (1.4-fold) and upregulated quercetin biosynthesis. Furthermore, two SG44 R2R3-MYB members, MrMYB5 and MrMYB5L, were identified by yeast one-hybrid library screening using the promoter of flavonoid 3',5'-hydroxylase (MrF3'5'H), and transcript levels of these R2R3-MYBs were correlated with accumulation of myricetin derivatives during leaf development. Dual-luciferase and electrophoretic mobility shift assays demonstrated that both MrMYB5 and MrMYB5L could bind directly to MYB recognition sequence elements in promoters of MrF3'5'H or MrFLS1 and activate their expression. Protein-protein interactions of MrMYB5 or MrMYB5L with MrbHLH2 were confirmed by yeast two-hybrid and bimolecular fluorescence complementation assays. MrMYB5L-MrbHLH2 showed much higher synergistic activation of MrF3'5'H or MrFLS1 promoters than MrMYB5-MrbHLH2. Studies with Arabidopsis thaliana homologs AtMYB5 and AtTT8 indicated that similar synergistic regulatory effects occur with promoters of MrF3'5'H or MrFLS1. Transient overexpression of MrMYB5L-MrbHLH2 in Nicotiana benthamiana induced a higher accumulation of myricetin derivatives (57.70 µg g-1 FW) than MrMYB5-MrbHLH2 (7.43 µg g-1 FW) when MrMYB12 was coexpressed with them. This study reveals a novel transcriptional mechanism regulating myricetin biosynthesis with the potential use for future metabolic engineering of health-promoting flavonols.

Tumor cell SPTBN1 inhibits M2 polarization of macrophages by suppressing CXCL1 expression.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, and the M2-type TAMs can promote tumor growth, invasion and angiogenesis, and suppress antitumor immune responses. It has been reported that spectrin beta, non-erythrocytic 1 (SPTBN1) may inhibit the infiltration of macrophages in Sptbn1+/-  mouse liver, but whether tumor SPTBN1 affects TAMs polarization remains unclear. This study investigated the effect and mechanism of tumor cell SPTBN1 on polarization and migration of TAMs in hepatoma and breast cancer. By analyzing tumor immune databases, we found a negative correlation between SPTBN1 and abundance of macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. By reverse transcription-quantitative real-time PCR assays and cell migration assays, the migration and M2 polarization of macrophages were enhanced by the culture medium from hepatocellular carcinoma cell line PLC/PRF/5, SNU449, and breast cancer cell line MDA-MB-231 with SPTBN1 suppression, which could be reversed by CXCL1 neutralizing antibody MAB275. Meanwhile, the ability of migration and colony formation of PLC/PRF/5, SNU449, and MDA-MB-231 cells were promoted when coculture with M2 macrophages. We also found that SPTBN1 regulated CXCL1 through p65 by cytoplasmic-nuclear protein isolation experiments and ChIP-qPCR. Our data suggest that tumor cell SPTBN1 inhibits migration and M2-type polarization of TAMs by reducing the expression and secretion of CXCL1 via inhibiting p65 nuclear localization.

PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. METHODS: This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. RESULTS: Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). CONCLUSIONS: Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer.

BACKGROUND: Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity. METHODS: The abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation. RESULTS: We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer. CONCLUSIONS: Aberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.

Mass spectrometry analysis of phosphotyrosine-containing proteins.

Tyrosine phosphorylation is a crucial posttranslational modification that is involved in various aspects of cell biology and often has functions in cancers. It is necessary not only to identify the specific phosphorylation sites but also to quantify their phosphorylation levels under specific pathophysiological conditions. Because of its high sensitivity and accuracy, mass spectrometry (MS) has been widely used to identify endogenous and synthetic phosphotyrosine proteins/peptides across a range of biological systems. However, phosphotyrosine-containing proteins occur in extremely low abundance and they degrade easily, severely challenging the application of MS. This review highlights the advances in both quantitative analysis procedures and enrichment approaches to tyrosine phosphorylation before MS analysis and reviews the differences among phosphorylation, sulfation, and nitration of tyrosine residues in proteins. In-depth insights into tyrosine phosphorylation in a wide variety of biological systems will offer a deep understanding of how signal transduction regulates cellular physiology and the development of tyrosine phosphorylation-related drugs as cancer therapeutics.

