Effective amendment of cadmium in water and soil before and after aging of nitrogen-doped biochar: Preparation optimization, removal efficiency and mechanism.

Nitrogen-doped biochar (NBC) is a green material for remediating heavy metal pollution, but it undergoes aging under natural conditions, affecting its interaction with heavy metals. The preparation conditions of NBC were optimized using response surface methodology (RSM), and NBC was subjected to five different aging treatments to analyze the removal efficiency of Cd(II) and soil remediation capability before and after aging. The results indicated that NBC achieved optimal performance with a mass ratio of 5:2.43, an immersion time of 10.66 h, and a pyrolysis temperature of 900 °C. Aging diminished NBC's adsorption capacity for Cd(II) but did not change the main removal mechanism of monolayer chemical adsorption. Freeze-thaw cycles (FT), UV aging (L), and composite aging (U) treatments increased the proportion of bioavailable-Cd, and all aging treatments facilitated the conversion of potentially bioavailable-Cd to non-bioavailable-Cd. The application of NBC and five aged NBCs reduced the proportion of bioavailable-Cd in the soil through precipitation and complexation, increasing the proportion of non-bioavailable-Cd. Aging modifies the physicochemical properties of NBC, thus influencing soil characteristics and ultimately diminishing NBC's ability to passivate Cd in the soil. This study provides reference for the long-term application of biochar in heavy metal-contaminated environments.

Crosstalk of ubiquitin system and non-coding RNA in fibrosis.

Chronic tissue injury triggers changes in the cell type and microenvironment at the site of injury and eventually fibrosis develops. Current research suggests that fibrosis is a highly dynamic and reversible process, which means that human intervention after fibrosis has occurred has the potential to slow down or cure fibrosis. The ubiquitin system regulates the biological functions of specific proteins involved in the development of fibrosis, and researchers have designed small molecule drugs to treat fibrotic diseases on this basis, but their therapeutic effects are still limited. With the development of molecular biology technology, researchers have found that non-coding RNA (ncRNA) can interact with the ubiquitin system to jointly regulate the development of fibrosis. More in-depth explorations of the interaction between ncRNA and ubiquitin system will provide new ideas for the clinical treatment of fibrotic diseases.

New Myzostomids (Annelida) in Symbiosis with Feather Stars in the Shallow Waters of the South China Sea (Hainan Island).

This research delves into the molecular and morphological characteristics of myzostomid worms associated with common shallow-water feather stars (Echinodermata: Crinoidea: Comatulidae) in the coastal waters near Sanya, Hainan Island. Through the examination of specimens collected at depths of up to 10 m using scuba diving techniques, we describe three new species (Myzostoma ordinatum sp. nov., M. scopus sp. nov., and M. solare sp. nov.) and report the first record of Myzostoma polycyclus Atkins, 1927 in the South China Sea. The absence of overlap with the seven previously documented Myzostomida species in the shallow waters of Hong Kong and Shenzhen reveals significant gaps in our understanding of marine biodiversity in the South China Sea. These findings, combined with an analysis of available molecular data, underscore the potential existence of unexplored and diverse symbiotic relationships among marine invertebrates within the region.

A Scoring System to Predict Severe Acute Lower Respiratory Infection in Children Caused by Respiratory Syncytial Virus.

There were several factors associated with respiratory syncytial virus (RSV) severe acute lower respiratory infection (RSV-sALRI) in infants and young children. It is vital to develop a convenient scoring system to predict RSV-sALRI in children. Pediatric patients with RSV-ALRI from January 2009 to December 2021 were recruited retrospectively. Two-third of them were randomly grouped into the development set and one-third to the validation set. In the development set, risk factors for RSV-sALRI were transferred into the logistic regression analysis, then their receiver operating characteristic (ROC) curves were built to obtain the area under the ROC curve (AUC), and regression coefficients for each predictor were converted to points. Finally, the value of the scoring system was evaluated in the validation set. A total of 1 066 children with RSV-ALRI were recruited, including 710 in the development set and 356 in the validation set. By logistic regression analysis, six factors (younger than 2 years, gestational age <37 weeks, have siblings, birth weight ≤2500 g, artificial/mix feeding, CHD) showed statistical difference and then were scored with points according to the coefficient value (OR) in the development set. In the validation set, the sensitivity of the scoring system was 70.25%, the specificity 85.53%, the positive predictive value 71.43%, the negative predictive value 84.81%, and coincidence rate 0.80. The Kolmogorov-Smirnov test showed the distribution of AUC 0.765 (SE = 0.027; 95% CI = 0.713-0.818; p < 0.001). A simplified scoring system was developed in the study with high prediction value for RSV-sALRI in children.

