Dose-effect of exercise intervention on heart rate variability of acclimatized young male lowlanders at 3,680 m.

This study investigated whether exercise could improve the reduced HRV in an environment of high altitude. A total of 97 young, healthy male lowlanders living at 3,680 m for >1 year were recruited. They were randomized into four groups, of which three performed-low-, moderate-, and high-intensity (LI, MI, HI) aerobic exercise for 4 weeks, respectively. The remaining was the control group (CG) receiving no intervention. For HI, compared to other groups, heart rate (p = 0.002) was significantly decreased, while standard deviation of RR intervals (p < 0.001), SD2 of Poincaré plot (p = 0.046) and the number of successive RR interval pairs that differ by > 50 ms divided by total number of RR (p = 0.032), were significantly increased after intervention. For MI, significantly increase of trigonometric interpolation in NN interval (p = 0.016) was observed after exercise. Further, a decrease in systolic blood pressure (SBP) after high-intensity exercise was found significantly associated with an increase in SD2 (r = - 0.428, p = 0.042). These results indicated that there was a dose effect of different intensities of aerobic exercise on the HRV of acclimatized lowlanders. Moderate and high-intensity aerobic exercise would change the status of the autonomic nervous system (ANS) and decrease the blood pressure of acclimatized lowlanders exposed to high altitude.

Innate lymphoid cell subsets in the pathogenesis of primary biliary cholangitis.

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by destructive lymphocytic cholangitis and specific anti-mitochondrial antibodies. Innate lymphoid cells (ILCs) have been reported to play a role in liver homeostasis and autoimmunity. METHODS: We evaluated the features of peripheral ILC1s and ILC3 in patients with PBC and hepatic ILC1 and ILC3 in two different PBC mouse models (dominant-negative transforming growth factor-beta receptor II [dnTGFßRII] and 2-octynoic acid-bovine serum albumin [2OA-BSA]). RESULTS: A total of 115 patients and 18 healthy controls were enrolled in the study. Decreased circulating ILC1/3s were observed in early-stage PBC patients, and the numbers of ILC1/3s were negatively correlated with specific parameters and the proportion of T-helper (Th) 1 and Th17 cells. Reduced numbers of ILC1s were observed in PBC mouse models with different etiologies. ILC1-deficient mice had more severe hepatic inflammation after inducing the 2OA-BSA model. Continuous low-dose injections of lipopolysaccharide (LPS) reduced ILC1 levels in mice, consistent with the lower level of ILC1s in PBC patients with high LPS (> 50 ng/mL), and aggravated hepatic lymphocyte infiltration. CONCLUSION: Patients with PBC had decreased ILC1s, which were negatively correlated with CD4+ T cells. Deficient ILC1 populations led to disease exacerbations in mice. Our results indicated that ILC1s may participate in the pathogenesis of PBC.

Accuracy of Genomic prediction for fleece traits in Inner Mongolia Cashmere goats.

The fleece traits are important economic traits of goats. With the reduction of sequencing and genotyping cost and the improvement of related technologies, genomic selection for goats has become possible. The research collect pedigree, phenotype and genotype information of 2299 Inner Mongolia Cashmere goats (IMCGs) individuals. We estimate fixed effects, and compare the estimates of variance components, heritability and genomic predictive ability of fleece traits in IMCGs when using the pedigree based Best Linear Unbiased Prediction (ABLUP), Genomic BLUP (GBLUP) or single-step GBLUP (ssGBLUP). The fleece traits considered are cashmere production (CP), cashmere diameter (CD), cashmere length (CL) and fiber length (FL). It was found that year of production, sex, herd and individual ages had highly significant effects on the four fleece traits (P < 0.01). All of these factors should be considered when the genetic parameters of fleece traits in IMCGs are evaluated. The heritabilities of FL, CL, CP and CD with ABLUP, GBLUP and ssGBLUP methods were 0.26 ~ 0.31, 0.05 ~ 0.08, 0.15 ~ 0.20 and 0.22 ~ 0.28, respectively. Therefore, it can be inferred that the genetic progress of CL is relatively slow. The predictive ability of fleece traits in IMCGs with GBLUP (56.18% to 69.06%) and ssGBLUP methods (66.82% to 73.70%) was significantly higher than that of ABLUP (36.73% to 41.25%). For the ssGBLUP method is significantly (29% ~ 33%) higher than that with ABLUP, and which is slightly (4% ~ 14%) higher than that of GBLUP. The ssGBLUP will be as an superiors method for using genomic selection of fleece traits in Inner Mongolia Cashmere goats.

