Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development.

Metabolites such as crotonyl-CoA and lactyl-CoA influence gene expression by covalently modifying histones, known as histone lysine crotonylation (Kcr) and lysine lactylation (Kla). However, the existence patterns, dynamic changes, biological functions and associations of these modifications with histone lysine acetylation and gene expression during mammalian development remain largely unknown. Here, we find that histone Kcr and Kla are widely distributed in the brain and undergo global changes during neural development. By profiling the genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC and RNA sequencing, we reveal that these marks are tightly correlated with chromatin state and gene expression, and extensively involved in transcriptome remodeling to promote cell-fate transitions in the developing telencephalon. Importantly, we demonstrate that global Kcr and Kla levels are not the consequence of transcription and identify the histone deacetylases (HDACs) 1-3 as novel 'erasers' of H3K18la. Using P19 cells as an induced neural differentiation system, we find that HDAC1-3 inhibition by MS-275 pre-activates neuronal transcriptional programs by stimulating multiple histone lysine acylations simultaneously. These findings suggest that histone Kcr and Kla play crucial roles in the epigenetic regulation of neural development.

Correlation between white blood cell count and intestinal resection in patients with acute mesenteric vein thrombosis.

OBJECTIVE: Acute mesenteric vein thrombosis (AMVT) is an acute abdominal disease with onset, rapid progression, and extensive intestinal necrosis that requires immediate surgical resection. The purpose of this study was to determine the risk factors for nosocomial intestinal resection in patients with AMVT. METHODS: We retrospectively analysed 64 patients with AMVT diagnosed by CTA at the Affiliated Hospital of Kunming University of Science and Technology from January 2013 to December 2021. We compared patients who underwent intestinal resection (42 patients) with those who did not undergo intestinal resection (22 patients). The area under the ROC curve was evaluated, and a forest map was drawn. RESULTS: Among the 64 patients, 6 (9.38%) had a fever, 60 (93.75%) had abdominal pain, 9 (14.06%) had a history of diabetes, 8 (12.5%) had a history of deep vein thrombosis (DVT), and 25 (39.06%) had ascites suggested by B ultrasound or CT after admission. The mean age of all patients was 49.86 ± 16.25 years. The mean age of the patients in the enterectomy group was 47.71 ± 16.20 years. The mean age of the patients in the conservative treatment group (without enterectomy) was 53.95 ± 15.90 years. In the univariate analysis, there were statistically significant differences in leukocyte count (P = 0.003), neutrophil count (P = 0.001), AST (P = 0.048), total bilirubin (P = 0.047), fibrinogen (P = 0.022) and DD2 (P = 0.024) between the two groups. The multivariate logistic regression analysis showed that admission white blood cell count (OR = 1.153, 95% CI: 1.039-1.280, P = 0.007) was an independent risk factor for intestinal resection in patients with AMVT. The ROC curve showed that the white blood cell count (AUC = 0.759 95% CI: 0.620-0.897; P = 0.001; optimal threshold: 7.815; sensitivity: 0.881; specificity: 0.636) had good predictive value for emergency enterectomy for AMVT. CONCLUSIONS: Among patients with AMVT, patients with a higher white blood cell count at admission were more likely to have intestinal necrosis and require emergency enterectomy. This study is helpful for clinicians to accurately determine whether emergency intestinal resection is needed in patients with AMVT after admission, prevent further intestinal necrosis, and improve the prognosis of patients.