Regioselective Homolytic C2-H Borylation of Unprotected Adenosine and Adenine Derivatives via Minisci Reaction.

A Minisci-type borylation of unprotected adenosine, adenine nucleotide, and adenosine analogues was successfully achieved through photocatalysis or thermal activation. Despite the challenges posed by the presence of two potential reactive sites (C2 and C8) in the purine motif, the unique nucleophilic amine-ligated boryl radicals effortlessly achieved excellent C2 site selectivity and simultaneously avoided the formation of multifunctionalized products. This protocol proved effective for the late-stage borylation of some important biomolecules as well as a few antiviral and antitumor drug molecules, such as AMP, cAMP, Vidarabine, Cordycepin, Tenofovir, Adefovir, GS-441524, etc. Theoretical calculations shed light on the site selectivity, revealing that the free energy barriers for the C2-Minisci addition are further lowered through the chelation of additive Mg2+ to N3 and furyl oxygen. This phenomenon has been confirmed by an IGMH analysis. Preliminary antitumor evaluation, derivation of the C2-borylated adenosine to other analogues with high-value functionalities, along with the CuAAC click reactions, suggest the potential application of this methodology in drug molecular optimization studies and chemical biology.

Dysregulated energy and protein homeostasis and the loss of GABAergic amacrine cells in aging retina.

Aging is a major risk factor for the development or the worsening of retinal degenerative conditions. The intricate network of the neural retina determined that the retinal aging is a complicated process. The aim of this study is to delineate the transcriptomic changes of major retinal neurons during aging in C57BL/6 mice at single-cell level. We analyzed the transcriptional profiles of the photoreceptor, bipolar, amacrine, and Müller glial cells of 1.5-2 and 24-30 months old mice using single-cell RNA sequencing technique. We selectively confirmed the differences in gene expression using immunofluorescence staining and RNA in situ hybridization analysis. We found that each retinal cell type had unique changes upon aging. However, they all showed signs of dysregulated glucose and energy metabolism, and perturbed proteostasis. In particular, old Müller glia exhibited the most profound changes, including the upregulation of cell metabolism, stress-responses, antigen-presentation and immune responses and metal ion homeostasis. The dysregulated gliogenesis and differentiation was confirmed by the presence of Müller glia expressing rod-specific genes in the inner nuclear layer and the outer plexiform layer of the old retina. We further pinpointed the specific loss of GABAergic amacrine cells in old retina. Our study emphasized changes of amacrine and Müller glia during retinal aging, provided resources for further research on the molecular and cellular regulatory mechanisms underlying aging-associated retinal deterioration.

Multi-output neural network model for predicting biochar yield and composition.

In biomass pyrolysis for biochar production, existing prediction models face computational challenges and limited accuracy. This study curated a comprehensive dataset, revealing pyrolysis parameters' dominance in biochar yield (54.8 % importance). Pyrolysis temperature emerged as pivotal (PCC = -0.75), influencing yield significantly. Artificial Neural Network (ANN) outperformed Random Forest (RF) in testing set predictions (R2 = 0.95, RMSE = 3.6), making it apt for complex multi-output predictions and software development. The trained ANN model, employed in Partial Dependence Analysis, uncovered nonlinear relationships between biomass characteristics and biochar yield. Findings indicated optimization opportunities, correlating low pyrolysis temperatures, elevated nitrogen content, high fixed carbon, and brief residence times with increased biochar yields. A multi-output ANN model demonstrated optimal fit for biochar yield. A user-friendly Graphical User Interface (GUI) for biochar synthesis prediction was developed, exhibiting robust performance with a mere 0.52 % prediction error for biochar yield. This study showcases practical machine learning application in biochar synthesis, offering valuable insights and predictive tools for optimizing biochar production processes.

Fine-YOLO: A Simplified X-ray Prohibited Object Detection Network Based on Feature Aggregation and Normalized Wasserstein Distance.