The RALF2-FERONIA-MYB63 module orchestrates growth and defense in tomato roots.

Plant secreted peptides RAPID ALKALINISATION FACTORs (RALFs), which act through the receptor FERONIA (FER), play important roles in plant growth. However, it remains unclear whether and how RALF-FER contributes to the trade-off of plant growth-defense. Here, we used a variety of techniques such as CRISPR/Cas9, protein-protein interaction and transcriptional regulation methods to investigate the role of RALF2 and its receptor FER in regulating lignin deposition, root growth, and defense against Fusarium oxysporum f. sp. lycopersici (Fol) in tomato (Solanum lycopersicum). The ralf2 and fer mutants show reduced primary root length, elevated lignin accumulation, and enhanced resistance against Fol than the wild-type. FER interacts with and phosphorylates MYB63 to promote its degradation. MYB63 serves as an activator of lignin deposition by regulating the transcription of dirigent protein gene DIR19. Mutation of DIR19 suppresses lignin accumulation, and reverses the short root phenotype and Fol resistance in ralf2 or fer mutant. Collectively, our results demonstrate that the RALF2-FER-MYB63 module fine-tunes root growth and resistance against Fol through regulating the deposition of lignin in tomato roots. The study sheds new light on how plants maintain the growth-defense balance via RALF-FER.

A transcriptional regulation of ERF15 contributes to ABA-mediated cold tolerance in tomato.

Cold stress is a major meteorological threat to crop growth and yield. Abscisic acid (ABA) plays important roles in plant cold tolerance by activating the expression of cold-responsive genes; however, the underlying transcriptional regulatory module remains unknown. Here, we demonstrated that the cold- and ABA-responsive transcription factor ETHYLENE RESPONSE FACTOR 15 (ERF15) positively regulates ABA-mediated cold tolerance in tomato. Exogenous ABA treatment significantly enhanced cold tolerance in wild-type tomato plants but failed to rescue erf15 mutants from cold stress. Transcriptome analysis showed that ERF15 was associated with the expression of cold-responsive transcription factors such as CBF1 and WRKY6. Further RT-qPCR assays confirmed that the ABA-induced increased in CBF1 and WRKY6 transcripts was suppressed in erf15 mutants when the plants were subjected to cold treatment. Moreover, yeast one-hybrid assays, dual-luciferase assays and electrophoretic mobility shift assays demonstrated that ERF15 activated the transcription of CBF1 and WRKY6 by binding their promoters. Silencing CBF1 or WRKY6 significantly decreased cold tolerance. Overall, our study identified the role of ERF15 in conferring ABA-mediated cold tolerance in tomato plants by activating CBF1 and WRKY6 expression. This study not only broadens our knowledge of the mechanism of ABA-mediated cold tolerance in plants but also highlights ERF15 as an ideal target gene for cold-tolerant crop breeding.

Curcumin-mediated enhancement of lung barrier function in rats with high-altitude-associated acute lung injury via inhibition of inflammatory response.

