Atmosphere teleconnections from abatement of China aerosol emissions exacerbate Northeast Pacific warm blob events.

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

GDPF: a data resource for the distribution of prokaryotic protein families across the global biosphere.

Microorganisms encode most of the functions of life on Earth. However, conventional research has primarily focused on specific environments such as humans, soil and oceans, leaving the distribution of functional families throughout the global biosphere poorly comprehended. Here, we present the database of the global distribution of prokaryotic protein families (GDPF, http://bioinfo.qd.sdu.edu.cn/GDPF/), a data resource on the distribution of functional families across the global biosphere. GDPF provides global distribution information for 36 334 protein families, 19 734 superfamilies and 12 089 KEGG (Kyoto Encyclopedia of Genes and Genomes) orthologs from multiple source databases, covering typical environments such as soil, oceans, animals, plants and sediments. Users can browse, search and download the distribution data of each entry in 10 000 global microbial communities, as well as conduct comparative analysis of distribution disparities among multiple entries across various environments. The GDPF data resource contributes to uncovering the geographical distribution patterns, key influencing factors and macroecological principles of microbial functions at a global level, thereby promoting research in Earth ecology and human health.

MESPEUS: a database of metal coordination groups in proteins.

MESPEUS is a freely accessible database which uses carefully selected metal coordination groups found in metalloprotein structures taken from the Protein Data Bank. The database contains geometrical information of metal sites within proteins, including 40 metal types. In order to completely determine the metal coordination, the symmetry-related units of a given protein structure are taken into account and are generated using the appropriate space group symmetry operations. This permits a more complete description of the metal coordination geometry by including all coordinating atoms. The user-friendly web interface allows users to directly search for a metal site of interest using several useful options, including searching for metal elements, metal-donor distances, coordination number, donor residue group, and structural resolution. These searches can be carried out singly or in combination. The details of a metal site and the metal site(s) in the whole structure can be graphically displayed using the interactive web interface. MESPEUS is automatically updated monthly by synchronizing with the PDB database. An investigation for the Mg-ATP interaction is given to demonstrate how MESPEUS can be used to extract information about metal sites by selecting structure and coordination features. MESPEUS is available at http://mespeus.nchu.edu.tw/.

Hypomorphic and dominant-negative impact of truncated SOX9 dysregulates Hedgehog-Wnt signaling, causing campomelia.

Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9+/-) with the Sox9+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some Sox9+/Y440X mice survived, all Sox9+/- mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in Sox9+/Y440X compared with Sox9+/-. Activating Sox9Y440X specifically in the chondrocyte-osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing Sox9+/Y440X limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9Y440X failed to interact with ß-catenin and was unable to suppress transactivation of Ihh in cell-based assays. We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia.

CTP-Defined Large Core Is a Better Predictor of Poor Outcome for Endovascular Treatment Than ASPECTS-Defined Large Core.

BACKGROUND: Recent trials confirmed the effectiveness of endovascular therapy in patients with large ischemic cores. Yet the optimal neuroimaging modalities to define large core remains unclear. We tried to address this question by comparing the functional outcomes in patients receiving thrombectomy selected by either noncontrast computed tomography Alberta Stroke Program Early Computed Tomography Score (ASPECTS) or computed tomography perfusion (CTP). METHODS: This study retrospectively selected patients enrolled in the International Stroke Perfusion Registry between August 2011 and April 2022. Patients with acute stroke with large vessel occlusion in anterior circulation treated with endovascular therapy were included. All received both CTP and noncontrast computed tomography. The primary outcome was defined as poor functional outcome represented by a modified Rankin Scale score of 5 to 6 at 3 months. Large cores were defined in terms of either (1) noncontrast computed tomography ASPECTS ≤5 or (2) core volume ≥70 mL on CTP. RESULTS: A total of 1115 patients were included in the analysis, of which 90 patients had ASPECTS ≤5 (8.1%) and 97 patients CTP core ≥70 mL (8.7%). A fair agreement between ASPECTS and CTP with a κ value of 0.31 (0.21-0.40) was found. Compared with patients with neither CTP nor ASPECTS large cores, those with only ASPECTS-defined large cores (ie, ASPECTS ≤5; n=56) did not have a higher adjusted odds of poor outcome (29%; odds ratio, 1.84 [0.91-3.73]; P=0.089). However, patients with CTP large core but not ASPECTS-defined large core (n=63) had a higher adjusted odds of poor outcome (60%; odds ratio, 3.91 [2.01-7.60]; P<0.001). In time-stratified subgroup analysis (>6 versus ≤6 hours), ASPECTS showed no discriminative difference between ≤5 and >5 in poor outcome for patients receiving endovascular therapy within 6 hours. CONCLUSIONS: CTP core ≥70 mL-defined large cores are more predictive of poor outcome than ASPECTS ≤5-defined core in endovascular therapy patients, particularly within 6 hours after stroke onset.