X-ray images typically contain complex background information and abundant small objects, posing significant challenges for object detection in security tasks. Most existing object detection methods rely on complex networks and high computational costs, which poses a challenge to implement lightweight models. This article proposes Fine-YOLO to achieve rapid and accurate detection in the security domain. First, a low-parameter feature aggregation (LPFA) structure is designed for the backbone feature network of YOLOv7 to enhance its ability to learn more information with a lighter structure. Second, a high-density feature aggregation (HDFA) structure is proposed to solve the problem of loss of local details and deep location information caused by the necked feature fusion network in YOLOv7-Tiny-SiLU, connecting cross-level features through max-pooling. Third, the Normalized Wasserstein Distance (NWD) method is employed to alleviate the convergence complexity resulting from the extreme sensitivity of bounding box regression to small objects. The proposed Fine-YOLO model is evaluated on the EDS dataset, achieving a detection accuracy of 58.3% with only 16.1 M parameters. In addition, an auxiliary validation is performed on the NEU-DET dataset, the detection accuracy reaches 73.1%. Experimental results show that Fine-YOLO is not only suitable for security, but can also be extended to other inspection areas.

High-Frequency Recombination of Human Adenovirus in Children with Acute Respiratory Tract Infections in Beijing, China.

Recombination events in human adenovirus (HAdV) have led to some new highly pathogenic or infectious types. It is vital to monitor recombinant HAdVs, especially in children with acute respiratory tract infections (ARIs). In the retrospective study, HAdV positive specimens were collected from pediatric patients with ARIs during 2015 to 2021, then typed by sequence analysis of the penton base, hexon and fiber gene sequence. For those with inconsistent typing results, a modified method with species-specific primer sets of a fiber gene sequence was developed to distinguish co-infections of different types from recombinant HAdV infections. Then, plaque assays combined with meta-genomic next-generation sequencing (mNGS) were used to reveal the HAdV genomic characteristics. There were 466 cases positive for HAdV DNA (2.89%, 466/16,097) and 350 (75.11%, 350/466) successfully typed with the most prevalent types HAdV-B3 (56.57%, 198/350) and HAdV-B7 (32.00%, 112/350), followed by HAdV-C1 (6.00%, 21/350). Among 35 cases (7.51%, 35/466) with inconsistent typing results, nine cases were confirmed as co-infections by different types of HAdVs, and 26 cases as recombinant HAdVs in six genetic patterns primarily clustered to species C (25 cases) in pattern 1-5, or species D (1 case) in pattern 6. The novel recombinant HAdV of species D was identified with multiple recombinant events among HAdV-D53, HAdV-D64, and HAdV-D8, and officially named as HAdV-D115. High-frequency recombination of HAdVs in six genetic recombination patterns were identified among children with ARIs in Beijing. Specifically, there is a novel Adenovirus D human/CHN/S8130/2023/115[P22H8F8] designed as HAdV D115.

Constructing Self-Healing Polydimethylsiloxane through Molecular Structure Design and Metal Ion Bonding.

Self-healing polydimethylsiloxane (PDMS) has garnered significant attention due to its potential applications across various fields. In this study, a functionalized modification of PDMS containing di-aminos was initially conducted using 2,6-pyridinedicarbonyl chloride to synthesize pyridine-PDMS (Py-PDMS). Subsequently, rare earth metal europium ions (Eu3+) were incorporated into Py-PDMS. Due to the coordination interaction between Eu3+ and organic ligands, a coordination cross-linking network was created within the Py-PDMS matrix, resulting in the fabrication of Eu3+-Py-PDMS elastomer. At a molar ratio of Eu3+ to ligands of 1:1, the tensile strength of Eu3+-Py-PDMS reached 1.4 MPa, with a fracture elongation of 824%. Due to the dynamic reversibility of coordination bonds, Eu3+-Py-PDMS with a metal-to-ligand molar ratio of 1:2 exhibited varying self-healing efficiencies at different temperatures. Notably, after 4 h of repair at 60 °C, its self-healing efficiency reached nearly 100%. Furthermore, the gas barrier properties of Eu3+-Py-PDMS with a molar ratio of 1:1 was improved compared with that of Eu3+-Py-PDMS with a molar ratio of 1:1. This study provides an effective strategy for the design and fabrication of PDMS with high mechanical strength, high gas barrier properties, and exceptional self-healing efficiency.