BACKGROUND: Exposure to a hypobaric hypoxic environment at high altitudes can lead to lung injury. In this study, we aimed to determine whether curcumin (Cur) could improve lung barrier function and protect against high-altitude-associated acute lung injury. METHODS: Two hundred healthy rats were randomly divided into standard control, high-altitude control (HC), salidroside (40 mg/kg, positive control), and Cur (200 mg/kg) groups. Each group was further divided into five subgroups. Basic vital signs, lung injury histopathology, routine blood parameters, plasma lactate level, and arterial blood gas indicators were evaluated. Protein and inflammatory factor (tumor necrosis factor α (TNF-α), interleukin [IL]-1ß, IL-6, and IL-10) concentrations in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method and enzyme-linked immunosorbent assay, respectively. Inflammation-related and lung barrier function-related proteins were analyzed using immunoblotting. RESULTS: Cur improved blood routine indicators such as hemoglobin and hematocrit and reduced the BALF protein content and TNF-α, IL-1ß, and IL-6 levels compared with those in the HC group. It increased IL-10 levels and reduced pulmonary capillary congestion, alveolar hemorrhage, and the degree of pulmonary interstitial edema. It increased oxygen partial pressure, oxygen saturation, carbonic acid hydrogen radical, and base excess levels, and the expression of zonula occludens 1, occludin, claudin-4, and reduced carbon dioxide partial pressure, plasma lactic acid, and the expression of phospho-nuclear factor kappa. CONCLUSIONS: Exposure to a high-altitude environment for 48 h resulted in severe lung injury in rats. Cur improved lung barrier function and alleviated acute lung injury in rats at high altitudes.

Confining Ionic Liquids in Developing Quasi-Solid-State Electrolytes for Lithium Metal Batteries.

The concept of confining ionic liquids (ILs) in developing quasi-solid-state electrolytes (QSSEs) has been proposed, where ILs are dispersed in polymer networks/backbones and/or filler/host pores, forming the so-called confinement, and great research progress and promising research results have been achieved. In this review, the progress and achievement in developing QSSEs using IL-confinement for lithium metal batteries (LMBs), together with advanced characterizations and simulations, were surveyed, summarized, and analyzed, where the influence of specific parameters, such as IL (type, content, etc.), substrate (type, structure, surface properties, etc.), confinement methods, and so on, was discussed. The confinement concept was further compared with the conventional one in other research areas. It indicates that the IL-confinement in QSSEs improves the performance of electrolytes, for example, increasing the ionic conductivity, widening the electrochemical window, and enhancing the cycle performance of the assembled cells, and being different from those in other areas, that is, the IL-confinement concept in the battery area is in a broad extent. Finally, insights into developing QSSEs in LMBs with the confinement strategy were provided to promote the development and application of QSSE LMBs.

A radiomics model for predicting perineural invasion in stage II-III colon cancer based on computer tomography.

BACKGROUND: Colon cancer, a frequently encountered malignancy, exhibits a comparatively poor survival prognosis. Perineural invasion (PNI), highly correlated with tumor progression and metastasis, is a substantial effective predictor of stage II-III colon cancer. Nonetheless, the lack of effective and facile predictive methodologies for detecting PNI prior operation in colon cancer remains a persistent challenge. METHOD: Pre-operative computer tomography (CT) images and clinical data of patients diagnosed with stage II-III colon cancer between January 2015 and December 2023 were obtained from two sub-districts of Sun Yat-sen Memorial Hospital (SYSUMH). The LASSO/RF/PCA filters were used to screen radiomics features and LR/SVM models were utilized to construct radiomics model. A comprehensive model, shown as nomogram finally, combining with radiomics score and significant clinical features were developed and validated by area under the curve (AUC) and decision curve analysis (DCA). RESULT: The total cohort, comprising 426 individuals, was randomly divided into a development cohort and a validation cohort as a 7:3 ratio. Radiomics scores were extracted from LASSO-SVM models with AUC of 0.898/0.726 in the development and validation cohorts, respectively. Significant clinical features (CA199, CA125, T-stage, and N-stage) were used to establish combining model with radiomics scores. The combined model exhibited superior reliability compared to single radiomics model in AUC value (0.792 vs. 0.726, p = 0.003) in validation cohorts. The radiomics-clinical model demonstrated an AUC of 0.918/0.792, a sensitivity of 0.907/0.813 and a specificity of 0.804/0.716 in the development and validation cohorts, respectively. CONCLUSION: The study developed and validated a predictive nomogram model combining radiomics scores and clinical features, and showed good performance in predicting PNI pre-operation in stage II-III colon cancer patients.