Genome-wide identification and expression analysis of the SPL transcription factor family and its response to abiotic stress in Pisum sativum L.

Squamous promoter binding protein-like (SPL) genes encode plant-specific transcription factors (TFs) that play essential roles in modulating plant growth, development, and stress response. Pea (Pisum sativum L.) is a coarse grain crop of great importance in food production, biodiversity conservation and molecular genetic research, providing genetic information and nutritional resources for improving agricultural production and promoting human health. However, only limited researches on the structure and functions of SPL genes exist in pea (PsSPLs). In this study, we identified 22 PsSPLs and conducted a genome-wide analysis of their physical characteristics, chromosome distribution, gene structure, phylogenetic evolution and gene expression patterns. As a result, the PsSPLs were unevenly distributed on the seven chromosomes of pea and harbored the SBP domain, which is composed of approximately 76 amino acid residues. The phylogenetic analysis revealed that the PsSPLs clustered into eight subfamilies and showed high homology with SPL genes in soybean. Further analysis showed the presence of segmental duplications in the PsSPLs. The expression patterns of 22 PsSPLs at different tissues, developmental stages and under various stimulus conditions were evaluated by qRT-PCR method. It was found that the expression patterns of PsSPLs from the same subfamily were similar in different tissues, the transcripts of most PsSPLs reached the maximum peak value at 14 days after anthesis in the pod. Abiotic stresses can cause significantly up-regulated PsSPL19 expression with spatiotemporal specificity, in addition, four plant hormones can cause the up-regulated expression of most PsSPLs including PsSPL19 in a time-dependent manner. Therefore, PsSPL19 could be a key candidate gene for signal transduction during pea growth and development, pod formation, abiotic stress and plant hormone response. Our findings should provide insights for the elucidating of development regulation mechanism and breeding for resistance to abiotic stress pea.

Men with nonobstructive coronary disease have higher burden of ischemic heart disease detected by cardiopulmonary exercise test.

BACKGROUND: Nonobstructive coronary artery disease (NOCAD), characterized by the presence of myocardial ischemic symptoms and signs without obstructive coronaries, is a common clinical condition, but it is less well understood. Few studies have analyzed the gender differences in inducible myocardial ischemia assessed by cardiopulmonary exercise test (CPET) in NOCAD. METHODS: We conducted a study of 289 NOCAD patients (mean age 60, 56% women) with ischemic symptoms and confirmed ⫹50% coronaries stenoses by coronary angiography who underwent symptom-limited CPET. We assessed ischemic response using predicted % peak VO2 , O2 pulse trajectory, and exercise ECG test. RESULTS: Men with NOCAD had significantly lower predicted % peak VO2 (62% vs. 73%), higher proportions of flattening pattern (16% vs. 2%), and downward patterns of O2 pulse trajectory (2% vs. 0%) (p < .0001) compared with women. In contrast, women with NOCAD had a higher prevalence of shallow patterns of O2 pulse trajectory (21% vs. 6%, p < .0001). Men with NOCAD had a higher risk ischemic profile (medium risk: 63% vs. 54%, high risk: 18% vs. 4%, p < .0001). After adjustment, men with NOCAD had significantly lower predicted % peak VO2 (ß -27.4, 95% CI -30.74 to -24.07), higher risk for abnormal O2 pulse trajectories (OR 4.21, 95% CI 1.93 to 9.19), and myocardial ischemia risk per CPET parameters (OR 3.14, 95% CI 1.78 to 5.54) (p < .0001). CONCLUSION: Men with NOCAD had a higher risk profile for ischemic heart disease per CPET. Therefore, they should receive rigorous management and follow-up to prevent cardiovascular events.

Aggregation-Induced Enhanced Electrochemiluminescence from Tris(bipyridine)ruthenium(II) Derivative Nanosheets for the Ultrasensitive Detection of Human Telomerase RNA.