Thermal Oxidative Aging and Service Life Prediction of Commercial Ethylene-Propylene-Diene Monomer Spacer Damping Composites for High-Voltage Transmission Lines.

The aging behavior and life prediction of rubber composites are crucial for ensuring high-voltage transmission line safety. In this study, commercially available ethylene-propylene-diene monomer (EPDM) spacer composites were chosen and investigated to elucidate the structure and performance changes under various aging conditions. The results showed an increased C=O peak intensity with increasing aging time, suggesting intensified oxidation of ethylene and propylene units. Furthermore, the surface morphology of commercial EPDM composites displayed increased roughness and aggregation after aging. Furthermore, hardness, modulus at 100% elongation, and tensile strength of commercial EPDM composites exhibited a general increase, while elongation at break decreased. Additionally, the damping performance decreased significantly after aging, with a 20.6% reduction in loss factor (20 °C) after aging at 100 °C for 672 h. With increasing aging time and temperature, the compression set gradually rose due to the irreversible movement of the rubber chains under stress. A life prediction model was developed based on a compression set to estimate the lifetime of rubber composites for spacer bars. The results showed that the product's life was 8.4 years at 20 °C. Therefore, the establishment of a life prediction model for rubber composites can provide valuable technical support for spacer product services.

Comparative metabolomics combined with genome sequencing provides insights into novel wolfberry-specific metabolites and their formation mechanisms.

Wolfberry (Lycium, of the family Solanaceae) has special nutritional benefits due to its valuable metabolites. Here, 16 wolfberry-specific metabolites were identified by comparing the metabolome of wolfberry with those of six species, including maize, rice, wheat, soybean, tomato and grape. The copy numbers of the riboflavin and phenyllactate degradation genes riboflavin kinase (RFK) and phenyllactate UDP-glycosyltransferase (UGT1) were lower in wolfberry than in other species, while the copy number of the phenyllactate synthesis gene hydroxyphenyl-pyruvate reductase (HPPR) was higher in wolfberry, suggesting that the copy number variation of these genes among species may be the main reason for the specific accumulation of riboflavin and phenyllactate in wolfberry. Moreover, the metabolome-based neighbor-joining tree revealed distinct clustering of monocots and dicots, suggesting that metabolites could reflect the evolutionary relationship among those species. Taken together, we identified 16 specific metabolites in wolfberry and provided new insight into the accumulation mechanism of species-specific metabolites at the genomic level.

m6A-dependent upregulation of DDX21 by super-enhancer-driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6-methyladenosine (m6A) RNA methylation and super-enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated. METHODS: Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE-related genes. The mechanisms of m6 A-binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co-immunoprecipitation (Co-IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21. RESULTS: We identified two SE-associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A-dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells. CONCLUSIONS: Dysregulation of SE-IGF2BP2/IGF2BP3-DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.

A Risk Model for 28-Day in-Hospital Mortality in 173 COVID-19 Patients Admission to ICU: A Retrospective Study.

Background: The surge in the number of patients diagnosed with COVID-19 since China's open-door policy has placed a huge burden on the public healthcare system, especially the intensive care system. This study's objective was to discover possible clinical outcome predictors in COVID-19 patients treated in intensive care units (ICUs) and to provide useful information for future preventative efforts and therapies. Methods: This retrospective study included 173 COVID-19 critically ill patients and reviewed the 28-day survival outcome in the First Affiliated Hospital of Nanjing Medical University. Competing risk analysis was performed to predict the cumulative incidence function (CIF) of mortality in hospital. The independent prognostic factors were identified by applying the Fine-Gray proportional subdistribution hazard model. Receiver operating characteristic (ROC) curves were used to evaluate model efficacy, and calibration curves were used to validate the model. Finally, we compared the competing risk model with the traditional proportional hazards model (Cox regression model) using CIF. Results: Of these 173 patients, 66 (38.2%) survived, 55 (31.8%) died, and 52 (30.0%) discharged. In univariate analysis, 12 variables were significantly correlated with mortality. In multivariate analysis, Age, Neutrophil ratio, Direct Bilirubin (DBIL) and Renal disease were independent predictors of 28-day outcome. The ROC curve of the multivariate prediction model showed an AUC (area under the curve) of 0.790. The results of the calibration curve and the concordance index (C-index) show that the model has good discriminatory power. The competing risk model we applied was more accurate than the Cox model. Conclusion: We presented a more accurate multivariate prediction model for 28-day in-hospital mortality for ICU COVID-19 patients using a competing risk model.

