MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. METHODS: The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. RESULTS: In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. CONCLUSION: In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

LncRNA-mir3471-limd1 regulatory network plays critical roles in HIBD.

The purpose of this study was to identify the target genes of tcon_00044595, elucidate its activation site, and provide novel insights into the pathogenesis and treatment of neonatal hypoxic-ischemic brain damage (HIBD). Through homologous blast analysis, we identified predicted target sequences in the neighboring regions of the long non-coding RNA (lncRNA) tcon_00044595, suggesting that limd1 is its target gene. Starbase was utilized to identify potential candidate microRNAs associated with the lncRNA. The interaction between the candidate microRNAs and limd1 was investigated and validated using various experimental methods including in vitro cell culture, cell transfection, dual fluorescence reporter detection system, and real-time PCR. Homology alignment analysis revealed that the lncRNA tcon_00044595 exhibited a 246 bp homologous sequence at the 3' end of the adjacent limd1 gene, with a conservation rate of 68%. Analysis conducted on Starbase online identified three potential microRNA candidates: miR-3471, miR-883a-5p, and miR-214-3p. Intracellular expression of the limd1 gene was significantly down-regulated upon transfection with miR-3471, while the other two microRNAs did not produce noticeable effects. Luciferase reporter assays identified two interaction sites (UTR-1, UTR-2) between miR-3471 and the limd1 3'UTR, with UTR-1 exhibiting a strong influence. Further CCK8 assay indicated a protective role of miR-3471 during low oxygen stroke in HIBD. The potential regulatory relationship between lncRNA (tcon_00044595), miR-3471, and the target gene limd1 suggests their involvement in the occurrence and development of HIBD, providing new insights for investigating the underlying mechanisms and exploring targeted therapeutic approaches for HIBD.

PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy.

Hypoxia-ischemia (HI) is one of the main causes of neonatal brain injury. Mitophagy has been implicated in the degradation of damaged mitochondria and cell survival following neonatal brain HI injury. Pleckstrin homology-like domain family A member 1 (PHLDA1) plays vital roles in the progression of various disorders including the regulation of oxidative stress, the immune responses and apoptosis. In the present study we investigated the role of PHLDA1 in HI-induced neuronal injury and further explored the mechanisms underlying PHLDA1-regulated mitophagy in vivo and in vitro. HI model was established in newborn rats by ligation of the left common carotid artery plus exposure to an oxygen-deficient chamber with 8% O2 and 92% N2. In vitro studies were conducted in primary hippocampal neurons subjected to oxygen and glucose deprivation/-reoxygenation (OGD/R). We showed that the expression of PHLDA1 was significantly upregulated in the hippocampus of HI newborn rats and in OGD/R-treated primary neurons. Knockdown of PHLDA1 in neonatal rats via lentiviral vector not only significantly ameliorated HI-induced hippocampal neuronal injury but also markedly improved long-term cognitive function outcomes, whereas overexpression of PHLDA1 in neonatal rats via lentiviral vector aggravated these outcomes. PHLDA1 knockdown in primary neurons significantly reversed the reduction of cell viability and increase in intracellular reactive oxygen species (ROS) levels, and attenuated OGD-induced mitochondrial dysfunction, whereas overexpression of PHLDA1 decreased these parameters. In OGD/R-treated primary hippocampal neurons, we revealed that PHLDA1 knockdown enhanced mitophagy by activating FUNDC1, which was abolished by FUNDC1 knockdown or pretreatment with mitophagy inhibitor Mdivi-1 (25 µM). Notably, pretreatment with Mdivi-1 or the knockdown of FUNDC1 not only increased brain infarct volume, but also abolished the neuroprotective effect of PHLDA1 knockdown in HI newborn rats. Together, these results demonstrate that PHLDA1 contributes to neonatal HI-induced brain injury via inhibition of FUNDC1-mediated neuronal mitophagy.

