Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

HCC1, a Polygalacturonase, Regulates Chlorophyll Degradation via the Ethylene Synthesis Pathway.

Chlorophyll degradation is an important physiological process and is essential for plant growth and development. However, how chlorophyll degradation is controlled at the cellular and molecular level remains largely elusive. Pectin is a main component of the primary cell wall, and polygalacturonases (PGs) is a group of pectin-hydrolases that cleaves the pectin backbone and release oligogalacturonide. Whether and how PGs affect chlorophyll degradation metabolism and its association with ethylene (ETH) have not been reported before. Here, we report a novel function of PG in a mutant 'high chlorophyll content1' hcc1, which displayed a decrease in growth and yield. Our morphological, biochemical and genetic analyses of hcc1, knockout lines and complementation lines confirm the function of HCC1 in chlorophyll degradation. In hcc1, the PG activity, ETH content and D-galacturonic acid (D-GA) was significantly decreased and showed an increase in the thickness of the cell wall. Exogenous application of ETH and D-GA can increase ETH content and induce the expression of HCC1, which further can successfully induce the chlorophyll degradation in hcc1. Together, our data demonstrated a novel function of HCC1 in chlorophyll degradation via the ETH pathway.

Recent Progress and Future Prospects of Anions O-site Doped Perovskite Oxides in Electrocatalysis for Various Electrochemical Systems.

With the rapid development of novel energy conversion and storage technologies, there is a growing demand for enhanced performance in a wide range of electrocatalysts. Perovskite oxides (ABO3 ) have caused widespread concerns due to their excellent electrocatalytic properties, low cost, stable and reliable performance. In recent years, the research on anion O-site doping of perovskite oxides has been a cynosure, which is considered as a promising route for enhancing performance. However, a systematic review summarizing the research progress of anion-doped perovskite oxides is still lacking. Therefore, this review mainly introduces the elements and strategies of various common anions doped at O-site of perovskite oxides, analyzes their influence on the physical and chemical properties of perovskites, and separately concludes their applications in electrocatalysis. This review will provide ideas and prospects for the development of subsequent anion doping strategies for high performance perovskite oxides.

Boosting the Electrocatalytic Activity of Pr0.5Ba0.5FeO3-δ via Ni Doping in Symmetric Solid Oxide Electrolysis Cells.

Symmetric solid oxide electrolysis cells (SSOECs) have garnered significant scientific interest due to their simplified cell architecture, robust operational reliability, and cost-effectiveness, for which a highly electrocatalytically active electrode is the decisive main factor. This work evaluates the electrochemical performance of Ni-doped Pr0.5Ba0.5FeO3-δ (PBF) perovskite materials, with a focus on Pr0.5Ba0.5Fe0.8Ni0.2O3-δ (PBFN). The experimental findings herein prove the exceptional electrocatalytic ability of PBFN in facilitating the oxygen evolution and carbon dioxide reduction reaction, surpassing the electrochemical performance of PBF. In addition, the PBFN symmetric cell has excellent performance for CO2 electrolysis, and the cell has a low polarization resistance value of 0.1 Ω·cm2. Moreover, it achieves an impressive current density value of 1.118 A·cm-2 under operating conditions of 2.0 V and 800 °C, which is superior to those of the PBF symmetric cell and the PBFN asymmetric cell. It also has a good structural and performance stability. These results imply a bright development prospect of PBFN as electrodes for SSOECs.

Effects of water stress on starch synthesis and accumulation of two rice cultivars at different growth stages.

Rice is a water intensive crop and soil water conditions affect rice yield and quality. However, there is limited research on the starch synthesis and accumulation of rice under different soil water conditions at different growth stages. Thus, a pot experiment was conducted to explore the effects of IR72 (indica) and Nanjing (NJ) 9108 (japonica) rice cultivars under flood-irrigated treatment (CK, 0 kPa), light water stress treatment (L, -20 ± 5 kPa), moderate water stress treatment (M, -40 ± 5 kPa) and severe water stress treatment (S, -60 ± 5 kPa) on the starch synthesis and accumulation and rice yield at booting stage (T1), flowering stage (T2) and filling stage (T3), respectively. Under LT treatment, the total soluble sugar and sucrose contents of both cultivars decreased while the amylose and total starch contents increased. Starch synthesis-related enzyme activities and their peak activities at mid-late growth stage increased as well. However, applying MT and ST treatments produced the opposite effects. The 1000-grain weight of both cultivars increased under LT treatment while the seed setting rate increased only under LT3 treatment. Compared with CK, water stress at booting stage decreased grain yield. The principal component analysis (PCA) showed that LT3 got the highest comprehensive score while ST1 got lowest for both cultivars. Furthermore, the comprehensive score of both cultivars under the same water stress treatment followed the trend of T3 > T2 > T1, and NJ 9108 had a better drought-resistant ability than IR72. Compared with CK, the grain yield under LT3 increased by 11.59% for IR72 and 16.01% for NJ 9108, respectively. Overall, these results suggested that light water stress at filling stage could be an effective method to enhance starch synthesis-related enzyme activities, promote starch synthesis and accumulation and increase grain yield.