Late-stage guanine C8-H alkylation of nucleosides, nucleotides, and oligonucleotides via photo-mediated Minisci reaction.

Chemically modified nucleosi(ti)des and functional oligonucleotides (ONs, including therapeutic oligonucleotides, aptamer, nuclease, etc.) have been identified playing an essential role in the areas of medicinal chemistry, chemical biology, biotechnology, and nanotechnology. Introduction of functional groups into the nucleobases of ONs mostly relies on the laborious de novo chemical synthesis. Due to the importance of nucleosides modification and aforementioned limitations of functionalizing ONs, herein, we describe a highly efficient site-selective alkylation at the C8-position of guanines in guanosine (together with its analogues), GMP, GDP, and GTP, as well as late-stage functionalization of dinucleotides and single-strand ONs (including ssDNA and RNA) through photo-mediated Minisci reaction. Addition of catechol to assist the formation of alkyl radicals via in situ generated boronic acid catechol ester derivatives (BACED) markedly enhances the yields especially for the reaction of less stable primary alkyl radicals, and is the key to success for the post-synthetic alkylation of ONs. This method features excellent chemoselectivity, no necessity for pre-protection, wide range of substrate scope, various free radical precursors, and little strand lesion. Downstream applications in disease treatment and diagnosis, or as biochemical probes to study biological processes after linking with suitable fluorescent compounds are expected.

OsBCAT2, a gene responsible for the degradation of branched-chain amino acids, positively regulates salt tolerance by promoting the synthesis of vitamin B5.

Salt stress negatively affects rice growth, development and yield. Metabolic adjustments contribute to the adaptation of rice under salt stress. Branched-chain amino acids (BCAA) are three essential amino acids that cannot be synthesized by humans or animals. However, little is known about the role of BCAA in response to salt stress in plants. Here, we showed that BCAAs may function as scavengers of reactive oxygen species (ROS) to provide protection against damage caused by salinity. We determined that branched-chain aminotransferase 2 (OsBCAT2), a protein responsible for the degradation of BCAA, positively regulates salt tolerance. Salt significantly induces the expression of OsBCAT2 rather than BCAA synthesis genes, which indicated that salt mainly promotes BCAA degradation and not de novo synthesis. Metabolomics analysis revealed that vitamin B5 (VB5) biosynthesis pathway intermediates were higher in the OsBCAT2-overexpressing plants but lower in osbcat2 mutants under salt stress. The salt stress-sensitive phenotypes of the osbcat2 mutants are rescued by exogenous VB5, indicating that OsBCAT2 affects rice salt tolerance by regulating VB5 synthesis. Our work provides new insights into the enzymes involved in BCAAs degradation and VB5 biosynthesis and sheds light on the molecular mechanism of BCAAs in response to salt stress.

BCLAF1 is Expressed as a Potential Anti-oncogene in Bile Duct Cancer.

Validating the role of BCLAF1 in the development of Bile Duct Cancer. Differential expression of BCLAF1 in Bile Duct Cancer and normal tissues was analyzed bioinformatically, and immuno-infiltration analysis was performed by R. We also derived the correlation between the expression of BCLAF1 and HIF-1α by bioinformatics analysis and validated it by Western Blotting, qRT-PCR and scratch assays before and after hypoxia. Through bioinformatics analysis, we found that BCLAF1 mRNA was significantly higher in the tumor tissues of Bile Duct Cancer. The high expression of BCLAF1 implied a more advanced stage but a lower mortality rate. KEGG and GO enrichment analysis showed that BCLAF1 overexpression in Bile Duct Cancer was mainly associated with histone modification, peptidyl lysine modification, and macromolecular methylation. We used the TIMER algorithm to show that BCLAF1 expression in Bile Duct Cancer is associated with immune cell infiltration, which affects tumor progression and patient prognosis. We confirmed by normoxia and hypoxia qRT-PCR, Western Blotting and scratch assays that BCLAF1 and HIF-1α expression are positively correlated and that BCLAF1 may be expressed as anti-oncogene in Bile Duct Cancer. These findings demonstrate that BCLAF1 may act as anti-oncogene in Bile Duct Cancer and may be involved in immune cell infiltration in Bile Duct Cancer, suppressing the expression of HIF-1α.