The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a poor prognosis. The growth of GBM cells depends on the core transcriptional apparatus, thus rendering RNA polymerase (RNA pol) complex as a candidate therapeutic target. The RNA pol II subunit B (POLR2B) gene encodes the second largest subunit of the RNA pol II (RPB2); however, its genomic status and function in GBM remain unclear. Certain GBM data sets in cBioPortal were used for investigating the genomic status and expression of POLR2B in GBM. The function of RPB2 was analyzed following knockdown of POLR2B expression by shRNA in GBM cells. The cell counting kit-8 assay and PI staining were used for cell proliferation and cell cycle analysis. A xenograft mouse model was established to analyze the function of RPB2 in vivo. RNA sequencing was performed to analyze the RPB2-regulated genes. GO and GSEA analyses were applied to investigate the RPB2-regulated gene function and associated pathways. In the present study, the genomic alteration and overexpression of the POLR2B gene was described in glioblastoma. The data indicated that knockdown of POLR2B expression suppressed tumor cell growth of glioblastoma in vitro and in vivo. The analysis further demonstrated the identification of the RPB2-regulated gene sets and highlighted the DNA damage-inducible transcript 4 gene as the downstream target of the POLR2B gene. The present study provides evidence indicating that RPB2 functions as a growth regulator in glioblastoma and could be used as a potential therapeutic target for the treatment of this disease.

Discovery of Novel SIRT1/2 Inhibitors with Effective Cytotoxicity against Human Leukemia Cells.

The sirtuin enzyme family members, SIRT1 and SIRT2, play both tumor-promoting and tumor-suppressing roles, depending on the context and experimental conditions. Compounds that inhibit either SIRT1 or SIRT2 show promising antitumor effects in several types of cancer models, both in vitro and in vivo. The simultaneous inhibition of SIRT1 and SIRT2 is helpful in treating cancer by completely blocking p53 deacetylation, leading to cell death. However, only a few SIRT1/2 dual inhibitors have been developed. Here, we report the discovery of a novel series of SIRT1/2 dual inhibitors via a rational drug design that involved virtual screening and a substructure search. Eleven of the derived compounds exhibited high inhibitory activities, with IC50 < 5 µM and high specificity for both SIRT1 and SIRT2. Compounds hsa55 and PS9 strongly induced apoptosis and showed antiproliferative effects against human leukemia cell lines, which could be due to their ability to increase of p53 and α-tubulin acetylation, as we observed in MOLM-13 cells. Therefore, the new scaffolds of these compounds and their efficacy in leukemia cell lines provide important clues for the further development of novel anti-leukemia drugs.

Efficacy and Incidence of Treatment-Related Adverse Events of Thrombopoietin Receptor Agonists in Adults with Immune Thrombocytopenia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Study.

INTRODUCTION: The aim of the study was to conduct a network meta-analysis to assess the efficacy and incidence of treatment-related adverse events (TRAEs) of eltrombopag, romiplostim, avatrombopag, recombinant human thrombopoietin (rhTPO), and hetrombopag for adult immune thrombocytopenia (ITP). METHODS: Randomized controlled trials (RCTs) of the five therapies from inception to June 1, 2022, were included. The efficacy outcome was the rate of platelet response, defined as the achievement of platelet counts above 50 × 109/L. Pairwise odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The surface under the cumulative ranking (SUCRA) was used to rank the included therapies for each outcome. RESULTS: In total, 1,360 participants were analyzed in 14 eligible RCTs. All of the therapies showed a significantly better platelet response than the placebo, and avatrombopag (OR, 7.42; 95% CI: 1.74-31.69) and rhTPO (OR, 3.86; 95% CI: 1.62-9.18) were better than eltrombopag. Regarding TRAEs, no significant differences were found between patients receiving eltrombopag, romiplostim, and avatrombopag. Avatrombopag carried the highest platelet response rate with SUCRA value of 87.5, and carried the least TRAEs risk with SUCRA value of 37.0. CONCLUSIONS: These findings indicated that avatrombopag appeared to be the optimal choice as the second-line therapy for adult ITP.

Bimetallic FeMn@C derived from Prussian blue analogue as efficient nanozyme for glucose detection.

In recent decades, nanomaterial-based artificial enzymes called nanozymes have received more and more attention and have been applied in biological, chemical, medical, and other fields. In this work, bimetallic FeMn@C was synthesized by calcination from the Prussian blue analogue. The synthesized bimetallic FeMn@C exhibits efficient peroxidase-like activity. The effect of Mn doping amount, catalytic kinetics, and mechanism of FeMn@C nanozyme was further studied in detail. The results show that the peroxidase-like activity of bimetallic FeMn@C is nearly 16 times higher than that of single-metal Fe@C. The peroxidase-like activity of FeMn@C originates from its production of radicals. Compared with natural enzymes, FeMn@C nanozyme has a better affinity for the substrates. Besides, FeMn@C nanozyme has better stability than natural enzymes. Because of its strong magnetism, FeMn@C nanozyme can be recycled easily and exhibits excellent recycling performance. Based on the good affinity of FeMn@C for H2O2, a rapid and selective colorimetric assay for glucose detection is constructed, with a wide linear range of 0.01-0.75 mM and low detection limit of 4.28 µM. This sensor has been successfully applied to the determination of glucose in fruit juice, showing good selectivity and accuracy. The synthesis of bimetallic FeMn@C provides a feasible way to design nanozymes with excellent catalytic activity, high stability, and easy separation.

CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1.

BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. METHODS: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. RESULTS: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. CONCLUSION: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Th cytokine profile in childhood-onset systemic lupus erythematosus.

BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is a kind of chronic inflammatory disease characterized by a highly abnormal immune system. This study aimed to detect the serum levels of Th (T helper) cytokines (IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ and TNF-α) in cSLE and healthy controls, and then to elucidate their association with clinical manifestations, disease activity and laboratory parameters. In order to provide clues for early diagnosis and timely intervention treatment of cSLE patients. METHODS: A total of 33 children with cSLE and 30 healthy children were enrolled in this study. Children in the cSLE group were classified into the inactive or active cSLE group according to their SLE disease activity index 2000 (SLEDAI-2 K) score. Th cytokine profiles in the peripheral blood were detected and analysed. RESULTS: Levels of IL-2, IL-10 and IL-21 in the cSLE group were significantly higher than those in the healthy control group (P < 0.05, P < 0.01 and P < 0.01, respectively). Expression of IL-2, IL-10 and IL-21 in the active cSLE group was significantly higher than that in the healthy control group (P < 0.05, P < 0.01 and P < 0.05, respectively), but that of IL-22 expression was markedly lower in the active cSLE group than in the healthy control group (P < 0.001). IL-21 in the inactive SLE group was significantly higher than that in the healthy control group (P < 0.05), and levels of IL-2 and IL-10 in the active cSLE group were significantly higher than those in the inactive cSLE group (P < 0.01 and P < 0.05). In-depth analysis showed that after excluding age, gender and drug interference, the levels of IL-2 (P < 0.05), IL-6 (P < 0.05) and IL-10 (P < 0.05) were still positively correlated with SLEDAI-2 K scores. However, the levels of IL-6 (P < 0.05) and IFN- γ (P < 0.05) were still negatively correlated with CD4+/CD8+, and the concentration of IL-6 (P < 0.05) was still positively correlated with the occurrence of nephritis. CONCLUSION: This study provides a theoretical basis for the discovery of effective methods to regulate imbalance in T lymphocyte subsets in cSLE, which may lead to new approaches for the diagnosis of cSLE.

Predictive value of early amplitude integrated electroencephalogram (aEEG) in sleep related problems in children with perinatal hypoxic-ischemia (HIE).

BACKGROUND: While great attention has been paid to motor and cognitive impairments in children with neonatal Hypoxic-Ischemic Encephalopathy (HIE), sleep related circadian rhythm problems, although commonly present, are often neglected. Subsequently, no early clinical indicators have been reported to correlate with sleep-related circadian dysfunction during development. METHODS: In this study, we first analyzed patterns of the amplitude integrated electroencephalogram (aEEG) in a cohort of newborns with various degrees of HIE. Next, during follow-ups, we collected information of sleep and circadian related problems in these patients and performed correlation analysis between aEEG parameters and different sleep/circadian disorders. RESULTS: A total of 101 neonates were included. Our results demonstrated that abnormal aEEG background pattern is significantly correlated with circadian rhythmic (r = 0.289, P = 0.01) and breathing issues during sleep (r = 0.237, P = 0.037). In contrast, the establishment of sleep-wake cycle (SWC) showed no correlation with sleep/circadian problems. Detailed analysis showed that summation of aEEG score, along with low base voltage (r = 0.272, P = 0.017 and r = -0.228, P = 0.048, respectively), correlates with sleep circadian problems. In contrast, background pattern (BP) score highly correlates with sleep breathing problem (r = 0.319, P = 0.004). CONCLUSION: Abnormal neonatal aEEG pattern is correlated with circadian related sleep problems. Our study thus provides novel insights into predictive values of aEEG in sleep-related circadian problems in children with HIE.

The role of microglia mediated pyroptosis in neonatal hypoxic-ischemic brain damage.