Achieving Net-Zero Emissions with Solid Oxide Electrolysis Cells: The Power-to-X Approach.

Replacing fossil fuels with renewable energy sources is a crucial step for mitigating global warming. However, the intermittent nature of the most prevalent renewable sources, such as solar and wind, poses a significant challenge to their widespread deployment. One potential solution for renewable sources of storage is power-to-X, which involves the production of chemicals from electricity using solid oxide electrolysis cells. This process offers a flexible and efficient means of energy storage. This Perspective offers an overview of the characteristics, capabilities, and fundamental mechanisms of solid oxide electrolysis cells. It also examines the latest research progress and explores the prospects and challenges in this field.

High-Entropy Perovskites for Energy Conversion and Storage: Design, Synthesis, and Potential Applications.

Perovskites have shown tremendous promise as functional materials for several energy conversion and storage technologies, including rechargeable batteries, (electro)catalysts, fuel cells, and solar cells. Due to their excellent operational stability and performance, high-entropy perovskites (HEPs) have emerged as a new type of perovskite framework. Herein, this work reviews the recent progress in the development of HEPs, including synthesis methods and applications. Effective strategies for the design of HEPs through atomistic computations are also surveyed. Finally, an outlook of this field provides guidance for the development of new and improved HEPs.

Site-directed late-stage diversification of macrocyclic nannocystins facilitating anticancer SAR and mode of action studies.

Nannocystins are a family of 21-membered cyclodepsipeptides with excellent anticancer activity. However, their macrocyclic architecture poses a significant challenge to structure modification. Herein, this issue is addressed by leveraging the strategy of post-macrocyclization diversification. In particular, a novel serine-incorporating nannocystin was designed so that its appending hydroxyl group could diversify into a wide variety of side chain analogues. Such effort facilitated not only structure-activity correlation at the subdomain of interest, but also the development of a macrocyclic coumarin-labeled fluorescence probe. Uptake experiments indicated good cell permeability of the probe, and endoplasmic reticulum was identified as its subcellular localization site.

Rice ß-Glucosidase 4 (Os1ßGlu4) Regulates the Hull Pigmentation via Accumulation of Salicylic Acid.

Salicylic acid (SA) is a stress hormone synthesized in phenylalanine ammonia-lyase (PAL) and the branching acid pathway. SA has two interconvertible forms in plants: SAG (SA O-ß-glucoside) and SA (free form). The molecular mechanism of conversion of SA to SAG had been reported previously. However, which genes regulate SAG to SA remained unknown. Here, we report a cytoplasmic ß-glucosidase (ß-Glu) which participates in the SA pathway and is involved in the brown hull pigmentation in rice grain. In the current study, an EMS-generated mutant brown hull 1 (bh1) displayed decreased contents of SA in hulls, a lower photosynthesis rate, and high-temperature sensitivity compared to the wild type (WT). A plaque-like phenotype (brown pigmentation) was present on the hulls of bh1, which causes a significant decrease in the seed setting rate. Genetic analysis revealed a mutation in LOC_Os01g67220, which encodes a cytoplasmic Os1ßGlu4. The knock-out lines displayed the phenotype of brown pigmentation on hulls and decreased seed setting rate comparable with bh1. Overexpression and complementation lines of Os1ßGlu4 restored the phenotype of hulls and normal seed setting rate comparable with WT. Subcellular localization revealed that the protein of Os1ßGlu4 was localized in the cytoplasm. In contrast to WT, bh1 could not hydrolyze SAG into SA in vivo. Together, our results revealed the novel role of Os1ßGlu4 in the accumulation of flavonoids in hulls by regulating the level of free SA in the cellular pool.

Promoting Electrocatalytic Activity and Stability via Er0.4Bi1.6O3-δ In Situ Decorated La0.8Sr0.2MnO3-δ Oxygen Electrode in Reversible Solid Oxide Cell.

Weak electrocatalytic activity of the La0.8Sr0.2MnO3-δ (LSM) oxygen electrode at medium and low temperatures leads to decreasing performance both in the solid oxide fuel cell (SOFC) mode and the solid oxide electrolysis cell (SOEC) mode. Herein, we design an Er0.4Bi1.6O3-δ (ESB) functionalized La0.8Sr0.2MnO3-δ (labeled as LSM/ESB) oxygen electrode via a one-step co-synthesis modified Pechini method. The unique LSM/ESB with polarization resistance of only 0.029 Ω·cm2 at 750 °C enables a highly enhanced rate of oxygen reduction and evolution reaction. The single cell with the LSM/ESB electrode achieves a maximum power density of 1.747 W cm-2 at 750 °C, 2.6 times higher than that of the mechanically mixed LSM-ESB electrode (0.667 W cm-2). In the SOEC mode, it also shows the improved performance of the LSM/ESB electrode. Furthermore, the cell exhibits admirable durability of 90 h in the fuel cell mode and excellent reversibility. The better performance can be concluded as a better surface-active state and a tighter connection between the LSM and ESB particles of LSM/ESB via a co-synthesis process. This work proposes a novel strategy to advance the application of the one-step modified Pechini technology for an efficient and stable oxygen electrode.