Dual-Fuel Propelled Nanomotors with Two-Stage Permeation for Deep Bacterial Infection in the Treatment of Pulpitis.

Bacterial infection-induced inflammatory response could cause irreversible death of pulp tissue in the absence of timely and effective therapy. Given that, the narrow structure of root canal limits the therapeutic effects of passive diffusion-drugs, considerable attention has been drawn to the development of nanomotors, which have high tissue penetration abilities but generally face the problem of insufficient fuel concentration. To address this drawback, dual-fuel propelled nanomotors (DPNMs) by encapsulating L-arginine (L-Arg), calcium peroxide (CaO2 ) in metal-organic framework is developed. Under pathological environment, L-Arg could release nitric oxide (NO) by reacting with reactive oxygen species (ROS) to provide the driving force for movement. Remarkably, the depleted ROS could be supplemented through the reaction between CaO2 with acids abundant in the inflammatory microenvironment. Owing to high diffusivity, NO achieves further tissue penetration based on the first-stage propulsion of nanomotors, thereby removing deep-seated bacterial infection. Results indicate that the nanomotors effectively eliminate bacterial infection based on antibacterial activity of NO, thereby blocking inflammatory response and oxidative damage, forming reparative dentine layer to avoid further exposure and infection. Thus, this work provides a propagable strategy to overcome fuel shortage and facilitates the therapy of deep lesions.

Serum amyloid A aggravates endotoxin-induced ocular inflammation through the regulation of retinal microglial activation.

Serum amyloid A (SAA) are major acute-phase response proteins which actively participate in many inflammatory diseases. This study was designed to explore the function of SAA in acute ocular inflammation and the underlying mechanism. We found that SAA3 was upregulated in endotoxin-induced uveitis (EIU) mouse model, and it was primarily expressed in microglia. Recombinant SAA protein augmented intraocular inflammation in EIU, while the inhibition of Saa3 by siRNA effectively alleviated the inflammatory responses and rescued the retina from EIU-induced structural and functional damage. Further study showed that the recombinant SAA protein activated microglia, causing characteristic morphological changes and driving them further to pro-inflammatory status. The downregulation of Saa3 halted the amoeboid change of microglia, reduced the secretion of pro-inflammatory factors, and increased the expression of tissue-reparative genes. SAA3 also regulated the autophagic activity of microglial cells. Finally, we showed that the above effect of SAA on microglial cells was at least partially mediated through the expression and signaling of Toll-like receptor 4 (TLR4). Collectively, our study suggested that microglial cell-expressed SAA could be a potential target in treating acute ocular inflammation.

Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of venetoclax and MENIN inhibitor in KMT2Ar AML.

KMT2A-rearranged acute myeloid leukemia (KMT2Ar-AML) is an aggressive subtype of AML with poor response and prognosis. KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Herein, we investigated the effect and mechanism of VEN plus MEN1i in KMT2Ar-AML. Our results showed that VEN and MEN1i exhibited a striking synergistic effect in KMT2Ar-AML cell lines (in vitro), primary KMT2Ar-AML cells (ex vivo), and MOLM13 xenotransplantation model (in vivo). Furthermore, we found that VEN plus MEN1i significantly enhanced apoptotic induction in KMT2Ar-AML cell lines. VEN or MEN1i monotherapy disrupted balance of BCL-2/BCL-XL or down-regulated HOXA9/MEIS1, respectively, but these mechanisms were not further strengthened by their combination. RNA-Sequencing identified that HDAC9 was specifically repressed by VEN plus MEN1i rather than monotherapy. We demonstrated that HDAC9 was indispensable for KMT2Ar-AML proliferation and its repression contributed to proliferation inhibition of VEN plus MEN1i. Moreover, we found that hypoxia induced HDAC9 expression in KMT2Ar-AML, and VEN plus MEN1i inhibited hypoxia pathway, especially HIF-1A, and its target HDAC9. As our results indicated, VEN plus MEN1i-mediated HDAC9 down-regulation was partially dependent on HIF-1A repression in KMT2Ar-AML. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.