The traditional tris(bipyridine)ruthenium(II) complex suffers from the notorious aggregation-caused quenching effect, which greatly compromises its electrochemiluminescence (ECL) efficiency, thus hindering further applications in biosensing and clinical diagnosis. Here, the ultrathin tetraphenylethylene-active tris(bipyridine)ruthenium(II) derivative nanosheets (abbreviated as Ru-TPE NSs) are synthesized through a protein-assisted self-assembly strategy for ultrasensitive ECL detection of human telomerase RNA (hTR) for the first time. The synthesized Ru-TPE NSs exhibit the aggregation-induced enhanced ECL behavior and excellent water-dispersion. Surprisingly, up to a 106.5-fold increase in the ECL efficiency of Ru-TPE NSs is demonstrated compared with the dispersed molecules in an organic solution. The restriction of intramolecular motions is confirmed to be responsible for the significant ECL enhancement. Therefore, this proposed ECL biosensor shows high sensitivity and excellent selectivity for hTR based on Ru-TPE NSs as efficient ECL beacons and the catalytic hairpin assembly as signal amplification, whose detection limit is as low as 8.0 fm, which is far superior to the previously reported works. Here, a promising analytical method is provided for early clinical diagnosis and a new type of efficient ECL emitters with great application prospects is represented.

Endoscopic combined intrarenal surgery composed of micro-perc and retrograde intrarenal surgery in the treatment of complex kidney stones in children.

OBJECTIVE: This research aims to explore the efficiency and safety of endoscopic combined intrarenal surgery (Micro-ECIRS) composed of micro-percutaneous nephrolithotomy (Micro-perc) and retrograde intrarenal surgery (RIRS) in the Galdakao-modified supine Valdivia (GMSV) position for a single session for the treatment of complex nephrolithiasis in children. MATERIALS AND METHODS: This study retrospectively reviewed patients aged < 18 years who underwent Micro-ECIRS in the GMSV position for renal stones larger than 2 cm under ultrasound guidance between August 2020 to May 2022 at our institution. RESULTS: A total of 13 patients (8 males and 5 females) received Micro-ECIRS for renal stones under ultrasound guidancewhile adopting the GMSV position. The average stone size was 2.7 cm (range: 2.1-3.7 cm). Among them, 6 patients had left kidney stones, 5 patients had right kidney stones, and 2 patients had bilateral kidney stones. The mean operative time was 70.5 min (range: 54-93 min). The mean hospital stay was 6.4 days (range: 4-9 days). The mean hemoglobin decrease was 8.2 g/L (range: 5.1-12.4 g/L). The total number of kidneys that had complete stone clearance was 8 kidneys at 48 h postoperatively, 11 kidneys at 2 weeks postoperatively, and 14 kidneys at 1 month postoperatively. CONCLUSION: Our results demonstrate that Micro-ECIRS while patients are in the GMSV position is a safe and effective method for the treatment of complex children nephrolithiasis. However, all children made three hospital visits and received anesthesia three times. Further research is needed to confirm these findings.

An updated meta-analysis of optimal medical therapy with or without invasive therapy in patients with stable coronary artery disease.

BACKGROUND: The efficacy of optimal medical therapy (OMT) with or without revascularization therapy in patients with stable coronary artery disease (SCAD) remains controversial. We performed a meta-analysis of randomized controlled trials (RCTs) that compared OMT with or without revascularization therapy for SCAD patients. METHODS: Studies were searched in PubMed, EMBASE, and the Cochrane Central Register of Clinical Trials from January 1, 2005, to December 30, 2023. The main efficacy outcome was a composite of all-cause death, myocadiac infarction, revascularization, and cerebrovascular accident. Results were pooled using random effects model and fixed effects model and are presented as odd ratios (ORs) with 95% confidence intervals (CI). RESULTS: Ten studies involving 12,790 participants were included. The arm of OMT with revascularization compared with OMT alone was associated with decreased risks for MACCE (OR 0.55 [95% CI 0.38-0.80], I²=93%, P = 0.002), CV death (OR 0.84 [95% CI 0.73-0.97], I²=36%, P = 0.02), revascularization (OR 0.32 [95% CI 0.20-0.50], I²=92%, P < 0.001), and MI (OR 0.85 [95% CI 0.76-0.96], I²=45%, P = 0.007). While there was no significant difference between OMT with revascularization and OMT alone in the odds of all-cause death (OR 0.94 [95% CI 0.84-1.05], I²=0%, P = 0.30). CONCLUSIONS: The current updated meta-analysis of 10 RCTs shows that in patients with SCAD, OMT with revascularization would reduce the risk for MACCE, cardiovascular death, and MI. However, the invasive strategy does not decrease the risks for all-cause mortality when comparing with OMT alone.