Synthesis and biological evaluation of nannocystin analogues toward understanding the binding role of the (2R,3S)-Epoxide in nannocystin A.

Nannocystin A is a potent antiproliferative cyclodepsipeptide targeting eukaryotic translation elongation factor 1α. To elucidate the binding role of its (2R,3S)-epoxide, we designed and synthesized a focused library of 10 nannocystin analogues. Variable temperature NMR experiments demonstrated the importance of the (2R,3S)-epoxide in controlling the macrocyclic conformation. Biological evaluation of these compounds against three typical cancer cell lines established a clear structure-activity relationship at the epoxide region, which was rationalized by comparing the superimposed conformations of different nannocystin analogues and in silico docking analysis. Our results showed that the (2R,3S)-epoxide of nannocystin A is mainly responsible for controlling the macrocyclic conformation, rather than binding directly to the target.

Transient deformation during the Milashan Tunnel construction in northern Sangri-Cuona Rift, southern Tibet, China observed by Sentinel-1 satellites.

Using 3-year Sentinel-1 C-band synthetic aperture radar (SAR) data, we observed prominent ground subsidence around the construction site of the Milashan Tunnel, which is on top of the northern Sangri-Cuona Rift (SCR) in southern Tibet. The most deformed area extends ∼7 km in the north-south direction and ∼6 km in the east-west direction, with a peak subsidence rate of over 10 mm/a in the line of sight direction of both the descending and ascending satellites. Aside from the long-term ground subsidence arising directly from underground water outflow and rock excavation, a regional aseismic fault slip episode is also evident. The aseismic slip event began in May 2016 and ended in July 2016. The surface aseismic displacements can be explained by normal faulting with mainly down-dip movement and a modest right-lateral strike-slip component on a nearly north-south trending fault. The aseismic deformation triggered by the Milashan Tunnel construction demonstrates the sensitive response of crustal-scale tectonics to human activity, which poses high seismic hazards for the heavily populated region.

Total Synthesis of Nannocystin A.

Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anticancer properties. Described is the total synthesis of nannocystin A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient assembly of the penultimate open-chain precursor and a pivotal intramolecular Heck cross-coupling for the final macrocyclization.

A Novel Method for the Preparation of CdS Quantum Dots Sensitized Solar Cells Based on Free-Standing and Through-Hole TiO2 Nanotube Arrays.

The crystallized free-standing through-hole TiO2 nanotube arrays (TNAs) membranes were fabricated by a facile method. CdS quantum dots (QDs) are assembled onto free-standing through-hole NTAs films using successive ionic layer adsorption and reaction (SILAR) process. The CdS/TNAs were easily transferred to the fluorine-doped tin oxide glass to form photoanodes after they were sensitized by modifying the traditional procedure. The morphology and crystalline phase of the TiO2 nanotubes were studied by field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD). The cells with 5 SILAR cycles show photovoltaic conversion efficiency as high as 3.34% under simulated sunlight (AM 1.5, 100 mW x cm(-2)). Obviously, the new approach promotes the uniform distribution of CdS on the densely aligned TNAs and prevents the clogging of CdS quantum dots (QDs) at the TiO2 nanotube mouth. Such enhanced properties may be ascribed to the strong combination between CdS and TiO2, favorable for charge separation of TNAs.

[Design, synthesis and evaluation of 4-pyridinylthiazole-2-amines as acetylcholinesterase inhibitors].

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Compound I reported to have inhibitory activity on AChE was used as a lead compound in this study, and 4-pyridinylthiazole-2-amines were designed by optimizing compound I structure. The new compounds were synthesized from acetylpyridines through five-steps of reaction, and their inhibition activities on AChE were measured in vitro by Ellman method. The new compounds exhibited a clear inhibitory activity on AChE in vitro. The bioactivity of compound 13c was the best among them, and its IC(50) value was 0.15 µmol·L(-1), which was better than that of rivastigmine and compound I in the control. Meanwhile, it exhibited little inhibition on butyrylcholinesterase. So the selective inhibitory activities of 4-pyridinylthiazole-2-amines to acetylcholinesterase were worth of studying furtherly.

[Design, synthesis and evaluation of new L-proline derivatives as acetylcholinesterase inhibitors].

In this paper, fourteen new L-proline derivatives were designed and synthesized, and their acetlcholinesterase (AChE) inhibitory activities were also investigated in vitro. New L-proline derivatives were prepared from substituted 2-bromo-1-acetophenones through four-step reaction; and their bioactivities as AChE inhibitors were measured by Ellman spectrophotometry. The results showed that the target compounds had a certain AChE inhibitory activity to in vitro. The bioactivity of compound 8b was the best of them, and its IC50 value was 5.45 µmol.L-1, which was better than that of rivastigmine. So the acetylcholinesterase inhibitory activities of new L-proline derivatives were worth to be further studied.

[Design, synthesis and evaluation of 5-aminobenzimidazolone derivatives as acetylcholinesterase inhibitors].

The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 µmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching.