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Stereoisomeric polycyclic natural products are important for drug discovery-based screening campaigns, due to the close correlation of stereochemistry with diversified bioactivities. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the ten-carbon building block. In this work, we reset the stage by the development of a bioinspired coupling, in which the rapid construction of the entire pentacyclic skeleton and the complete control of all five stereogenic centers are achieved through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate. The stereochemical diversification from a common intermediate allows for the divergent and collective synthesis of all four stereoisomeric subfamilies of yohimbine alkaloids through orchestrated tackling of thermodynamic and kinetic preference. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the building block. Here, the authors reset the stage by the development of a bioinspired coupling, in which the pentacyclic skeleton is constructed through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate.

This study investigates the photocatalytic degradation capabilities of Co₃O₄ synthesized via the sol–gel method for 1,2,4-trichlorobenzene under visible light. Characterization of the composites through scanning electron microscopy (SEM), X-ray Diffraction (XRD), and Fourier Transform Infrared Spectroscopy (FTIR) confirmed the formation of a cubic-phase structure. The photocatalytic performance of the synthesized Co3O4 was rigorously evaluated using the Langmuir–Hinshelwood model across various operational parameters, including catalyst dosage, initial pollutant concentration, reaction temperature, pH, and the presence of impurities such as humic acid, hydrogen peroxide (H2O2), and surfactants. Optimal conditions for the degradation process were determined to be a catalyst dosage of 2.0 g/L, an initial 1,2,4-trichlorobenzene concentration of 7.5 mg/L, and a reaction temperature of 30 ℃. Degradation efficiency was found to decreasenear neutral pH levels. Notably, the presence of humic acid had a negative impact on the degradation rate, while cationic surfactants and H2O2 served to enhance the photocatalytic process. Additionally, the degradation pathway and mechanism of 1,2,4-trichlorobenzene were predicted and validated, providing essential insights into its photocatalytic conversion. These findings underscore the effectiveness of synthesized Co3O4 in the photocatalytic degradation of 1,2,4-trichlorobenzene and highlight the significant influence of environmental conditions on the degradation efficiency. This study offers valuable insights for developing efficient photocatalytic systems for treating chlorinated organic pollutants under visible light.

The effects of the influent nitrate (NO3−-N) concentration on reactor performance and microbial communities of anaerobic methane oxidation coupled to denitrification in a membrane biofilm reactor were emphatically investigated after prolonged storage. The system was run for a period of 185 days including the storage period, reactivating process, and stable operation phase. The influent NO3−-N concentrations varied from 10, 20, and 30 mg/L, and the reactor was continuously operated for 135 days. The denitrification rate in the reactor was activated first and then inhibited, with the average value of NO3−-N consumed of 0.42 mg/L·h−1 at influent NO3−-N of 20 mg/L; there was no obvious nitrite and ammonia–nitrogen accumulation in the whole stage. Illumina MiSeq sequencing results showed that increases in NO3−-N loading could improve the microbial abundance in the system. The highest value for variety and the lowest value for the evenness of the microbial community corresponded to the ideal value of 20 mg/L. It speculated that promoting biofilm bacteria (PBB) became the key functional bacterial group after prolonged storage. Besides, the abundance of methane-oxidizing bacteria was significantly increased in synergy with PBB and denitrifiers to achieve reactivating and stable operation of anaerobic methane oxidation coupled to denitrification.

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFβ1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFβ1 treatment exerted a more substantial effect than TGFβ1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.

Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.

Background The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. Methods Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the α1 or the α2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. Results Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the α1 isoform in primary MPT cells from α2 -/- mice (pharmacologically, via compound C) or inhibition of the α2 isoform in primary MPT cells from α1 -/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted α-isoform. As a consequence, total α-domain expression (i.e. α1 + α2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each α-isoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. Conclusions These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two α-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

BACKGROUND: The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. METHODS: Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the alpha1 or the alpha2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. RESULTS: Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the alpha1 isoform in primary MPT cells from alpha2-/- mice (pharmacologically, via compound C) or inhibition of the alpha2 isoform in primary MPT cells from alpha1-/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted alphaisoform. As a consequence, total As a consequence-domain expression (i.e. alpha1 + alpha2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each alphaisoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. CONCLUSIONS: These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two alpha-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the [alpha]1 or the [alpha]2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the [alpha]1 isoform in primary MPT cells from [alpha]2.sup.-/- mice (pharmacologically, via compound C) or inhibition of the [alpha]2 isoform in primary MPT cells from [alpha]1.sup.-/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted [alpha]-isoform. As a consequence, total [alpha]-domain expression (i.e. [alpha]1 + [alpha]2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each [alpha]-isoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two [alpha]-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

Developing predictive biomarkers that can detect the tipping point before metastasis of hepatocellular carcinoma (HCC), is critical to prevent further irreversible deterioration. To discover such early-warning signals or biomarkers of pulmonary metastasis in HCC, we analyse time-series gene expression data in spontaneous pulmonary metastasis mice HCCLM3-RFP model with our dynamic network biomarker (DNB) method, and identify CALML3 as a core DNB member. All experimental results of gain-of-function and loss-of-function studies show that CALML3 could indicate metastasis initiation and act as a suppressor of metastasis. We also reveal the biological role of CALML3 in metastasis initiation at a network level, including proximal regulation and cascading influences in dysfunctional pathways. Our further experiments and clinical samples show that DNB with CALML3 reduced pulmonary metastasis in liver cancer. Actually, loss of CALML3 predicts shorter overall and relapse-free survival in postoperative HCC patients, thus providing a prognostic biomarker and therapy target in HCC. Biomarkers of the tipping point before metastasis in hepatocellular carcinoma (HCC) could help stratify patient treatment. Here, the authors study dynamic network biomarkers to identify CALM3 as a potential suppressor of metastasis, the level of which can predict overall survival and relapse-free survival in postoperative HCC.

The new emerging type of El Niño brings challenges to the state-of-the-art coupled models to simulated features of El Niño - Southern Oscillation (ENSO) diversity. The Coupled Model Intercomparison Project (CMIP), containing the advanced worldwide coupled models, has recently released the model outputs in phase 6. In this paper, the characteristics of two types of ENSO in 19 models from CMIP phase 5 and their counterparts in phase 6 are assessed regarding the spatial and temporal features and the seasonal cycle features. The weaker amplitude of Eastern Pacific (EP) and Central Pacific (CP) ENSO in CMIP5 is increased and the spatial structure of CP ENSO is better depicted in CMIP6. However, no significant improvement in the ENSO periodicity and the ENSO phase-locking behavior compared to CMIP5. A synthetic ENSO score, containing eight metrics, is defined and employed to evaluate the performance of each CMIP model. The average ENSO score for CMIP6 is 2.375, indicating modest improvement compared to the average score of 2.441 for CMIP5. Furthermore, the slight improvement in the ENSO score is partly related to the reduced climatology bias of sea surface temperature in the Niño4 region. The overall evaluation provides necessary information for future investigation about the mechanism exploration of the ENSO diversity based on the models with better performance.