Neonatal hypoxic-ischemic encephalopathy (HIE) often leads to neonatal death or severe, irreversible neurological deficits. Pathologically, the occurrence of massive cell death and subsequent inflammation suggested that pyroptosis, an inflammation associated programed cell death, might play a role in HIE. Here, by measuring changes of key molecules in pyroptosis pathway in HIE patients, we discovered that their elevation levels tightly correlate with the severity of HIE. Next, we demonstrated that application of MCC950, a small molecule to inhibit NLRP3 inflammasome and thus pyroptosis, substantially alleviated pyroptosis and the injury severity in rats with neonatal hypoxic-ischemic brain damage (HIBD). Mechanistically, we showed that NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. Our data demonstrated that microglia mediated pyroptosis played a crucial role in neonatal HIE, which shed lights into the development of intervention avenues targeting pyroptosis to treat HIE and traumatic brain injuries.

The role of a lncRNA (TCONS_00044595) in regulating pineal CLOCK expression after neonatal hypoxia-ischemia brain injury.

A common, yet often neglectable, feature of neonatal hypoxic-ischemic brain damage (HIBD) is circadian rhythm disorders resulted from pineal gland dysfunction. Our previous work demonstrated that miRNAs play an important role in regulating key circadian genes in the pineal gland post HIBD [5,21]. In current study, we sought out to extend our investigation by profiling expression changes of pineal long non-coding RNAs (lncRNAs) upon neonatal HIBD using RNA-Seq. After validating lncRNA changes, we showed that one lncRNA: TCONS_00044595 is highly enriched in the pineal gland and exhibits a circadian expression pattern. Next, we performed bioinformatic analysis to predict the lncRNA-miRNA regulatory network and identified 168 miRNAs that potentially targetlncRNA TCONS_00044595. We further validated the bona fide interaction between one candidate miRNA: miR-182, a known factor to regulate pineal Clock expression, and lncRNA TCONS_00044595. Finally, we showed that suppression of lncRNA TCONS_00044595 alleviated the CLOCK activation both in the cultured pinealocytes under OGD conditions and in the pineal gland post HIBD in vivo. Our study thus shed light into novel mechanisms of pathophysiology of pineal dysfunction post neonatal HIBD.

Significance of sTREM-1 in early prediction of ventilator-associated pneumonia in neonates: a single-center, prospective, observational study.

BACKGROUND: To evaluate whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) can be used as an early predictor of ventilator-associated pneumonia (VAP). METHODS: Ventilated neonatal patients admitted into the neonatology department between January 2017 and January 2018 were divided into VAP (n = 30) and non-VAP (n = 30) groups. Serum sTREM, procalcitonin (PCT), C-reactive protein and interleukin-6 levels were measured at 0, 24, 72, and 120 h after initiation of mechanical ventilation (MV). Correlations between blood biomarker concentrations and VAP occurrence were analyzed. Predictive factors for VAP were identified by logistic regression analysis and Hosmer-Lemeshow test, and the predictive value of sTREM-1 and biomarker combinations for VAP was determined by receiver operating characteristic curve analysis. RESULTS: The serum sTREM-1 concentration was significantly higher in the VAP group than in the non-VAP group after 72 and 120 h of MV (72 h: 289.5 (179.6-427.0) vs 202.9 (154.8-279.6) pg/ml, P < 0.001; 120 h: 183.9 (119.8-232.1) vs 141.3 (99.8-179.1) pg/ml, P = 0.042). The area under the curve (AUC) for sTREM-1 at 72 h was 0.902 with a sensitivity of 90% and specificity of 77% for the optimal cut-off value of 165.05 pg/ml. Addition of PCT to sTERM-1 at 72 h further improved the predictive value, with this combination having an AUC of 0.971 (95% confidence interval: 0.938-1.000), sensitivity of 0.96, specificity of 0.88, and Youden index of 0.84. CONCLUSION: sTREM-1 is a reliable predictor of VAP in neonates, and combined measurement of serum levels of sTREM-1 and PCT after 72 h of MV provided the most accurate prediction of VAP in neonatal patients.

Male sterile 305 Mutation Leads the Misregulation of Anther Cuticle Formation by Disrupting Lipid Metabolism in Maize.

