Redox homeostasis maintained by GPX4 facilitates STING activation.

Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.

The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy.

BACKGROUND: Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated. METHODS: We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression. RESULTS: SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression. CONCLUSIONS: By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

Selenoprotein K enhances STING oligomerization to facilitate antiviral response.

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.

Antibody-mediated antigen loss switches augmented immunity to antibody-mediated immunosuppression.

Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen. The lack of similar interventions that mitigate immune responses toward other RBC alloantigens reflects an incomplete understanding of AMIS mechanisms. AMIS has been previously attributed to rapid antibody-mediated RBC removal, resulting in B-cell ignorance of the RBC alloantigen. However, our data demonstrate that antibody-mediated RBC removal can enhance de novo alloimmunization. In contrast, inclusion of antibodies that possess the ability to rapidly remove the target antigen in the absence of detectable RBC clearance can convert an augmented antibody response to AMIS. These results suggest that the ability of antibodies to remove target antigens from the RBC surface can trigger AMIS in situations in which enhanced immunity may otherwise occur. In doing so, these results hold promise in identifying key antibody characteristics that can drive AMIS, thereby facilitating the design of AMIS approaches toward other RBC antigens to eliminate all forms of HDFN.

Distinct virtual histology of grey matter atrophy in four neuroinflammatory diseases.

Gray matter (GM) atrophies were observed in multiple sclerosis, neuromyelitis optica spectrum disorders (both anti-aquaporin-4 antibody-positive [AQP4+], and -negative [AQP4-] subtypes NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicenter cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD, and 2,169 healthy controls (HCs). First, interregional GM atrophy profiles across the cortical and subcortical regions were determined by Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, MOGAD and HCs. Then, the GM atrophy profiles were spatially correlated with the gene expressions extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical feature relevant GM atrophy by subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden, and cognitive function. Multiple sclerosis showed severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed obvious widespread GM atrophy pattern, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes, and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD had spatial correlations with GM atrophy profiles were observed, while no atrophy profile related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature relevant GM atrophy mainly pointed to the shared neuronal and endothelial cells among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes, and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings might help their differential diagnosis and optimal therapeutic strategies.

Monitoring Glutathione Content of the Endoplasmic Reticulum under Scrap Leather-Induced Endoplasmic Reticulum Stress via an Endoplasmic Reticulum-Targeted Two-Photon Fluorescent Probe.

Maintaining tissue homeostasis necessitates the coordinated efforts of various cell types to regulate inflammation. Endoplasmic reticulum (ER) stress, a hallmark of inflammation, exacerbates tissue pathology in various human diseases. Glutathione (GSH), a pivotal regulator of cellular redox balance, controls disulfide bond formation in the ER, thereby shielding cells from oxidative stress. In this study, we developed a two-photon fluorescent probe, ER-GSH, with specific ER targeting and demonstrated its high sensitivity and rapid response to GSH. Experiments conducted on BV2 cells and a mice model of neuroinflammation induced by scrap leather revealed that inflammatory reactions led to ER stress and a substantial reduction in GSH levels. Notably, the anti-inflammatory drug NS-398 effectively inhibited cell inflammation and ER stress by maintaining GSH levels. These findings underscore the potential therapeutic significance of modulating GSH levels to alleviate the impact of neuroinflammation.

An S-locus F-box protein as pollen S determinant targets non-self S-RNase underlying self-incompatibility in Citrus.

Self-incompatibility (SI) is a crucial mechanism that prevents self-fertilization and inbreeding in flowering plants. Citrus exhibits SI regulated by a polymorphic S-locus containing an S-RNase gene and multiple S-locus F-box (SLF) genes. It has been documented that S-RNase functions as the pistil S determinant, but there is no direct evidence that the SLF genes closely linked with S-RNase function as pollen S determinants in Citrus. This study assembled the genomes of two pummelo (Citrus grandis) plants, obtained three novel complete and well-annotated S-haplotypes, and isolated 36 SLF or SLF-like alleles on the S-loci. Phylogenetic analysis of 138 SLFs revealed that the SLF genes were classified into 12 types, including six types with divergent or missing alleles. Furthermore, transformation experiments verified that the conserved S6-SLF7a protein can lead to the transition of SI to self-compatibility by recognizing non-self S8-RNase in 'Mini-Citrus' plants (S7S8 and S8S29, Fortunella hindsii), a model plant for citrus gene function studies. In vitro assays demonstrated interactions between SLFs of different S haplotypes and the Skp1-Cullin1-F-box subunit CgSSK1 protein. This study provides direct evidence that SLF controls the pollen function in Citrus, demonstrating its role in the 'non-self recognition' SI system.

Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis.

The cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1(+) myeloid cells were uniformly distributed in the BM, and all c-kit(+) progenitor cells were adjacent to Gr1(+) myeloid cells. Inflammation-induced ROS production in the BM played a critical role in myeloid progenitor expansion during emergency granulopoiesis. ROS elicited oxidation and deactivation of phosphatase and tensin homolog (PTEN), resulting in upregulation of PtdIns(3,4,5)P3 signaling in BM myeloid progenitors. We further revealed that BM myeloid cell-produced ROS stimulated proliferation of myeloid progenitors via a paracrine mechanism. Taken together, our results establish that phagocytic NADPH oxidase-mediated ROS production by BM myeloid cells plays a critical role in mediating emergency granulopoiesis during acute infection.

Dinaciclib exerts a tumor-suppressing effect via ß-catenin/YAP axis in pancreatic ductal adenocarcinoma.

Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing ß-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating ß-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

Reliability and validity of rapid assessment tools for measuring 24-hour movement behaviours in children aged 0-5 years: the Movement Behaviour Questionnaire Baby (MBQ-B) and child (MBQ-C).

BACKGROUND: The development of validated "fit-for-purpose" rapid assessment tools to measure 24-hour movement behaviours in children aged 0-5 years is a research priority. This study evaluated the test-retest reliability and concurrent validity of the open-ended and closed-ended versions of the Movement Behaviour Questionnaire for baby (MBQ-B) and child (MBQ-C). METHODS: 300 parent-child dyads completed the 10-day study protocol (MBQ-B: N = 85; MBQ-C: N = 215). To assess validity, children wore an accelerometer on the non-dominant wrist (ActiGraph GT3X+) for 7 days and parents completed 2 × 24-hour time use diaries (TUDs) recording screen time and sleep on two separate days. For babies (i.e., not yet walking), parents completed 2 × 24-hour TUDs recording tummy time, active play, restrained time, screen time, and sleep on days 2 and 5 of the 7-day monitoring period. To assess test-retest reliability, parents were randomised to complete either the open- or closed-ended versions of the MBQ on day 7 and on day 10. Test-retest intraclass correlation coefficients (ICC's) were calculated using generalized linear mixed models and validity was assessed via Spearman correlations. RESULTS: Test-retest reliability for the MBQ-B was good to excellent with ICC's ranging from 0.80 to 0.94 and 0.71-0.93 for the open- and closed-ended versions, respectively. For both versions, significant positive correlations were observed between 24-hour diary and MBQ-B reported tummy time, active play, restrained time, screen time, and sleep (rho = 0.39-0.87). Test-retest reliability for the MBQ-C was moderate to excellent with ICC's ranging from 0.68 to 0.98 and 0.44-0.97 for the open- and closed-ended versions, respectively. For both the open- and closed-ended versions, significant positive correlations were observed between 24-hour diary and MBQ-C reported screen time and sleep (rho = 0.44-0.86); and between MBQ-C reported and device-measured time in total activity and energetic play (rho = 0.27-0.42). CONCLUSIONS: The MBQ-B and MBQ-C are valid and reliable rapid assessment tools for assessing 24-hour movement behaviours in infants, toddlers, and pre-schoolers. Both the open- and closed-ended versions of the MBQ are suitable for research conducted for policy and practice purposes, including the evaluation of scaled-up early obesity prevention programs.

A great way to bring up health behaviour topics at playgroup: a qualitative evaluation of the Healthy Conversations @ Playgroup program.

BACKGROUND: The early years is a critical stage to establish optimal nutrition and movement behaviours. Community playgroups are a relaxed environment for parents with a focus on social connection and supporting parents in their role as 'First Teachers'. Playgroups are therefore an opportunistic setting to promote health behaviours in the early years. To support parents with young children around healthy lifestyle behaviours, the Healthy Conversations @ Playgroup program was delivered in urban and regional areas, across three Australian jurisdictions between 2021-2023. OBJECTIVE: This qualitative evaluation aimed to understand how the Healthy Conversations @ Playgroup program was experienced by parents, playgroup coordinators and peer facilitators. DESIGN: Semi-structured virtual interviews and focus groups were conducted with parents, playgroup coordinators (i.e., person responsible for coordinating the playgroup) and peer facilitators (i.e., trained facilitator for the program) that participated in the Healthy Conversations @ Playgroup study. Transcripts were analysed following a thematic analysis approach. RESULTS: Twenty-eight playgroup parents, coordinators or peer facilitators participated in one of 8 focus groups or 5 interviews. Four themes were developed: Program strengths and challenges; Setting strengths and challenges; Factors that impact program delivery; Participant's suggestions for future program delivery. CONCLUSIONS: The Healthy Conversations @ Playgroup program was valued by parents, providing validation and normalisation of parenting practices, and fostering a shared experience of parenting. Playgroups are a convenient setting for families to attend. The dynamic and distracting nature of the playgroup setting were carefully considered when designing the program. Strategies to further enhance program engagement could include use of coordinator or parent champions, tailored delivery, and extending the reach to other family members. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12621000055808, registered 22 January 2021, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380890.