The neuroimmune pathway of high-altitude adaptation: influence of erythrocytes on attention networks through inflammation and the autonomic nervous system.

Introduction: Many studies have shown that the functional adaptation of immigrants to high-altitude is closely related to oxygen transport, inflammatory response and autonomic nervous system. However, it remains unclear how human attention changes in response to hypoxia-induced neurophysiological activity during high-altitude exposure. Methods: In the present study, we analyzed the relationship between hypoxic-induced neurophysiological responses and attention networks in 116 immigrants (3,680 m) using an attention network test to simultaneously record electroencephalogram and electrocardiogram in combination with specific routine blood markers. Results: Our analysis revealed that red blood cells exert an indirect influence on the three attention networks, mediated through inflammatory processes and heart rate variability. Discussion: The present study provides experimental evidence for the role of a neuroimmune pathway in determining human attention performance at high- altitude. Our findings have implications for understanding the complex interactions between physiological and neurocognitive processes in immigrants adapting to hypoxic environments.

The effects of long-term high-altitude exposure on cognition: A meta-analysis.

Long-term high altitudes (HA) exposure's impact on cognition has yielded inconsistent findings in previous research. To address this, we conducted a meta-analysis of 49 studies (6,191 individuals) to comprehensively evaluate this effect. Moderating factors such as cognitive task type, altitude (1,500-2,500m, 2,500-4,000m, and above 4,000m), residential type (chronic and lifelong), adaptation level and demographic factors were analyzed. Cognitive tasks were classified into eight categories: perceptual processes, psychomotor function, long-term memory, working memory, inhibitory control, problem-solving, language, and others. Results revealed a moderate negative effect of HA on cognitive performance (g = -.40, SE =.18, 95% CI = -.76 to -.05). Psychomotor function and long-term memory notably experience the most pronounced decline, while working memory and language skills show moderate decreases due to HA exposure. However, perceptual processes, inhibitory control, and problem-solving abilities remain unaffected. Moreover, residing at altitudes above 4,000m and being a HA immigrant are associated with significant cognitive impairment. In summary, our findings indicate a selective adaptation of cognitive performance to HA conditions.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

DIAGNOSTIC PERFORMANCE OF CENTRAL NERVOUS SYSTEM INFECTIONS IN PATIENTS WITH NEUROSURGICAL INTENSIVE CARE USING METAGENOMIC NEXT-GENERATION SEQUENCING: A PROSPECTIVE OBSERVATIONAL STUDY.

ABSTRACT: Background. Identifying the causative pathogens of central nervous system infections (CNSIs) is crucial, but the low detection rate of traditional culture methods in cerebrospinal fluid (CSF) has made the pathogenic diagnosis of CNSIs a longstanding challenge. Patients with CNSIs after neurosurgery often overlap with inflammatory and bleeding. Metagenomic next-generation sequencing (mNGS) has shown some benefits in pathogen detection. This study aimed to investigate the diagnostic performance of mNGS in the etiological diagnosis of CNSIs in patients after neurosurgery. Methods. In this prospective observational study, we enrolled patients with suspected CNSIs after neurosurgical operations who were admitted to the intensive care unit of Beijing Tiantan Hospital. All enrolled patients' CSF was tested using mNGS and pathogen culture. According to comprehensive clinical diagnosis, the enrolled patients were divided into CNSIs group and non-CNSIs group to compare the diagnostic efficiency of mNGS and pathogen culture. Results. From December 2021 to March 2023, 139 patients were enrolled while 66 in CNSIs group and 73 in non-CNSIs. The mNGS exceeded culture in the variety and quantity of pathogens detected. The mNGS outperformed traditional pathogen culture in terms of positive percent agreement (63.63%), accuracy (82.01%), and negative predictive value (75.00%), with statistically significant differences ( P < 0.05) for traditional pathogen culture. The mNGS also detected bacterial spectrum and antimicrobial resistance genes. Conclusions. Metagenomics has the potential to assist in the diagnosis of patients with CNSIs who have a negative culture.