Comparison of Three Detection Methods for Seoul Virus Causing Hemorrhagic Fever with Renal Syndrome.

BACKGROUND: Seoul virus (SEOV) is a significant causative pathogen of hemorrhagic fever with renal syndrome (HFRS). Accurate discrimination of SEOV infection from other viral or bacterial infections holds vital clinical importance. METHODS: Our study utilized quantitative real-time PCR (qRT-PCR), metagenomic next-generation sequencing (mNGS), and immunological assays to identify the pathogen causing HFRS. RESULTS: For the case, mNGS identified SEOV and suspected host or environmental microorganisms at 5 days from symptom onset. qRT-PCR detected SEOV between 5 to 8 days from symptom onset. Anti-hantavirus IgM antibodies reached positive criteria at 7 days and IgG antibodies at 9 days from symptom onset. CONCLUSIONS: qRT-PCR, mNGS, and immunological assays each have merits and drawbacks. Optimal selection depends on laboratory conditions and clinical requirements.

Loss of function of a DMR6 ortholog in tomato confers broad-spectrum disease resistance.

Plant diseases are among the major causes of crop yield losses around the world. To confer disease resistance, conventional breeding relies on the deployment of single resistance (R) genes. However, this strategy has been easily overcome by constantly evolving pathogens. Disabling susceptibility (S) genes is a promising alternative to R genes in breeding programs, as it usually offers durable and broad-spectrum disease resistance. In Arabidopsis, the S gene DMR6 (AtDMR6) encodes an enzyme identified as a susceptibility factor to bacterial and oomycete pathogens. Here, we present a model-to-crop translational work in which we characterize two AtDMR6 orthologs in tomato, SlDMR6-1 and SlDMR6-2. We show that SlDMR6-1, but not SlDMR6-2, is up-regulated by pathogen infection. In agreement, Sldmr6-1 mutants display enhanced resistance against different classes of pathogens, such as bacteria, oomycete, and fungi. Notably, disease resistance correlates with increased salicylic acid (SA) levels and transcriptional activation of immune responses. Furthermore, we demonstrate that SlDMR6-1 and SlDMR6-2 display SA-5 hydroxylase activity, thus contributing to the elucidation of the enzymatic function of DMR6. We then propose that SlDMR6 duplication in tomato resulted in subsequent subfunctionalization, in which SlDMR6-2 specialized in balancing SA levels in flowers/fruits, while SlDMR6-1 conserved the ability to fine-tune SA levels during pathogen infection of the plant vegetative tissues. Overall, this work not only corroborates a mechanism underlying SA homeostasis in plants, but also presents a promising strategy for engineering broad-spectrum and durable disease resistance in crops.

HBV confers innate immune evasion through triggering HAT1/acetylation of H4K5/H4K12/miR-181a-5p or KPNA2/cGAS-STING/IFN-I signaling.

Viral immune evasion is crucial to the pathogenesis of hepatitis B virus (HBV) infection. However, the role of HBV in the modulation of innate immune evasion is poorly understood. A liver-specific histone acetyltransferase 1 (Hat1) knockout (KO) mouse model and HAT1 KO cell line were established. Immunohistochemistry staining, Western blot analysis, Southern blot analysis, Northern blot analysis, immunofluorescence assays, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and chromatin immunoprecipitation assays were performed in the livers of mouse models, primary human hepatocytes, HepG2-NTCP, and Huh7 and HepG2 cell lines. HBV-elevated HAT1 increased the expression of miR-181a-5p targeting cyclic GMP-AMP synthase (cGAS) messenger RNA 3' untranslated regions through modulating acetylation of H4K5 and H4K12 in vitro and in vivo, leading to the inability of cGAS-stimulator of interferon genes (STING) pathway and type I interferon (IFN-I) signaling. Additionally, HBV-elevated HAT1 promoted the expression of KPNA2 through modulating acetylation of H4K5 and H4K12 in the system, resulting in nuclear translocation of cGAS, HBx was responsible for the events by HAT1, suggesting that HBV-elevated HAT1 controls the cGAS-STING pathway and IFN-I signaling to modulate viral innate immune evasion. HBV confers innate immune evasion through triggering HAT1/acetylation of H4K5/H4K12/miR-181a-5p or KPNA2/cGAS-STING/IFN-I signaling. Our finding provides new insights into the mechanism by which HBV drives viral innate immune evasion.