Development of a prognostic risk model of uveal melanoma based on N7-methylguanosine-related regulators.

BACKGROUND: Uveal melanoma (UVM) stands as the predominant type of primary intraocular malignancy among adults. The clinical significance of N7-methylguanosine (m7G), a prevalent RNA modifications, in UVM remains unclear. METHODS: Primary information from 80 UVM patients were analyzed as the training set, incorporating clinical information, mutation annotations and mRNA expression obtained from The Cancer Genome Atlas (TCGA) website. The validation set was carried out using Gene Expression Omnibus (GEO) database GSE22138 and GSE84976. Kaplan-Meier and Cox regression of univariate analyses were subjected to identify m7G-related regulators as prognostic genes. RESULT: A prognostic risk model comprising EIF4E2, NUDT16, SNUPN and WDR4 was established through Cox regression of LASSO. Evaluation of the model's predictability for UVM patients' prognosis by Receiver Operating Characteristic (ROC) curves in the training set, demonstrated excellent performance Area Under the Curve (AUC) > 0.75. The high-risk prognosis within the TCGA cohort exhibit a notable worse outcome. Additionally, an independent correlation between the risk score and overall survival (OS) among UVM patients were identified. External validation of this model was carried out using the validation sets (GSE22138 and GSE84976). Immune-related analysis revealed that patients with high score of m7G-related risk model exhibited elevated level of immune infiltration and immune checkpoint gene expression. CONCLUSION: We have developed a risk prediction model based on four m7G-related regulators, facilitating effective estimate UVM patients' survival by clinicians. Our findings shed novel light on essential role of m7G-related regulators in UVM and suggest potential novel targets for the diagnosis, prognosis and therapy of UVM.

Pseudoamaolide P, a 1,2:3,4:9,10:9,19-tetraseco-cycloartane triterpene spiroketal lactone from seeds of Pseudolarix amabilis.

A 1,2:3,4:9,10:9,19-tetraseco-cycloartane triterpene spiroketal lactone, pseudoamaolide P (1), two new labdane-type diterpenoids, pseudoamains A and B (2-3), and four known cembrane-type diterpenoids (4-7) were isolated from the seeds of Pseudolarix amabilis. The structures of these compounds were elucidated by spectroscopic analyses, including HRESIMS, 1D-, and 2D-NMR. The anti-inflammatory activities of the compounds were evaluated by suppressing the transcription of the NF-κB-dependent reporter gene in LPS-induced 293 T/NF-κB-luc cells. All compounds do not show potent activity.

Cucumis sativus PHLOEM PROTEIN 2-A1 like gene positively regulates salt stress tolerance in cucumber seedlings.

PHLOEM PROTEIN 2-A1 like (PP2-A1) gene is a member of the PP2 multigene family, and the protein encoded by which has the function of stress defense. Based on our previous proteomic study of cucumber phloem sap, CsPP2-A1 protein expression was significantly enriched under salt stress. In this paper, we obtained CsPP2-A1 interfering (CsPP2-A1-RNAi) cucumber by Agrobacterium tumefaciens-mediated method. The phenotypic changes of wild-type (WT) cucumber, CsPP2-A1-overexpressing (OE) cucumber, and CsPP2-A1-RNAi cucumber under salt treatment were observed and compared. Furthermore, physiological indicators were measured in four aspects: osmoregulation, membrane permeability, antioxidant system, and photosynthetic system. The analysis of contribution and correlation for each variable were conducted by principal component analysis (PCA) and Pearson's correlation coefficient. The above results showed that CsPP2-A1-RNAi cucumber plants exhibited weaker salt tolerance compared to WT cucumber and CsPP2-A1-OE cucumber plants in terms of phenotype and physiological indicators in response to salt stress, while CsPP2-A1-OE cucumber always showed the robust salt tolerance. Together, these results indicated that CsPP2-A1 brought a salinity tolerance ability to cucumber through osmoregulation and reactive oxygen species (ROS) homeostasis. The results of the study provided evidence for the function of CsPP2-A1 in plant salt tolerance enhancement, and they will serve as a reference for future salt-tolerant cucumber genetic manipulation.

Endoplasmic Reticulum Peroxynitrite Fluctuations in Hypoxia-Induced Endothelial Injury and Sepsis with a Two-Photon Fluorescence Probe.