Association of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage in chronic HBV infection.

The natural progression of chronic hepatitis B virus (HBV) infection is dynamic, but the longitudinal landscape of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage remains undetermined. To this issue, we studied the association of HBV serological markers with the severity of hepatic inflammatory damage and enumerated HBV-specific T cells using the cultured enzyme-linked immune absorbent spot (ELISpot). Five hundred and twenty-four treatment-naïve chronic HBV infection patients were enrolled. The Spearman correlation analysis revealed that in hepatitis B e antigen (HBeAg)-positive patients, all HBV virologic indicators negatively correlated with liver inflammatory damage and fibrosis (p < 0.01). Stronger correlations were accessed in the subgroup of HBeAg-positive patients with HBV DNA > 2 × 106 IU/mL (p < 0.01), whereas negative correlations disappeared in patients with HBV DNA ≤ 2 × 106 IU/mL. Surprisingly, in HBeAg-negative patients, the HBV DNA level was positively correlated with the hepatic inflammatory damage (p < 0.01). The relationship between type Ⅱ interferon genes expression and HBV DNA levels also revealed a direct shift from the initial negative to positive in HBeAg-positive patients with HBV DNA declined below 2 × 106 IU/mL. The number of HBV-specific T cells were identified by interferon γ ELISpot assays and showed a significant increase from HBeAg-positive to HBeAg-negative group. The host's anti-HBV immunity remains effective in HBeAg-positive patients with HBV DNA levels exceeding 2 × 106 IU/mL, as it efficiently eliminates infected hepatocytes and inhibits HBV replication. However, albeit the increasing number of HBV-specific T cells, the host antiviral immune response shifts towards dysfunctional when the HBV DNA load drops below this threshold, which causes more pathological damage and disease progression.

Efficient Fermentative Production of d-Alanine and Other d-Amino Acids by Metabolically Engineered Corynebacterium glutamicum.

d-Amino acids (d-AAs) have wide applications in industries such as pharmaceutical, food, and cosmetics due to their unique properties. Currently, the production of d-AAs has relied on chemical synthesis or enzyme catalysts, and it is challenging to produce d-AAs via direct fermentation from glucose. We observed that Corynebacterium glutamicum exhibits a remarkable tolerance to high concentrations of d-Ala, a crucial characteristic for establishing a successful fermentation process. By optimizing meso-diaminopilmelate dehydrogenases in different C. glutamicum strains and successively deleting l-Ala biosynthetic pathways, we developed an efficient d-Ala fermentation system. The d-Ala titer was enhanced through systems metabolic engineering, which involved strengthening glucose assimilation and pyruvate supply, reducing the formation of organic acid byproducts, and attenuating the TCA cycle. During fermentation in a 5-L bioreactor, a significant accumulation of l-Ala was observed in the broth, which was subsequently diminished by introducing an l-amino acid deaminase. Ultimately, the engineered strain DA-11 produced 85 g/L d-Ala with a yield of 0.30 g/g glucose, accompanied by an optical purity exceeding 99%. The fermentation platform has the potential to be extended for the synthesis of other d-AAs, as demonstrated by the production of d-Val and d-Glu.

Internal m 6 A and m 7 G RNA modifications in hematopoietic system and acute myeloid leukemia.