Prognostic value of triglyceride glucose index in population at high cardiovascular disease risk.

BACKGROUND: Early identification of populations at high cardiovascular disease (CVD) risk and improvement of risk factors can significantly decrease the probability of CVD development and improve outcomes. Insulin resistance (IR) is a CVD risk factor. The triglyceride glucose (TyG) index is a simple and reliable index for evaluating IR. However, no clinical studies on the prognostic value of the TyG index in a high risk CVD population have been conducted. This study evaluated the relationship between the TyG index and prognosis in a high risk CVD population. METHODS: This study enrolled 35,455 participants aged 35-75 years who were at high CVD risk and visited selected health centers and community service centers between 2017 and 2021. Their general clinical characteristics and baseline blood biochemical indicators were recorded. The TyG index was calculated as ln[fasting triglyceride (mg/dl)× fasting blood glucose (mg/dl)/2]. The endpoints were all-cause death and cardiovascular death during follow-up. Cox proportional hazard models and restricted cubic spline (RCS) analysis were used to evaluate the correlation between the TyG index and endpoints. RESULTS: In the overall study population, the mean age of all participants was 57.9 ± 9.6 years, 40.7% were male, and the mean TyG index was 8.9 ± 0.6. All participants were divided into two groups based on the results of the RCS analysis, with a cut-off value of 9.83. There were 551 all-cause deaths and 180 cardiovascular deaths during a median follow-up time of 3.4 years. In the multivariate Cox proportional hazard model, participants with a TyG index ≥ 9.83 had a higher risk of all-cause death (Hazard ratio [HR] 1.86, 95% Confdence intervals [CI] 1.37-2.51, P<0.001) and cardiovascular death (HR 2.41, 95%CI 1.47-3.96, P = 0.001) than those with a TyG index < 9.83. Subgroup analysis revealed that there was no interaction between the TyG index and variables in all subgroup analyses. CONCLUSIONS: The high TyG index was associated with an increased risk of all-cause death and cardiovascular death in people at high risk of CVD. This finding demonstrates the value of the TyG index in the primary prevention of CVD. TRIAL REGISTRATION: retrospectively registered, the registration number is K2022-01-005 and the date is 2022.01.30.

Single-center experience of micro-perc in the treatment of children with 1.0-2.0 cm sized kidney stones in the Galdakao-modified supine Valdivia position.

OBJECTIVE: We aimed to explore the applicability and safety of micro-percutaneous nephrolithotomy (micro-perc) in the treatment of children with kidney stones in the Galdakao-modified supine Valdivia (GMSV) position under the guidance of whole-course ultrasound. MATERIALS AND METHODS: Patients were aged < 18 years in the GMSV position who underwent micro-perc for kidney stones under ultrasound guidance between August 2020 and May 2022 at our institution were reviewed retrospectively. RESULTS: A total of 23 patients, 15 males and 8 females, received micro-perc. The average stone size was 1.6 cm (range 1.1-2.0 cm). Among them, 12 patients had left kidney stones, 10 patients had right kidney stones, and 1 patient had bilateral kidney stones. The mean operative time was 55.3 min (range 35-86 min). The mean hospital stay was 2.9 days (range 2-4 days). The mean hemoglobin decrease was 1.7 g/L (range 0.9-3.2 g/L). A total of 17 patients had complete stone clearance at 48 h postoperatively. A total of 22 patients had complete stone clearance at 2 weeks postoperatively. CONCLUSION: Our results demonstrate that micro-perc under ultrasound guidance is a safe and effective method for the treatment of children with kidney stones in the GMSV position. Further research is warranted to confirm these results.

Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis.

Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.

Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer.