Sepsis is a serious systemic inflammatory disease that frequently results in death. Early diagnosis and timely targeted interventions could improve the therapeutic effect. Recent work has revealed that the reactive oxygen species (ROS) in the endoplasmic reticulum (ER) and hypoxia-induced endothelial injury play significant roles in sepsis. However, the relationship between the levels of peroxynitrite (ONOO-) and hypoxia-induced endothelial injury as well as different states of sepsis remain unexplored. Herein, we developed a unique two-photon fluorescent probe (ER-ONOO-) for detecting ONOO- in aqueous solution that has high sensitivity, high selectivity, and ultrafast response time. In addition, ER-ONOO- was successfully used to evaluate the levels of ONOO- at the ER with three kinds of methods in a hypoxia-induced endothelial injury model. Furthermore, ER-ONOO- is capable of monitoring the changes in organ fluorescence through ONOO- variation in different stages of a cecum ligation and puncture (CLP) mouse model. Moreover, we also confirmed that the endoplasmic reticulum stress and oxidative stress participated in the CLP model. Consequently, this research can provide a reliable tool for studying ONOO- fluctuation in sepsis and provide new insights into the pathogenic and therapeutic mechanisms involved.

"Iridium Signature" Mass Spectrometric Probes: New Tools Integrated in a Liquid Chromatography-Mass Spectrometry Workflow for Routine Profiling of Nitric Oxide and Metabolic Fingerprints in Cells.

Nitric oxide (NO) is a highly reactive signaling molecule involved in diverse biological processes. Simultaneous profiling of NO and associated metabolic fingerprints in a single assay allows more accurate assessments of cell states and offers the possibility to better understand its exact biological roles. Herein, a multiplexing LC-MS workflow was established for simultaneous detection of intracellular NO and various metabolites based on a novel "iridium signature" mass spectrometric probe (Ir-MSP841). This Ir-MSP841 can convert highly liable NO to a stable permanently charged triazole product (Ir-TP852), enabling direct MS detection of NO. This 191/193Ir-signature mass spectrometric probe-based approach is endowed with overwhelming advantages of interference-free, high quantitative accuracy, and great sensitivity (limit of detection down to 0.14 nM). It also reveals good linearity over a wide concentration range 12.5-500 nM and has been successfully employed for exploring the release behaviors of three representative NO donors in cells. Meanwhile, metabolic profiling results reveal that varying the concentrations of NO has distinct effects on various cellular metabolites. This study provides a robust, sensitive, and versatile method for simultaneous detection of NO and numerous metabolites in a single LC-MS run and expands its applications in biomedical research.

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML.

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

Human footprints in the Global South accelerate biomass carbon loss in ecologically sensitive regions.

Human activities have placed significant pressure on the terrestrial biosphere, leading to ecosystem degradation and carbon losses. However, the full impact of these activities on terrestrial biomass carbon remains unexplored. In this study, we examined changes in global human footprint (HFP) and human-induced aboveground biomass carbon (AGBC) losses from 2000 to 2018. Our findings show an increasing trend in HFP globally, resulting in the conversion of wilderness areas to highly modified regions. These changes have altered global biomes' habitats, particularly in tropical and subtropical regions. We also found accelerated AGBC loss driven by HFP expansion, with a total loss of 19.99 ± 0.196 PgC from 2000 to 2018, especially in tropical regions. Additionally, AGBC is more vulnerable in the Global South than in the Global North. Human activities threaten natural habitats, resulting in increasing AGBC loss even in strictly protected areas. Therefore, scientifically guided planning of future human activities is crucial to protect half of Earth through mitigation and adaptation under future risks of climate change and global urbanization.

Lentibacillus daqui sp. nov., isolated from high-temperature Daqu, a starter for production of Chinese Jiang-flavour Baijiu.

A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterial strain, designated ZS110521T, was isolated from high-temperature Daqu, a starter for production of Chinese Jiang-flavour Baijiu and was characterised by polyphasic taxonomy. This novel isolate grew in the presence of 0-20 % (w/v) NaCl, at pH 6.0-9.0 and 20-50 °C; optimum growth was observed with 8-10 % (w/v) NaCl, at pH 7.0 and 37 °C. A comparative analysis of the 16S rRNA gene sequence (1460 bp) of ZS110521T revealed that it displayed the highest similarity to Lentibacillus populi WD4L-1T (95.5 %), followed by Lentibacillus garicola SL-MJ1T (95.4 %) and Lentibacillus lacisalsi BH260T (95.2 %). ANI and dDDH values between ZS110521T and other strains of species of the genus Lentibacillus were less than 78 and 28 %, respectively. The predominant cellular fatty acids (> 10 %) of ZS110521T were anteiso-C17 : 0 (37.8 %), anteiso-C15 : 0 (28.1 %) and iso-C16 : 0 (15.5 %). The respiratory quinone was identified as menaquinone-7 (MK-7) and the major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The polyphasic taxonomic data and the results of chemotaxonomic analysis confirmed that ZS110521T represents a novel species, for which the name Lentibacillus daqui sp. nov. is proposed. The type strain of this proposed species is ZS110521T (=CGMCC 1.19456T =JCM 35213T).