ABSTRACT: Epitranscriptomics focuses on RNA modifications-mediated post-transcriptional regulation of gene expression. The current decade has witnessed tremendous progress in understanding the landscapes and biological functions of RNA modifications as prompted by potent analytical approaches. The hematopoietic system provides a lifelong supply of blood cells, and gene expression is tightly modulated during the differentiation of hematopoietic stem cells (HSCs). Dysregulation of gene expression during hematopoiesis may lead to severe disorders, including acute myeloid leukemia (AML). Emerging evidence has indicated the involvement of mRNA modification system in normal hematopoiesis and AML pathogenesis, which led to the accelerating development of small-molecule inhibitors targeting N6-methyladenosine (m 6 A) modification machinery for treatment. Here, we summarize the latest findings and address the state-of-the-art knowledge on the role of m 6 A and N7-methylguanine (m 7 G) in both physiological and pathological conditions in the hematopoietic system. Furthermore, we discuss the therapeutic potential and limitations of cancer treatment targeting m 6 A.

Effect of GABAa-receptors on neuronal discharge and ion activity in focal seizures.

Focal seizures are a type of epileptic event that has plagued the medical community for a long time, and the existing drug treatment is mainly based on the modulation of ${GABA}_a$-receptors to affect GABAergic signaling to achieve the therapeutic purpose. The majority of research currently focuses on the impact of ${GABA}_a$-receptors on neuronal firing, failing to analyze the molecular and ionic mechanisms involved. Specifically, the research on deeper-level mechanisms on how ${GABA}_a$-receptors affect neuronal firing by altering ion activity has not been addressed. This research aimed to study the effects of different ${GABA}_a$-receptor structures on ion activity in focal seizures model by adjusting parameters of the ${GABA}_a$-receptors: the rise time constant (${tau}_1$) and decay time constant (${tau}_2$). The research indicates that as the values of ${tau}_1$ and ${tau}_2$ of the ${GABA}_a$-receptor change, the ion concentration will vary based on the change of the ${GABA}_a$-receptor potential. To a certain extent, the duration of epileptic activity will also be affected to a certain extent. In conclusion, the alteration of ${GABA}_a$-receptor structure will affect the inhibitory effect of interneurons on pyramidal neurons, and different parameters of the ${GABA}_a$-receptor will directly impact the therapeutic effect.

STCGRU: A hybrid model based on CNN and BiGRU for mild cognitive impairment diagnosis.

BACKGROUND AND OBJECTIVE: Early diagnosis of mild cognitive impairment (MCI) is one of the essential measures to prevent its further development into Alzheimer's disease (AD). In this paper, we propose a hybrid deep learning model for early diagnosis of MCI, called spatio-temporal convolutional gated recurrent unit network (STCGRU). METHODS: The STCGRU comprises three bespoke convolutional neural network (CNN) modules and a bi-directional gated recurrent unit (BiGRU) module, which can effectively extract the spatial and temporal features of EEG and obtain excellent diagnostic results. We use a publicly available EEG dataset that has not undergone pre-processing to verify the robustness and accuracy of the model. Ablation experiments on STCGRU are conducted to showcase the individual performance improvement of each module. RESULTS: Compared with other state-of-the-art approaches using the same publicly available EEG dataset, the results show that STCGRU is more suitable for early diagnosis of MCI. After 10-fold cross-validation, the average classification accuracy of the hybrid model reached 99.95 %, while the average kappa value reached 0.9989. CONCLUSIONS: The experimental results show that the hybrid model proposed in this paper can directly extract compelling spatio-temporal features from the raw EEG data for classification. The STCGRU allows for accurate diagnosis of patients with MCI and has a high practical value.

Efficient catalyst-free N2 fixation by water radical cations under ambient conditions.

The growth and sustainable development of humanity is heavily dependent upon molecular nitrogen (N2) fixation. Herein we discover ambient catalyst-free disproportionation of N2 by water plasma which occurs via the distinctive HONH-HNOH+• intermediate to yield economically valuable nitroxyl (HNO) and hydroxylamine (NH2OH) products. Calculations suggest that the reaction is prompted by the coordination of electronically excited N2 with water dimer radical cation, (H2O)2+•, in its two-center-three-electron configuration. The reaction products are collected in a 76-needle array discharge reactor with product yields of 1.14 µg cm-2 h-1 for NH2OH and 0.37 µg cm-2 h-1 for HNO. Potential applications of these compounds are demonstrated to make ammonia (for NH2OH), as well as to chemically react and convert cysteine, and serve as a neuroprotective agent (for HNO). The conversion of N2 into HNO and NH2OH by water plasma could offer great profitability and reduction of polluting emissions, thus giving an entirely look and perspectives to the problem of green N2 fixation.