Aspirin as a chemopreventive agent is able to restrict the tumor growth. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme of glycolysis, playing an important role in the development of cancer. However, the underlying mechanism by which aspirin inhibits the proliferation of cancer cells is poorly understood. This study aims to identify the effects of aspirin on modulating PGAM1 enzymatic activities in liver cancer. Here, we found that aspirin attenuated the PGAM1 succinylation to suppress the PGAM1 enzymatic activities and glycolysis in hepatoma cells. Mechanically, aspirin remarkably reduced the global succinylation levels of hepatoma cells, including the PGAM1 succinylation, which led to the block of conversion from 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG) in cells. Interestingly, RNA-seq analysis identified that aspirin could significantly decrease the levels of histone acetyltransferase 1 (HAT1), a writer of PGAM1 succinylation, in liver cancer. As a target of aspirin, NF-κB p65 could effectively up-regulate the expression of HAT1 in the system, resulting in the increase of PGAM1 enzymatic activities. Moreover, we observed that the PGAM1-K99R mutant failed to rescue the aspirin-induced inhibition of PGAM1 activities, glycolysis, and proliferation of hepatoma cells relative to PGAM1-WT. Functionally, aspirin down-regulated HAT1 and decreased the PGAM1 succinylation levels in the tumor tissues from mice treated with aspirin in vivo. Thus, we conclude that aspirin modulates PGAM1K99 succinylation to restrict the PGAM1 activities and glycolysis through NF-κB p65/HAT1/PGAM1 signaling in liver cancer. Our finding provides new insights into the mechanism by which aspirin inhibits glycolysis in hepatocellular carcinoma.

Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription.

A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 µM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.

HOXB13 facilitates hepatocellular carcinoma progression by activating AKT/mTOR signaling pathway.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the sixth most common malignancies worldwide and is accompanied by high mortality. Homeobox B13 (HOXB13) has been shown to be involved in the development of various cancers. This study aimed to investigate the role of HOXB13 in HCC progression. MATERIALS AND METHODS: The expression of HOXB13 in HCC tumor tissues was analyzed using qRT-PCR and immunohistochemical staining . After overexpression or downregulation of HOXB13 in HCC cell lines, cell proliferation was detected by CCK8 assay and Ki67 staining and cell invasion ability were tested by transwell assay. Western blot assay was applied to analyze the effect of HOXB13 on related signaling pathways. In addition, the role of HOXB13 on HCC in vivo was explored using a HCC mouse model. IF and WB were performed to detect cell proliferation, apoptosis and related protein expression in mice tumor tissues. RESULTS: The results showed that the expression of HOXB13 was significantly increased in HCC tissues compared with adjacent tissues and positively correlated with the tumor stage and survival of HCC patients. Overexpression of HOXB13 promoted the proliferation and invasion of HCC cells and up-regulated the protein expression of AKT, mTOR and MMP2. In contrast, the downregulation of HOXB13 resulted in the opposite results. In vivo experiments, HOXB13 significantly promoted tumor growth in mice bearing HCC by promoting cell proliferation and inhibiting cell apoptosis. CONCLUSIONS: This study suggested that HOXB13 can facilitate HCC progression by activation of the AKT/mTOR signaling pathway. HOXB13 may be a novel target for HCC therapy.

A longitudinal study of humoral immune responses induced by a 3-dose inactivated COVID-19 vaccine in an observational, prospective cohort.

BACKGROUND: To determine the dynamic SARS-CoV-2 specific antibody levels induced by 3 doses of an inactivated COVID-19 vaccine, CoronaVac. An observational, prospective cohort study was performed with 93 healthy healthcare workers from a tertiary hospital in Nanjing, China. Serum SARS-CoV-2 specific IgM, IgG, and neutralizing antibodies (NAb) were measured at different time points among participants who received 3 doses of inactivated COVID-19 vaccine. RESULTS: 91.3% (85/93) and 100% (72/72) participants showed positive both for SARS-CoV-2 specific IgG and NAb after 2-dose CoronaVac and after 3-dose CoronaVac, respectively. Anti-SARS-CoV-2 IgG responses reached 91.21 (55.66-152.06) AU/mL, and surrogate NAb was 47.60 (25.96-100.81) IU/mL on day 14 after the second dose. Anti-SARS-CoV-2 IgG responses reached 218.29 (167.53-292.16) AU/mL and surrogate NAb was 445.54 (171.54-810.90) IU/mL on day 14 after the third dose. Additionally, SARS-CoV-2 specific surrogate neutralizing antibody titers were highly correlated with serum neutralization activities against Ancestral, Omicron, and Delta strains. Moreover, significantly higher SARS-CoV-2 IgG responses, but not NAb responses, were found in individuals with breakthrough infection when compared to that of 3-dose CoronaVac recipients. CONCLUSIONS: CoronaVac elicited robust SARS-CoV-2 specific humoral responses. Surrogate NAb assay might substitute for pseudovirus neutralization assay. Monitoring SARS-CoV-2 antibody responses induced by vaccination would provide important guidance for the optimization of COVID-19 vaccines.