Deciphering a cell death-associated signature for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell carcinoma, accounting for about 30% of all lung cancers. Yet, the evaluation of prognostic outcome and therapy response of patients with LUSC remains to be resolved. This study aimed to explore the prognostic value of cell death pathways and develop a cell death-associated signature for predicting prognosis and guiding treatment in LUSC. METHODS: Transcriptome profiles and corresponding clinical information of LUSC patients were gathered from The Cancer Genome Atlas (TCGA-LUSC, n = 493) and Gene Expression Omnibus database (GSE74777, n = 107). The cell death-related genes including autophagy (n = 348), apoptosis (n = 163), and necrosis (n = 166) were retrieved from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases. In the training cohort (TCGA-LUSC), LASSO Cox regression was used to construct four prognostic signatures of respective autophagy, apoptosis, and necrosis pathway and genes of three pathways. After comparing the four signatures, the cell death index (CDI), the signature of combined genes, was further validated in the GSE74777 dataset. We also investigated the clinical significance of the CDI signature in predicting the immunotherapeutic response of LUSC patients. RESULTS: The CDI signature was significantly associated with the overall survival of LUSC patients in the training cohort (HR, 2.13; 95% CI, 1.62‒2.82; P < 0.001) and in the validation cohort (HR, 1.94; 95% CI, 1.01‒3.72; P = 0.04). The differentially expressed genes between the high- and low-risk groups contained cell death-associated cytokines and were enriched in immune-associated pathways. We also found a higher infiltration of naive CD4+ T cells, monocytes, activated dendritic cells, neutrophils, and lower infiltration of plasma cells and resting memory CD4+ T cells in the high-risk group. Tumor stemness indices, mRNAsi and mDNAsi, were both negatively correlated with the risk score of the CDI. Moreover, LUSC patients in the low-risk group are more likely to respond to immunotherapy than those in the high-risk group (P = 0.002). CONCLUSIONS: This study revealed a reliable cell death-associated signature (CDI) that closely correlated with prognosis and the tumor microenvironment in LUSC, which may assist in predicting the prognosis and response to immunotherapy for patients with LUSC.

Loss of microglial EED impairs synapse density, learning, and memory.

The embryonic ectoderm development (EED) is a core component of the polycomb-repressive complex 2 (PRC2) whose mutations are linked to neurodevelopmental abnormalities, intellectual disability, and neurodegeneration. Although EED has been extensively studied in neural stem cells and oligodendrocytes, its role in microglia is incompletely understood. Here, we show that microglial EED is essential for synaptic pruning during the postnatal stage of brain development. The absence of microglial EED at early postnatal stages resulted in reduced spines and impaired synapse density in the hippocampus at adulthood, accompanied by upregulated expression of phagocytosis-related genes in microglia. As a result, deletion of microglial Eed impaired hippocampus-dependent learning and memory in mice. These results suggest that microglial EED is critical for normal synaptic and cognitive functions during postnatal development.

Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters.

Histone lysine crotonylation (Kcr), an evolutionarily conserved and widespread non-acetyl short-chain lysine acylation, plays important roles in transcriptional regulation and disease processes. However, the genome-wide distribution, dynamic changes, and associations with gene expression of histone Kcr during developmental processes are largely unknown. In this study, we find that histone Kcr is mainly located in active promoter regions, acts as an epigenetic hallmark of highly expressed genes, and regulates genes participating in metabolism and proliferation. Moreover, elevated histone Kcr activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells (NSPCs) by increasing chromatin openness and recruitment of RNA polymerase II (RNAP2). Functionally, these activated genes contribute to transcriptome remodeling and promote neuronal differentiation. Overall, histone Kcr marks active promoters with high gene expression and modifies the local chromatin environment to allow gene activation.

Decoding the dynamic H3K9cr landscapes during neural commitment of P19 embryonal carcinoma cells.

Histone lysine crotonylation (Kcr) is a novel hydrophobic histone acylation modification, and we recently report its crucial roles in neural differentiation. However, it is still unclear how histone Kcr involve in early neural commitment. Here, we systematically investigate the H3K9cr landscapes during neuroectodermal differentiation of pluripotent P19 embryonal carcinoma cells (ECCs). We reveal that the genome-wide changes in H3K9cr favor neural fate specification, and identify potential co-factors binding H3K9cr. We also uncover that H3K9cr collaborates with H3K9ac to regulate gene expression changes. Our results provide novel insights into the epigenetic mechanisms underlying neural commitment.

An alanine to valine mutation of glutamyl-tRNA reductase enhances 5-aminolevulinic acid synthesis in rice.