Development and Validation of a Machine Learning Prognostic Model of m5C Related immune Genes in Lung Adenocarcinoma.

BACKGROUND: The aim of this retrospective research was to develop an immune-related genes significantly associated with m5C methylation methylation (m5C-IRGs)-related signature associated with lung adenocarainoma (LUAD). METHODS: We introduced transcriptome data to screen out m5C-IRGs in The Cancer Genome Atlas (TCGA)-LUAD dataset. Subsequently, the m5C-IRGs associated with survival were certificated by Kaplan Meier (K-M) analysis. The univariate Cox, least absolute shrinkage and selection operator (LASSO) regression, and xgboost.surv tool were adopted to build a LUAD prognostic signature. We further conducted gene functional enrichment, immune microenvironment and immunotherapy analysis between 2 risk subgroups. Finally, we verified m5C-IRGs-related prognostic gene expression in transcription level. RESULTS: A total of 76 m5C-IRGs were identified in TCGA-LUAD dataset. Furthermore, 27 m5C-IRGs associated with survival were retained. Then, a m5C-IRGs prognostic signature was build based on the 3 prognostic genes (HLA-DMB, PPIA, and GPI). Independent prognostic analysis suggested that stage and RiskScore could be used as independent prognostic factors. We found that 4104 differentially expressed genes (DEGs) between the 2 risk subgroups were mainly concerned in immune receptor pathways. We found certain distinction in LUAD immune microenvironment between the 2 risk subgroups. Then, immunotherapy analysis and chemotherapeutic drug sensitivity results indicated that the m5C-IRGs-related gene signature might be applied as a therapy predictor. Finally, we found significant higher expression of PPIA and GPI in LUAD group compared to the normal group. CONCLUSIONS: The prognostic signature comprised of HLA-DMB, PPIA, and GPI based on m5C-IRGs was established, which might provide theoretical basis and reference value for the research of LUAD. PUBLIC DATASETS ANALYZED IN THE STUDY: TCGA-LUAD dataset was collected from the TCGA (https://portal.gdc.cancer.gov/) database, GSE31210 (validation set) was retrieved from GEO (https://www.ncbi.nlm.nih.gov/geo/) database.

Moxibustion pre-treatment attenuates seizure severity during status epilepticus and counteracts the proconvulsant function of the purinergic P2X7 receptor.

Moxibustion, traditional Chinese medicine treatment, involves the warming of specific acupuncture points of the body using ignited herbal materials. Evidence suggests beneficial effects of moxibustion in several brain diseases including epilepsy, however, whether moxibustion pretreatment impacts on seizures and what are the underlying mechanisms remains to be established. Evidence has suggested the purinergic ATP-gated P2X7 receptor (P2X7R) to be involved in the actions of moxibustion. Moreover, P2X7R signalling is now well established to contribute to long-lasting brain hyperexcitability underlying epilepsy development. Whether P2X7R signalling is involved in the seizure-reducing actions of moxibustion has not been investigated to date. For our studies we used C57BL/6 male mice that received moxibustion pre-treatments at the acupoints Zusanli (ST36) and Dazhui (GV14) once daily for either 7, 14, or 21 days. This was followed by an intraperitoneal injection of kainic acid (KA, 30 mg/kg) to induce status epilepticus. Behavioral changes during KA-induced status epilepticus were analyzed according to the Racine scale. Changes in electrographic seizures were analyzed via cortical implanted electroencephalogram (EEG) electrodes. While no effect on seizure severity was observed following 7 days of moxibustion pre-treatment, moxibustion pre-treatment at both ST36 and GV14 for 14 or 21 days significantly reduced KA-induced behavior seizures at a similar rate. Cortical EEG recordings showed that 14 days of moxibustion pre-treatments also reduced electrographic seizures, confirming the anticonvulsant actions of moxibustion pre-treatment. To determine whether moxibustion impacts the pro-convulsant actions of P2X7R signaling, mice were treated with the P2X7R agonist BzATP or P2X7R antagonist A438079. While treatment with the P2X7R agonist BzATP exacerbated seizure severity, treatment with the P2X7R antagonist reduced seizure severity. We further found that moxibustion pre-treatment attenuated epileptic seizures by counteracting the effects of BzATP. These results suggest that moxibustion pre-treatment at the acupoints ST36 and GV14 for 14 days has anti-epileptic effects, which may counteract the proconvulsant functions of the P2X7R.

Photo-Mediated RAFT Step-Growth Polymerization With Diacrylate Monomers: Investigating Versatility and Oxygen Tolerance.

Photomediated reversible addition fragmentation chain transfer (RAFT) step-growth polymerization is performed using a trithiocarbonate-based chain transfer agent (CTA) and acrylate-based monomers both with and without a photocatalyst. The versatility of photo-mediated RAFT step-growth is demonstrated by one-pot synthesis of a graft copolymer via sequential monomer addition. Furthermore, oxygen-tolerant photo-mediated RAFT step-growth is demonstrated, facilitated by the appropriate selection of photocatalyst and solvent pair (zinc tetraphenyl porphyrin [ZnTPP] and dimethyl sulfoxide [DMSO]), enabling ultralow volume polymerization under open-air conditions.

Tuning the Mechanical Properties of 3D-printed Objects by Mixing Chain Transfer Agents in Radical Promoted Cationic RAFT Polymerization.

The utilization of (cationic) reversible addition-fragmentation chain transfer (RAFT) polymerization in photoinduced three-dimensional (3D) printing has emerged as a robust technique for fabricating a variety of stimuli-responsive materials. However, methods for precisely adjusting the mechanical properties of these materials remain limited, thereby constraining their broader applicability. In this study, a facile way is introduced to modulate the mechanical properties of 3D printed objects by mixing two chain transfer agents (CTAs) within a radical-promoted cationic RAFT (RPC-RAFT) polymerization-based 3D printing process. Through systematic investigations employing tensile testing and dynamic mechanical analysis (DMA), the influence of CTA concentration and molar ratio between two CTAs on the mechanical behavior of the printed objects are explored. These findings demonstrate that higher concentrations of CTAs or a greater molar ratio of the more active CTA within the mixed CTAs result in decreased Young's modulus and glass transition temperatures of the printed objects. Moreover, the tensile failure strain increased with the increasing CTA content, i.e., the samples became more ductile. This methodology broadens the toolbox available for tailoring the mechanical properties of 3D printed materials.

Nanocurcumin attenuates pyroptosis and inflammation through inhibiting NF-κB/GSDMD signal in high altitude-associated acute liver injury.

Exposure to a hypobaric hypoxic environment at high altitudes can lead to liver injury, and mounting evidence indicates that pyroptosis and inflammation play important roles in liver injury. Curcumin (Cur) can inhibit pyroptosis and inflammation. Therefore, our purpose here was to clarify the mechanism underlying the protective effect of nanocurcumin (Ncur) and Cur in a rat model of high altitude-associated acute liver injury. Eighty healthy rats were selected and exposed to different altitudes (6000 or 7000 m) for 0, 24, 48, or 72 h. Fifty normal healthy rats were divided into normal control, high-altitude control, salidroside (40 mg/kg [Sal-40]), Cur (200 mg/kg [Cur-200]), and Ncur (25 mg/kg [Ncur-25]) groups and exposed to a high-altitude hypobaric hypoxic environment (48 h, 7000 m). Serum-liver enzyme activities (alanine transaminase, aspartate transaminase, and lactate dehydrogenase were detected and histopathology of liver injury was evaluated by hematoxylin and eosin staining, and inflammatory factors were detected in liver tissues by enzyme-linked immunosorbent assays. Pyroptosis-associated proteins (gasdermin D, gasdermin D N-terminal [GSDMD-N], pro-Caspase-1, and cleaved-Caspase-1 [cleaved-Casp1]) and inflammation-associated proteins (nuclear factor-κB [NF-κB], phospho-NF-κB [P-NF-κB], and high-mobility group protein B1 [HMGB1]) levels were analyzed by immunoblotting. Ncur and Cur inhibited increased serum-liver enzyme activities, alleviated liver injury in rats caused by high-altitude hypobaric hypoxic exposure, and downregulated inflammatory factors, including tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-18, in rat liver tissues. The level of P-NF-κB, GSDMD-N, cleaved-Casp1, and HMGB1 in rat liver tissues increased significantly after high-altitude exposure. Ncur and Cur downregulated P-NF-κB, GSDMD-N, cleaved-Casp-1, and HMGB1. Ncur and Cur may inhibit inflammatory responses and pyroptosis in a rat model of high altitude-associated acute liver injury.