The anther cuticle, which is mainly composed of lipid polymers, functions as physical barriers to protect genetic material intact; however, the mechanism of lipid biosynthesis in maize (Zea mays. L.) anther remains unclear. Herein, we report a male sterile mutant, male sterile 305 (ms305), in maize. It was shown that the mutant displayed a defective anther tapetum development and premature microspore degradation. Three pathways that are associated with the development of male sterile, including phenylpropanoid biosynthesis, biosynthesis of secondary metabolites, as well as cutin, suberine, and wax biosynthesis, were identified by transcriptome analysis. Gas chromatography-mass spectrometry disclosed that the content of cutin in ms305 anther was significantly lower than that of fertile siblings during the abortion stage, so did the total fatty acids, which indicated that ms305 mutation might lead to blocked synthesis of cutin and fatty acids in anther. Lipidome analysis uncovered that the content of phosphatidylcholine, phosphatidylserine, diacylglycerol, monogalactosyldiacylglycerol, and digalactosyldiacylglycerol in ms305 anther was significantly lower when compared with its fertile siblings, which suggested that ms305 mutation disrupted lipid synthesis. In conclusion, our findings indicated that ms305 might affect anther cuticle and microspore development by regulating the temporal progression of the lipidome in maize.

[Role of microglial pyroptosis in hypoxic-ischemic brain damage].

OBJECTIVE: To investigate the role of microglial pyroptosis in hypoxic-ischemic brain damage. METHODS: An oxygen-glucose deprivation/reoxygenation (OGD/R) model of rat microglial cells were cultured in vitro. Western blot was used to measure the expression of the pyroptosis-related proteins caspase-1, interleukin-1ß (IL-1ß), and N-terminal gasdermin D (GSDMD-N) at 0, 1, 3, 6, 12, and 24 hours after OGD/R. After the microglial cells were transfected with lentivirus-mediated silenced gasdermin D (GSDMD), immunofluorescence assay and Western blot were used to measure the transfection rate of GSDMD. Microglial cell lines were divided into three groups: normal control, negative control, and LV-sh_GSDMD (lentivirus-mediated GSDMD silencing). CCK-8 assay and LDH kit were used to observe the effect of GSDMD silencing on the viability and toxicity of microglial cells at 24 hours after OGD/R. Western blot was used to observe the effect of GSDMD silencing on the levels of caspase-1, GSDMD-N, and IL-1ß in the microglial cells at 24 hours after OGD/R. RESULTS: The expression levels of the pyroptosis-related proteins caspase-1, GSDMD-N, and IL-1ß in microglial cells were upregulated since 0 hour after OGD/R and reached the peak levels at 24 hours. A microglial cell model of lentivirus-mediated GSDMD silencing was successfully constructed. At 24 hours after OGD/R, compared with the normal control group, the GSDMD silencing group had a significant increase in the cell viability and a significant reduction in the cytotoxicity (P<0.05), as well as significant reductions in the protein expression levels of caspase-1, GSDMD-N, and IL-1ß in microglial cells (P<0.05). CONCLUSIONS: Lentivirus silencing of the key substrate protein for pyroptosis GSDMD can alleviate hypoxic-ischemic brain damage, suggesting that microglial pyroptosis aggravates hypoxic-ischemic brain damage.

Pedobacter pollutisoli sp. nov., Isolated from Tetrabromobisphenol A-Contaminated Soil.

A Gram-stain negative, strictly aerobic, non-spore forming, non-motile, rod-shaped bacterium, designated TBBPA-24T, was isolated from tetrabromobisphenol A-contaminated soil in China. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain TBBPA-24T was most closely related to Pedobacter nanyangensis Q4T (96.5%) and Pedobacter 'zeaxanthinifaciens' TDMA-5T (96.1%). Chemotaxonomic analysis revealed that strain TBBPA-24T possessed MK-7 as the major respiratory quinone and lipid, aminolipid, phospholipid, phosphatidylethanolamine, and phosphoaminolipid as the major polar lipid. The major fatty acids were iso-C15:0 (40.2%), summed feature 3 (C16:1ω6c and/or C16:1ω7c, 25.6%) and iso-C17:0 3-OH (16.4%). The genomic DNA G+C content of strain TBBPA-24T was 43.9 mol%. Based on the phylogenetic, phenotypic characteristics, and chemotaxonomic data, strain TBBPA-24T is considered a novel species of the genus Pedobacter, for which the name Pedobacter pollutisoli sp. nov. is proposed. The type strain TBBPA-24T (= KCTC 62314T = CCTCC AB 2017244T) is proposed.

Microdroplet assisted hollow ZnCdS@PDA nanocages' synergistic confinement effect for promoting photocatalytic H2O2 production.