KEY MESSAGE: An alanine to valine mutation of glutamyl-tRNA reductase's 510th amino acid improves 5-aminolevulinic acid synthesis in rice. 5-aminolevulinic acid (ALA) is the common precursor of all tetrapyrroles and plays an important role in plant growth regulation. ALA is synthesized from glutamate, catalyzed by glutamyl-tRNA synthetase (GluRS), glutamyl-tRNA reductase (GluTR), and glutamate-1-semialdehyde aminotransferase (GSAT). In Arabidopsis, ALA synthesis is the rate-limiting step in tetrapyrrole production via GluTR post-translational regulations. In rice, mutations of GluTR and GSAT homologs are known to confer chlorophyll deficiency phenotypes; however, the enzymatic activity of rice GluRS, GluTR, and GSAT and the post-translational regulation of rice GluTR have not been investigated experimentally. We have demonstrated that a suppressor mutation in rice partially reverts the xantha trait. In the present study, we first determine that the suppressor mutation results from a G → A nucleotide substitution of OsGluTR (and an A → V change of its 510th amino acid). Protein homology modeling and molecular docking show that the OsGluTRA510V mutation increases its substrate binding. We then demonstrate that the OsGluTRA510V mutation increases ALA synthesis in Escherichia coli without affecting its interaction with OsFLU. We further explore homologous genes encoding GluTR across 193 plant species and find that the amino acid (A) is 100% conserved at the position, suggesting its critical role in GluTR. Thus, we demonstrate that the gain-of-function OsGluTRA510V mutation underlies suppression of the xantha trait, experimentally proves the enzymatic activity of rice GluRS, GluTR, and GSAT in ALA synthesis, and uncovers conservation of the alanine corresponding to the 510th amino acid of OsGluTR across plant species.

Distinct lipid membrane interaction and uptake of differentially charged nanoplastics in bacteria.

BACKGROUND: Nanoplastics have been recently found widely distributed in our natural environment where ubiquitously bacteria are major participants in various material cycles. Understanding how nanoplastics interact with bacterial cell membrane is critical to grasp their uptake processes as well as to analyze their associated risks in ecosystems and human microflora. However, little is known about the detailed interaction of differentially charged nanoplastics with bacteria. The present work experimentally and theoretically demonstrated that nanoplastics enter into bacteria depending on the surface charges and cell envelope structural features, and proved the shielding role of membrane lipids against nanoplastics. RESULTS: Positively charged polystyrene nanoplastics (PS-NH2, 80 nm) can efficiently translocate across cell membranes, while negatively charged PS (PS-COOH) and neutral PS show almost no or much less efficacy in translocation. Molecular dynamics simulations revealed that the PS-NH2 displayed more favourable electrostatic interactions with bacterial membranes and was subjected to internalisation through membrane penetration. The positively charged nanoplastics destroy cell envelope of Gram-positive B. subtilis by forming membrane pore, while enter into the Gram-negative E. coli with a relatively intact envelope. The accumulated positively charged nanoplastics conveyed more cell stress by inducing a higher level of reactive oxygen species (ROS). However, the subsequently released membrane lipid-coated nanoplastics were nearly nontoxic to cells, and like wise, stealthy bacteria wrapped up with artifical lipid layers became less sensitive to the positively charged nanoplastics, thereby illustrating that the membrane lipid can shield the strong interaction between the positively charged nanoplastics and cells. CONCLUSIONS: Our findings elucidated the molecular mechanism of nanoplastics' interaction and accumulation within bacteria, and implied the shielding and internalization effect of membrane lipid on toxic nanoplastics could promote bacteria for potential plastic bioremediation.

Direct Measuring Particulate Matters in Smoke Plumes from Chimneys in a Textile Dyeing Industrial Park by a Self-Developed PM Detector on an UAV in Yangtze River Delta of China.

Directly measuring particulate matters (PM) from chimneys in an industrial park is difficult due to it being hard to reach the peak heights. A self-developed PM detector on an unmanned aerial vehicle (UAV) had been deployed to directly measure the PM emissions in smoke plumes from chimneys in a textile dyeing industrial park. Compared with a commercial PM device (LD-5R, SIBATA, Kyoto, Japan), the self-developed detector showed similar performance with a good correlation (R2 varying from 0.911 to 0.951) in simultaneously vertical PM measurements on UAV. The PM emissions from chimneys after different textile treating processes, including pigment printing, dyeing process, and digital printing, were investigated. PM mass concentrations and particle number concentrations (PNC) in different sizes were found to be significantly higher in pigment printing than those in dyeing process and digital printing by 2 or 3 times after electrostatic precipitation. The activated carbon adsorption and electrostatic precipitation were the major PM controlling techniques in the park. The PM mass concentrations and PNC were the highest in the process of dyeing after activated carbon adsorption with the concentrations of PM1 (1000 µg·m-3), PM2.5 (1600 µg·m-3), and PM10 (2000 µg·m-3), respectively. According to the results of PM and PNC, PM2.5 was found to be the dominant particles accounting for 99% of the PM emissions. It may be due to the high temperature in thermo-fixing machine, which is beneficial to the PM2.5 generation. This study revealed PM2.5 was the dominant particles to be reduced in textile dyeing enterprises to mitigate PM pollution.

Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration.

Neurotrauma has been recognized as a risk factor for neurodegenerative diseases, and sex difference of the incidence and outcome of neurodegenerative diseases has long been recognized. Past studies suggest that microglia could play a versatile role in both health and disease. So far, the microglial mechanisms underlying neurodegeneration and potentially lead to sex-specific therapies are still very open. Here we applied whole transcriptome analysis of microglia acutely isolated at different timepoints after a cortical stab wound injury to gain insight into genes that might be dysregulated and transcriptionally different between males and females after cortical injury. We found that microglia displayed distinct temporal and sexual molecular signatures of transcriptome after cortical injury. Hypotheses and gene candidates that we presented in the present study could be worthy to be examined to explore the roles of microglia in neurotrauma and in sex-biased neurodegenerative diseases.

Dynamic Polyphosphate Metabolism Coordinating with Manganese Ions Defends against Oxidative Stress in the Extreme Bacterium Deinococcus radiodurans.

Deinococcus radiodurans is an extreme bacterium with unparalleled resistance to oxidative stresses. Accumulation of intracellular Mn2+ complexing with small metabolites is the key contributor to the tolerance of D. radiodurans against oxidative stress. However, the intracellular reservoir of Mn ions and homeostatic regulation of the Mn complex in D. radiodurans remain unclear. We identified an evolutionarily ancient and negatively charged phosphate polymer (polyphosphate [PolyP]) in D. radiodurans We investigated PolyP metabolism in the response of D. radiodurans to oxidative stress. The genes dr1939, encoding polyphosphatase kinase (PPKDr; the subscript "Dr" refers to D. radiodurans), and dra0185, encoding exopolyphosphatase (PPXDr), were identified. PPXDr is a novel exopolyphosphatase with a cofactor preference to Mn2+, which enhances the dimerization and activity of PPXDr to allow the effective cleavage of PolyP-Mn. PPKDr and PPXDr exhibited different dynamic expression profiles under oxidative stress. First, ppkDr was upregulated leading to the accumulation of PolyP, which chelated large amounts of intracellular Mn ions. Subsequently, the expression level of ppkDr decreased while ppxDr was substantially upregulated and effectively hydrolyzed inactive PolyP-Mn to release phosphate (Pi) and Mn2+, which could form into Mn-Pi complexes to scavenge O2- and protect proteins from oxidative damage. Hence, dynamic cellular PolyP metabolites complexed with free Mn ions highlight a defense strategy of D. radiodurans in response to oxidative stress.IMPORTANCE The Mn-phosphate complex (Mn-Pi) plays a key role in the cellular resistance of radioresistant bacteria. The evolutionarily ancient polyphosphate polymers (polyphosphate [PolyP]) could effectively chelate Mn2+ and donate phosphates. However, the intracellular reservoir of Mn ions and homeostatic regulation of the Mn-Pi complex remain unclear. Here, we investigated the relationship of PolyP metabolites and Mn2+ homeostasis and how they function to defend against oxidative stress in the radioresistant bacterium Deinococcus radiodurans We found that PPXDr (the subscript "Dr" refers to D. radiodurans) is a novel exopolyphosphatase with a cofactor preference for Mn2+, mediating PolyP-Mn degradation into Pi and Mn ions. The formed Mn-Pi complexes effectively protect proteins. The dynamic PolyP metabolism coordinating with Mn ions is a defense strategy of D. radiodurans in response to oxidative stress. The findings not only provide new insights into the resistance mechanism of the extreme bacterium D. radiodurans but also broaden our understanding of the functions of PolyP metabolism in organisms.

DqsIR quorum sensing-mediated gene regulation of the extremophilic bacterium Deinococcus radiodurans in response to oxidative stress.

Here, we show that AHLs can be employed by Deinococcus radiodurans, which belongs to the unique phylum Deinococcus-Thermus and is known for its cellular resistance to environmental stresses. An AHL-mediated quorum-sensing system (DqsI/DqsR) was identified in D. radiodurans. We found that under non-stress conditions, the AHL level was "shielded" by quorum quenching enzymes, whereas AHLs accumulated when D. radiodurans was exposed to oxidative stress. Upon exposure to H2 O2 , AHL synthetic enzymes (DqsI) were immediately induced, while the expression of quorum-quenching enzymes began to increase approximately 30 min after exposure to H2 O2 , as shown by time-course analyses of gene expression. Both dqsI mutant (DMDqsI) and dqsR mutant (MDqsR) were more sensitive to oxidative stress compared with the wild-type strain. Exogenous AHLs (5 µM) could completely restore the survival fraction of DMDqsI under oxidative stress. RNA-seq analysis showed that a number of genes involved in stress-response, cellular cleansing, and DNA repair had altered transcriptional levels in MDqsR. The DqsR, acting as a regulator of quorum sensing, controls gene expression along with AHLs. Hence, the DqsIR-mediated quorum sensing that mediates gene regulation is an adaptive strategy for D. radiodurans in response to oxidative stresses and is conserved in the extremophilic Deinococcus bacteria.

Autoinducer-2 signaling is involved in regulation of stress-related genes of Deinococcus radiodurans.

Autoinducer-2 (AI-2) serves as a quorum-sensing signaling molecule that mediates both intraspecies and interspecies communication among bacteria, and plays critical roles in regulating various bacterial behaviors. In the present study, we investigated the functions of AI-2 signaling in the extremophilic bacterium Deinococcus radiodurans R1 by construction of the LuxS gene disruption mutant, survival phenotype assay and gene transcription assay. The gene mutant (DRΔLuxS), which was unable to produce AI-2, was significantly more sensitive to both gamma radiation and H2O2 compared with the wild-type strain. Addition of the wild-type-derived spent medium into the cell culture of DRΔLuxS fully restored the radioresistance of D. radiodurans. A higher level of reactive oxygen species accumulated in the mutant compared with the wild type under normal or oxidative stress. Quantitative real-time PCR assays showed that transcriptional levels of stress-related proteins, including catalase, extracellular nuclease, Dps-1 and ABC transporters, were decreased in DRΔLuxS, indicating that AI-2 is involved in regulation of stress-related genes of D. radiodurans. Hence, AI-2 signaling may contribute to the extreme resistance of D. radiodurans to radiation and oxidative stresses.

A PerR-like protein involved in response to oxidative stress in the extreme bacterium Deinococcus radiodurans.

Response and defense systems against reactive oxygen species (ROS) contribute to the remarkable resistance of Deinococcus radiodurans to oxidative stress induced by oxidants or radiation. However, mechanisms involved in ROS response and defense systems of D. radiodurans are not well understood. Fur family proteins are important in ROS response. Only a single Fur homolog is predicted by sequence similarity in the current D. radiodurans genome database. Our bioinformatics analysis demonstrated an additional guanine nucleotide in the genome of D. radiodurans that is not in the database, leading to the discovery of another Fur homolog DrPerR. Gene disruption mutant of DrPerR showed enhanced resistance to hydrogen peroxide (H2O2) and increased catalase activity in cell extracts. Real-time PCR results indicated that DrPerR functions as a repressor of the catalase gene katE. Meanwhile, derepression of dps (DNA-binding proteins from starved cells) gene under H2O2 stress by DrPerR point to its regulatory role in metal ions hemostasis. Thus, DrPerR might function as a Fur homolog protein which is involved in ROS response and defense. These results help clarify the complicated regulatory network that responds to ROS stress in D. radiodurans.

Development and characterization of ZnxCuyTizMo alloys for biomedical applications: A high-throughput gradient continuous casting approach.

The limited mechanical properties of pure Zn, such as its low strength and ductility, hinder its application as a material for biodegradable implants. Addressing this challenge, the current study focuses on the development of biodegradable Zn-based alloys, employing innovative alloy design and processing strategies. Here, alloys with compositions ranging from 0.02 to 0.10 weight percent (wt%) Cu, 1.22 to 1.80 wt% Ti, and 0.04 to 0.06 wt% Mo were produced utilizing a high-throughput gradient continuous casting process. This study highlights three specific alloys: Zn1.82Cu0.10Ti0.05Mo (HR8), Zn0.08Cu1.86Ti0Mo (HR7), and Zn1.26Cu0.13Ti0.06Mo (HR6), which were extensively evaluated for their microstructure, mechanical properties, electrochemical performance, potential as bioimplants, and cytotoxicity. These alloys were found to exhibit enhanced mechanical strength, optimal degradation rates, and superior biocompatibility, evidenced by in-vivo experiments with SD rats, positioning them as promising candidates for medical implants. This research not only introduces a significant advancement in biodegradable alloy development but also proposes an efficient method for their production, marking a pivotal step forward in biomedical engineering. STATEMENT OF SIGNIFICANCE: The limited mechanical properties of pure Zn have hindered its application in biodegradable implants. Our research primarily focuses on the alloy design and process strategies of biodegradable Zn-based alloys. We explore the ZnCuxTixMox alloys. This study introduces a high-throughput experimental approach for efficient screening of multi-component alloy systems with optimal properties. The ZnCuxTixMox alloys were designed and processed through gradient continuous casting, followed by homogenization and hot rolling. Our findings indicate that the Zn1.82Cu0.10Ti0.05Mo alloy demonstrates superior tensile, mechanical, and corrosion properties post hot rolling. The study suggests that Zn0.13Cu1.26Ti0.06Mo, Zn0.08Cu1.86Ti0Mo, and Zn1.82Cu0.10Ti0.05Mo alloys hold significant potential as biodegradable materials.

Structural Evolution of Bacterial Polyphosphate Degradation Enzyme for Phosphorus Cycling.

Living organisms ranging from bacteria to animals have developed their own ways to accumulate and store phosphate during evolution, in particular as the polyphosphate (polyP) granules in bacteria. Degradation of polyP into phosphate is involved in phosphorus cycling, and exopolyphosphatase (PPX) is the key enzyme for polyP degradation in bacteria. Thus, understanding the structure basis of PPX is crucial to reveal the polyP degradation mechanism. Here, it is found that PPX structure varies in the length of ɑ-helical interdomain linker (ɑ-linker) across various bacteria, which is negatively correlated with their enzymatic activity and thermostability - those with shorter ɑ-linkers demonstrate higher polyP degradation ability. Moreover, the artificial DrPPX mutants with shorter ɑ-linker tend to have more compact pockets for polyP binding and stronger subunit interactions, as well as higher enzymatic efficiency (kcat/Km) than that of DrPPX wild type. In Deinococcus-Thermus, the PPXs from thermophilic species possess a shorter ɑ-linker and retain their catalytic ability at high temperatures (70 °C), which may facilitate the thermophilic species to utilize polyP in high-temperature environments. These findings provide insights into the interdomain linker length-dependent evolution of PPXs, which shed light on enzymatic adaption for phosphorus cycling during natural evolution and rational design of enzyme.

Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects.

BACKGROUND: Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers. OBJECTIVE: To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects. METHOD: A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICP‒MS) method. The pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the curve concentration-time curve (AUC0-t and AUC0-∞), and safety were evaluated via noncompartment analysis. RESULTS: The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for Cmax, AUC0-t, and AUC0-∞ were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2-99.6%, 24.1-127.5%, and 23.7-175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects. CONCLUSION: The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.

Characterization and heterologous expression of plasmalogen synthase MeHAD from Megasphaera elsdenii.