Combination of histological and metabolomic assessments to evaluate the potential pharmacological efficacy of saikosaponin D.

Saikosaponin D (SsD), a natural triterpenoid saponin compound, exhibits notable potential in suppressing tumor growth and inhibiting metastasis, particularly in breast cancer. However, its underlying mechanism of action for SsD remains unclear. In this study, a combination strategy to reveal the metabolism modulation of SsD on breast cancer was performed by integration of histopathological assessments and untargeted metabolomics analysis. Pathological evaluation of the efficacy of SsD from a visual and intuitive perspective. Accordingly, a non-targeted metabolomics study was used to investigate the pharmacological efficacy using a set of serum samples from mice before and after (0-30 days) modulated with SsD based on ultra-high performance liquid chromatography tandem orbitrap mass spectrometry to discover metabolite biomarkers for finding the key metabolic mechanism in a molecular perspective. As a result, 20 metabolites were selected as potential biomarkers for SsD efficacy evaluation with high sensitivity and specificity. These metabolites changes were involved in sphingolipid metabolism, glycerophospholipid metabolism, phenylalanine and tryptophan metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis pathways, suggesting that SsD exerted anti-breast cancer effects through the regulation of the underlying metabolism. In conclusion, we developed a new analysis strategy that effectively discovers tumor-progressing related metabolite biomarkers in serum for pharmacological efficacy evaluation.

Marine fungus Aspergillus c1. sp metabolite activates the HSF1/PGC-1α axis, inducing a thermogenic program for treating obesity.

Background and aims: Obesity is one of the most prevalent diseases worldwide with less ideal approved agents in clinic. Activating the HSF1/PGC-1α axis in adipose tissues has been reported to induce thermogenesis in mice, which presents a promising therapeutic avenue for obesity treatment. The present study aimed to identified novel natural HSF1 activator and evaluated the therapeutic effects of the newly discovered compound on obesity-associated metabolic disorders and the molecular mechanisms of these effects. Methods: Our previous reported HSF1/PGC-1α activator screening system was used to identify novel natural HSF1 activator. The PGC-1α luciferase activity, immunoblot, protein nuclear-translocation, immunofluorescence, chromatin immunoprecipitation assays were used to evaluate the activity of compound HN-001 in activating HSF1. The experiments of mitochondrial number measurement, TG assay and imaging, cellular metabolic assay, gene assays, and CRISPR/Cas 9 were applied for investigating the metabolic effect of HN-001 in C3H10-T1/2 adipocytes. The in vivo anti-obesity efficacies and beneficial metabolic effects of HN-001 were evaluated by performing body and fat mass quantification, plasma chemical analysis, GTT, ITT, cold tolerance test, thermogenesis analysis. Results: HN-001 dose- and time-dependently activated HSF1 and induced HSF1 nuclear translocation, resulting in an enhancement in binding with the gene Pgc-1α. This improvement induced activation of adipose thermogenesis and enhancement of mitochondrial oxidation capacity, thus inhibiting adipocyte maturation. Deletion of HSF1 in adipocytes impaired mitochondrial oxidation and abolished the above beneficial metabolic effects of HN-001, including adipocyte browning induction, improvements in mitogenesis and oxidation capacity, and lipid-lowering ability. In mice, HN-001 treatment efficiently alleviated diet-induced obesity and metabolic disorders. These changes were associated with increased body temperature in mice and activation of the HSF1/PGC-1α axis in adipose tissues. UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of HN-001-treated mice. Conclusion: These data indicate that HN-001 may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues through a mechanism involving the HSF1/PGC-1α axis, which shed new light on the development of novel anti-obesity agents derived from marine sources.

EnAMP: A novel deep learning ensemble antibacterial peptide recognition algorithm based on multi-features.