Solar-driven photocatalytic H2O2 production is greatly impeded by the slow mass transfer and rapid recombination of photogenerated charge carriers for multiphase reactions. Polydopamine (PDA)-coated hollow ZnCdS (ZnCdS@PDA) octahedral cages with sulfur vacancies were constructed as micro-reactors to provide a delimited micro-environment for highly efficient paired H2O2 production through water oxidation coupled with oxygen reduction. At neutral pH, hollow ZnCdS@PDA cages exhibited a high H2O2 production yield of 45.5 mM g-1 h-1 without the assistance of sacrificial agents in bulk solution, which can be attributed to the distinguished space constraint in hollow nanocages and a surprisingly adjusted band structure. Compared to the bulk water system, H2O and O2 inside the hollow nanocage can form an ideal system for boosting such nanoconfined H2O or O2 molecules' adsorption/enrichment on the interior of the ZnCdS active sites. More importantly, the photocatalytic yield of H2O2 generation (H2O2 concentrations of 190-65.6 mM g-1 h-1) obtained in the abundant gas-liquid interface of microdroplets is dramatically higher than that obtained in an aqueous bulk environment under visible light conditions without using sacrificial agents. This enhancement can be attributed to the synergistic effect of the hollow ZnCdS@PDA nanocage reactor and the microdroplet confinement photocatalysis reaction. Particularly, the improved/confined enhancement of O2 availability and enhanced charge separation, along with high catalytic durability are the main reasons leading to significant H2O2 production due to an ultrahigh interfacial electric field and an extremely large specific surface area in microdroplets. In addition to producing a highly concentrated liquid of hydrogen peroxide during the microdroplet photoreaction, we also obtained white solid hydrogen peroxide powder with strong oxidizing properties reducing costs and increasing safety in storage and transportation. This study highlights that nano-liquid catalysis (using microdroplets) provides a very efficient pathway for accelerating semiconductor photocatalysis limited by gas diffusion in a liquid.

microRNA-9a-5p disrupts the ELAVL1/VEGF axis to alleviate traumatic brain injury.

Plasma microRNA (miR)-9 has been identified as a promising diagnostic biomarker for traumatic brain injury (TBI). This study aims to investigate the possible role and mechanisms of miR-9a-5p affecting TBI. Microarray-based gene expression profiling of TBI was used for screening differentially expressed miRNAs and genes. TBI rat models were established. miR-9a-5p, ELAVL1 and VEGF expression in the brain tissue of TBI rats was detected. The relationship among miR-9a-5p, ELAVL1 and VEGF was tested. TBI modeled rats were injected with miR-9a-5p-, ELAVL1 or VEGF-related sequences to identify their effects on TBI. miR-9a-5p was poorly expressed in the brain tissue of rats with TBI. ELAVL1 was a downstream target gene of miR-9a-5p, which could negatively regulate its expression. Enforced miR-9a-5p expression prevented brain tissue damage in TBI rats by targeting ELAVL1. Meanwhile, ELAVL1 could increase the expression of VEGF, which was highly expressed in the brain tissue of rats with TBI. In addition, ectopically expressed miR-9a-5p alleviated brain tissue damage in TBI rats by downregulating the ELAVL1/VEGF axis. Overall, miR-9a-5p can potentially reduce brain tissue damage in TBI rats by targeting ELAVL1 and down-regulating VEGF expression.

Engineering photo-methylotrophic Methylobacterium for enhanced 3-hydroxypropionic acid production during non-growth stage fermentation.

This study explored the potential of methanol as a sustainable feedstock for biomanufacturing, focusing on Methylobacterium extorquens, a well-established representative of methylotrophic cell factories. Despite this bacterium's long history, its untapped photosynthetic capabilities for production enhancement have remained unreported. Using genome-scale flux balance analysis, it was hypothesized that introducing photon fluxes could boost the yield of 3-hydroxypropionic acid (3-HP), an energy- and reducing equivalent-consuming chemicals. To realize this, M. extorquens was genetically modified by eliminating the negative regulator of photosynthesis, leading to improved ATP levels and metabolic activity in non-growth cells during a two-stage fermentation process. This modification resulted in a remarkable 3.0-fold increase in 3-HP titer and a 2.1-fold increase in its yield during stage (II). Transcriptomics revealed that enhanced light-driven methanol oxidation, NADH transhydrogenation, ATP generation, and fatty acid degradation were key factors. This development of photo-methylotrophy as a platform technology introduced novel opportunities for future production enhancements.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.