Plasmalogens (Pls) are vinyl-ether bond-containing glycerophospholipids or glycosyl diradyl glycerols, and are of great importance in the physiological functions and stability of cell membrane. Here, we identified and characterized that the plasmalogen synthase MeHAD from anaerobic Megasphaera elsdenii was responsible for vinyl-ether bond formation. Different from the 2-hydroxyacyl-CoA dehydratase (HAD) family plasmalogen synthase PlsA-PlsR which are encoded by two genes in Clostridium perfringens, the HAD homolog (MeHAD) encoded by a single gene MELS_0169 was found in M. elsdenii. By heterologous expression of the MeHAD gene into a nonplasmalogen-producing Escherichia coli strain, the expressed MeHAD was found to be located in the cell membrane region. Plasmalogens were detected in the recombinant strain using GC-MS and LC-MS, demonstrating that MeHAD was the key enzyme for plasmalogen synthesis. Moreover, the synthesized plasmalogens could enhance the oxidative stress-resistance and osmotic pressure-resistance of the recombinant strain, probably due to the ROS scavenging and decreased membrane permeability by the plasmalogens, respectively. The four-cysteine (Cys125, Cys164, Cys445 and Cys484) site-mutant of MeHAD, which were predicted binding to the [4Fe-4S] cluster, was unable to synthesize plasmalogens, indicating that the cysteines are important for the catalytic activity of MeHAD. Our results revealed the single gene encoded plasmalogen synthase in M. elsdenii and established a recombinant E. coli strain with plasmalogen production potential.

Risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection.

OBJECTIVE: To analyze the clinical characteristics of patients with overweight acute type A aortic dissection, and to explore the risk factors of acute kidney injury in patients with overweight acute type A aortic dissection. METHODS: From March 2019 to February 2022, the clinical data of 71 patients with acute type a aortic dissection diagnosed by CTA and undergoing surgical treatment with BMI > 24 in the First People's Hospital of Yunnan Province were retrospectively analyzed, and analyzed by univariate and logistic multivariate analysis methods. RESULTS: The mean BMI of all included patients was 27.23, The mean surface area of all included human populations was 1.833. The mean age of all patients was (52.06 ± 10.71) years old, and 35 patients developed acute kidney injury after surgery. Multi-factor Logistics regression analysis confirmed the risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection, including gender, CPB transit time and intraoperative infusion of suspended red blood cells. Seven patients in the AKI group died in hospital after surgery and two patients died in the non-AKI group. CONCLUSIONS: Among patients with overweight acute Type A aortic dissection, the incidence of AKI is 49.30%. According to multi-factor Logistics regression analysis, gender, CPB transit time and intraoperative suspended red blood cell volume are independent risk factors for postoperative acute kidney injury in patients with overweight acute Type A aortic dissection.

ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-ß signaling pathway.

The ability of neural stem/progenitor cells (NSPCs) to proliferate and differentiate is required through different stages of neurogenesis. Disturbance in the regulation of neurogenesis causes many neurological diseases, such as intellectual disability, autism, and schizophrenia. However, the intrinsic mechanisms of this regulation in neurogenesis remain poorly understood. Here, we report that Ash2l (Absent, small or homeotic discs-like 2), one core component of a multimeric histone methyltransferase complex, is essential for NSPC fate determination during postnatal neurogenesis. Deletion of Ash2l in NSPCs impairs their capacity for proliferation and differentiation, leading to simplified dendritic arbors in adult-born hippocampal neurons and deficits in cognitive abilities. RNA sequencing data reveal that Ash2l primarily regulates cell fate specification and neuron commitment. Furthermore, we identified Onecut2, a major downstream target of ASH2L characterized by bivalent histone modifications, and demonstrated that constitutive expression of Onecut2 restores defective proliferation and differentiation of NSPCs in adult Ash2l-deficient mice. Importantly, we identified that Onecut2 modulates TGF-ß signaling in NSPCs and that treatment with a TGF-ß inhibitor rectifies the phenotype of Ash2l-deficient NSPCs. Collectively, our findings reveal the ASH2L-Onecut2-TGF-ß signaling axis that mediates postnatal neurogenesis to maintain proper forebrain function.