NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitates HBV-related acute-on-chronic liver failure.

BACKGROUND AIMS: Hepatitis B virus (HBV) infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in pyroptotic liver, and HMGB1 derived from pyroptotic liver constituted an important factor triggering generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of MPO-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring liver function of HBV-related ACLF patients.

Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML.

M6A (N6-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified DDO-2728 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. DDO-2728 was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. DDO-2728 increased the abundance of m6A modifications in AML cells, reduced the mRNA stability of TACC3, and inhibited cell cycle progression. Furthermore, DDO-2728 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.

The complete chloroplast genome of Carex laevissima Nakai (Cyperaceae).

Carex laevissima Nakai 1914 (Cyperaceae) is vital for ecological conservation and land virescence, and has high ornamental value. Here the chloroplast genome of Carex laevissima was assembled and systematically analyzed for further genetic research of Carex plants. The chloroplast sequence of Carex laevissima was 188,029 bp in length, including two inverted repeat (IR) regions of 36,699 bp each, a large single-copy (LSC) region of 106,171 bp and a small single-copy region (SSC) of 8460 bp. The overall GC content is 34.0%. It contains 133 genes, including 89 protein-coding, 36 tRNA, and eight rRNA genes. Phylogenetic analysis showed that Carex laevissima is most closely related to Carex neurocarpa.

Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction.

Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells. Mechanism study showed Rabeprazole down-regulated the transcription of MLL-FPs related Hox and Meis1 genes and effectively inhibited MLL1 H3K4 methyltransferase (HMT) activity in MV4-11 cells bearing MLL-AF4 fusion protein. Displacement of MLL1 probe from WDR5 protein suggested that Rabeprazole may inhibit MLL1 HMT activity through disturbing MLL1-WDR5 protein-protein interaction. Moreover, other proton pump inhibitors (PPIs) also indicated the inhibition activity of MLL1-WDR5. Preliminary SARs showed the structural characteristics of PPIs were also essential for the activities of MLL1-WDR5 inhibition. Our results indicated the drug reposition of PPIs for MLL-rearranged leukemias and provided new insight for further optimization of targeting MLL1 methyltransferase activity, the MLL1-WDR5 interaction or WDR5.

[Study on GLI values of Polygonatum odoratum base on multi-temporal of unmanned aerial vehicle remote sensing].

Unmanned aerial vehicle(UAV) remote sensing and vegetation index have great potential in the field of Chinese herbal medicine planting. In this study, the visible light image of Polygonatum odoratum planting area in Changyi district of Jilin province were acquired by UAV, and the real-time monitoring of P. odoratum planting area was realized. The green leaf index(GLI) was established, and GLI values of P. odoratum were collected used the spatial sampling points. To compare the GLI values in different periods, it was found that the GLI values of P. odoratum have three stages changing rule of rising-gentle-falling related to the germination, vigorous growth and withered of P. odoratum growth. Meanwhile, the GLI values were compared with four biomass data of P. odoratum, including plant height, leaf area, chlorophyll a and chlorophyll b content in leaves, and it was found that the GLI value was related to the growth potential of P. odoratum. The GLI value with a rapid increase in rising stage or at a high level in the gentle stage means the P. odoratum was in a better growth potential. GLI value has a same change trend with plant height, and has certain correlation with plant height and leaf area. However, there is no obvious relationship between chlorophyll a and chlorophyll b contents in leaves and GLI value. The study clarified the change rule of GLI value of P. odoratum, explained the reason for the change of GLI value, and expanded the application range of GLI. The research shows that UAV and vegetation index can be applied to monitoring the Chinese herbal medicines planting, and provides a new idea for exploring more effective information extraction methods of Chinese herbal medicines.

Predictors of Cognitive Impairment After Stroke: A Prospective Stroke Cohort Study.

BACKGROUND: Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors' quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. OBJECTIVE: To develop a new clinical risk score for ischemic stroke survivors in predicting 6-12 months PSCI. METHODS: We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. RESULTS: One hundred forty-five subjects completed a 6-12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (ß= 0.065, OR = 1.067, 95% CI = 1.016-1.120), years of education (ß= -0.346, OR = 0.707, 95% CI = 0.607-0.824), periventricular hyperintensity grading (ß= 1.253, OR = 3.501, 95% CI = 1.652-7.417), diabetes mellitus (ß= 1.762, OR = 5.825, 95% CI = 2.068-16.412), and the number of acute nonlacunar infarcts (ß= 0.569, OR = 1.766, 95% CI = 1.243-2.510) were independently associated with 6-12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832-0.935). CONCLUSIONS: The optimized risk model was effective in screening stroke survivors at high risk of developing 6-12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation.

[Investigation and analysis of influence of geographical environment factors on spatial distribution of flavonoid of Epimedium koreanum].

The study is aimed to clarify the spatial distribution of Epimedium koreanum( Ek) high-quality production areas. Through visiting and field investigation,collecting the distribution information of Ek samples,and based on the four kinds of flavonoids in Ek,the high-quality production areas and distribution of Ek distribution of the main environmental factors were drawn using GIS technology,the maximum entropy model( MaxEnt),geographical detector statistical analysis method,and the statistical significance of regression equation were obtained. Considering the content of 4 main flavonoids in Ek,the results of this study showed that the main environmental factors,such as precipitation,annual precipitation variation coefficient,annual average temperature and clay content exhibited the greatest influence on the growth suitability of Ek. Ek materials quality concentrated distribution in southeastern Jilin province Changbai mountain hinterland and northeastern Liaoning province. Ek with high content of epimedine A and epimedine C are mainly distributed in the southeastern Jilin province and northeastern Liaoning province,Ek with high epimedine B is distributed in eastern Liaoning province; high icariin Ek was found in most area of northeastern Liaoning province,a small amount distributed in the southeast of Jilin province. This study predicted the climate suitability distribution of Ek,and provided reference for the rational planning and establishment of the standardized cultivation base of Ek.

[Characteristics of Bioaerosols Emitted from WWTP with SBR Treatment Process].

Sampling sites were located in a wastewater treatment plant (WWTP) with a sequencing batch reactor activated sludge process to investigate the characteristics of bioaerosol emissions. The results indicated that bioaerosols were detected from each treatment section of the WWTP, and concentrations of bioaerosols were in the range of 82-1525 CFU·m-3. The coarse screen, aeration tank, and sludge dewatering house were the main sources of bioaerosols. The dominant species in each treatment section was Cyanobacteria, and the other main bacterial taxa were Aeromonas, Peptostreptococcaceae, Moraxellaceae, Chroococcidiopsis, Sphingomonas, Arcobacter, and Acinetobacter. Among the identified bacterial genera, Aeromonas, Arcobacter, Acinetobacter, and Sphingomonas were potential pathogens. Bioaerosol concentration and abundance decreased along the vertical and horizontal directions. Appropriate temperature and relative humidity benefited the survival of bioaerosols in the air (P<0.01), whereas a negative relationship between bioaerosol concentration and wind speed was observed (P<0.05). Although exposure risks caused by bioaerosols were negligible in this study, the accumulation of bioaerosols would increase potential health risks. The bioreactor for odor treatment could effectively reduce bioaerosol emissions.

Increment of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice.

BACKGROUND: The incidence of atrial fibrillation (AF) is correlated with decreased levels of testosterone in elderly men. Late sodium current may exert a role in AF pathogenesis. OBJECTIVE: The purpose of this study was to explore the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice. METHODS: Male ICR mice (5 weeks old) were castrated to establish a testosterone deficiency model. One month after castration, dihydrotestosterone 5 mg/kg was administered subcutaneously for 2 months. Serum total testosterone level was assessed by enzyme-linked immunosorbent assay. High-frequency electrical stimulation was used to induce atrial arrhythmias. Whole-cell patch-clamp technique was used to for single-cell electrophysiologic study. RESULTS: Serum dihydrotestosterone levels of castration mice declined significantly but recovered with administration of exogenous dihydrotestosterone. In comparison with sham mice, the number of AF episodes significantly increased by 13.5-fold, AF rate increased by 3.75-fold, and AF duration prolonged in castrated mice. Dihydrotestosterone administration alleviated the occurrence of AF. Action potential duration at both 50% and 90% repolarization were markedly increased in castrated mice compared to sham controls. The late sodium current was enhanced in castrated male mice. These alterations were alleviated by treatment with dihydrotestosterone. Systemic application of the INa-L inhibitors ranolazine, eleclazine, and GS967 inhibited the occurrence of AF in castrated mice. CONCLUSION: Testosterone deficiency contributed to the increased late sodium current, prolonged action potential repolarization, and increased susceptibility to AF. Blocking of late sodium current is beneficial against the occurrence of AF in castrated mice.

Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFß1 and miR-29 pathways.

Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFß1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFß1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.

Granulation of activated sludge in a pilot-scale sequencing batch reactor for the treatment of low-strength municipal wastewater.

Aerobic granulation of activated sludge was achieved in a pilot-scale sequencing batch reactor (SBR) for the treatment of low-strength municipal wastewater (<200 mg L(-1) of COD, chemical oxygen demand). The volume exchange ratio and settling time of an SBR were found to be two key factors in the granulation of activated sludge grown on the low-strength municipal wastewater. After operation of 300 days, the mixed liquor suspended solids (MLSS) concentration in the SBR reached 9.5 g L(-1) and consisted of approximate 85% granular sludge. The average total COD removal efficiency kept at 90% and NH4+-N was almost completely depleted (approximately 95%) after the formation of aerobic granules. The granules (with a diameter over 0.212 mm) had a diameter ranging from 0.2 to 0.8 mm and had good settling ability with a settling velocity of 18-40 m h(-1). Three bacterial morphologies of rod, coccus and filament coexisted in the granules. Mathematical modeling was performed to get insight into this pilot-scale granule-based reactor. The modified IWA activated sludge model No 3 (ASM3) was able to adequately describe the pilot-scale SBR dynamics during its cyclic operation.