Antimicrobial peptides (AMPs), as the preferred alternatives to antibiotics, have wide application with good prospects. Identifying AMPs through wet lab experiments remains expensive, time-consuming and challenging. Many machine learning methods have been proposed to predict AMPs and achieved good results. In this work, we combine two kinds of word embedding features with the statistical features of peptide sequences to develop an ensemble classifier, named EnAMP, in which, two deep neural networks are trained based on Word2vec and Glove word embedding features of peptide sequences, respectively, meanwhile, we utilize statistical features of peptide sequences to train random forest and support vector machine classifiers. The average of four classifiers is the final prediction result. Compared with other state-of-the-art algorithms on six datasets, EnAMP outperforms most existing models with similar computational costs, even when compared with high computational cost algorithms based on Bidirectional Encoder Representation from Transformers (BERT), the performance of our model is comparable. EnAMP source code and the data are available at https://github.com/ruisue/EnAMP.

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity.

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

MiR-155-5p improves the insulin sensitivity of trophoblasts by targeting CEBPB in gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication featuring impaired insulin sensitivity. MiR-155-5p is associated with various metabolic diseases. However, its specific role in GDM remains unclear. CCAAT enhancer binding protein beta (CEBPB), a critical role in regulating glucolipid metabolism, has been identified as a potential target of miR-155-5p. This study aims to investigate the impact of miR-155-5p and CEBPB on insulin sensitivity of trophoblasts in GDM. METHODS: Placental tissues were obtained from GDM and normal pregnant women; miR-155-5p expression was then evaluated by RT‒qPCR and CEBPB expression by western blot and immunohistochemical staining. To investigate the impact of miR-155-5p on insulin sensitivity and CEBPB expression, HTR-8/SVneo cells were transfected with either miR-155-5p mimic or inhibitor under basal and insulin-stimulated conditions. Cellular glucose uptake consumption was quantified using a glucose assay kit. Furthermore, the targeting relationship between miR-155-5p and CEBPB was validated using a dual luciferase reporter assay. RESULTS: Reduced miR-155-5p expression and elevated CEBPB expression were observed in GDM placentas and high glucose treated HTR8/SVneo cells. The overexpression of miR-155-5p significantly enhanced insulin signaling and glucose uptake in trophoblasts. Conversely, inhibiting miR-155-5p induced the opposite effects. Additionally, CEBPB was directly targeted and negatively regulated by miR-155-5p in HTR8/SVneo cells. Silencing CEBPB effectively restored the inhibitory effect of miR-155-5p downregulation on insulin sensitivity in trophoblasts. DISCUSSION: These findings suggest that miR-155-5p could enhance insulin sensitivity in trophoblasts by targeting CEBPB, highlighting the potential of miR-155-5p as a therapeutic target for improving the intrauterine hyperglycemic environment in GDM.

A circular RNA-gawky-chromatin regulatory axis modulates stress-induced transcription.

In response to heavy metal stress, the RNA-binding protein (RBP) gawky translocates into the nucleus and acts as a chromatin-interacting factor to activate the transcription of many stress-responsive genes. However, the upstream regulators of gawky-mediated transcription and their mechanistic details remain unknown. Here, we identified a class of metal-responsive element-containing circRNAs (MRE circRNAs) which specifically interact with gawky during copper stress. Using classic stress-responsive genes as a readout (Drosophila MT), we found that overexpression of MRE circRNAs led to a significant repression in stress-induced transcription. Mechanistically, MRE circRNAs promote the dissociation of gawky from chromatin and increase its aberrant cytoplasmic accumulation, which ultimately impedes the loading of RNA polymerase II to the active gene loci. The MRE motif serves as an important RNA regulon for maintaining the circRNA-gawky interaction, loss of which impaired the inhibitory effects of MRE circRNAs on gawky. Through RNA-seq analyses, we then identified over 500 additional stress-responsive genes whose induced transcription was attenuated upon MRE circRNA overexpression. Finally, we uncovered the physiological relevance of MRE circRNA-mediated regulation in cellular defense against copper overloading. Taken together, this study proposes that the circRNA-RBP-chromatin axis may represent a fundamental regulatory network for gene expression in eukaryotic cells.