Reevaluating Adiponectin's impact on obesity hypertension: a Chinese case-control study.

BACKGROUND: Obesity and hypertension are major risk factors for cardiovascular diseases that affect millions of people worldwide. Both conditions are associated with chronic low-grade inflammation, which is mediated by adipokines such as adiponectin. Adiponectin is the most abundant adipokine that has a beneficial impact on metabolic and vascular biology, while high serum concentrations are associated with some syndromes. This "adiponectin paradox" still needs to be clarified in obesity-associated hypertension. The aim of this study was to investigate how adiponectin affects blood pressure, inflammation, and metabolic function in obesity hypertension using a Chinese adult case-control study. METHODS: A case-control study that had finished recruiting 153 subjects divided as four characteristic groups. Adiponectin serum levels were tested by ELISA in these subjects among these four characteristic Chinese adult physical examination groups. Waist circumference (WC), body mass index (BMI), systolic blood pressure (SB), diastolic blood pressure (DB), and other clinical laboratory data were collected. Analyzation of correlations between the research index and differences between groups was done by SPSS. RESULTS: Serum adiponectin levels in the| normal healthy group (NH group) were significantly higher than those in the newly diagnosed untreated just-obesity group (JO group), and negatively correlated with the visceral adiposity index. With multiple linear egression analysis, it was found that, for serum adiponectin, gender, serum albumin (ALB), alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDLC) were the significant independent correlates, and for SB, age and HDLC were the significant independent correlates, and for DB, alkaline phosphatase (ALP) was the significant independent correlate. The other variables did not reach significance in the model. CONCLUSIONS: Our study reveals that adiponectin's role in obesity-hypertension is multifaceted and is influenced by the systemic metabolic homeostasis signaling axis. In obesity-related hypertension, compensatory effects, adiponectin resistance, and reduced adiponectin clearance from impaired kidneys and liver all contribute to the "adiponectin paradox".

Early neural activity changes associated with stimulus detection during visual conscious perception.

The earliest cortical neural signals following consciously perceived visual stimuli in humans are poorly understood. Using intracranial electroencephalography, we investigated neural activity changes associated with the earliest stages of stimulus detection during visual conscious perception. Participants (N = 10; 1,693 electrode contacts) completed a continuous performance task where subjects were asked to press a button when they saw a target letter among a series of nontargets. Broadband gamma power (40-115 Hz) was analyzed as marker of cortical population neural activity. Regardless of target or nontarget letter type, we observed early gamma power changes within 30-180 ms from stimulus onset in a network including increases in bilateral occipital, fusiform, frontal (including frontal eye fields), and medial temporal cortex; increases in left lateral parietal-temporal cortex; and decreases in the right anterior medial occipital cortex. No significant differences were observed between target and nontarget stimuli until >180 ms post-stimulus, when we saw greater gamma power increases in left motor and premotor areas, suggesting a possible role in perceptual decision-making and/or motor responses with the right hand. The early gamma power findings support a broadly distributed cortical visual detection network that is engaged at early times tens of milliseconds after signal transduction from the retina.