Mechanism of bufalin inhibition of colon cancer liver metastasis by regulating M2-type polarization of Kupffer cells induced by highly metastatic colon cancer cells.

Patients with metastatic colorectal cancer often have poor outcomes, primarily due to hepatic metastasis. Colorectal cancer (CRC) cells have the ability to secrete cytokines and other molecules that can remodel the tumor microenvironment, facilitating the spread of cancer to the liver. Kupffer cells (KCs), which are macrophages in the liver, can be polarized to M2 type, thereby promoting the expression of adhesion molecules that aid in tumor metastasis. Our research has shown that huachanshu (with bufalin as the main active monomer) can effectively inhibit CRC metastasis. However, the underlying mechanism still needs to be thoroughly investigated. We have observed that highly metastatic CRC cells have a greater ability to induce M2-type polarization of Kupffer cells, leading to enhanced metastasis. Interestingly, we have found that inhibiting the expression of IL-6, which is highly expressed in the serum, can reverse this phenomenon. Notably, bufalin has been shown to attenuate the M2-type polarization of Kupffer cells induced by highly metastatic Colorectal cancer (mCRC) cells and down-regulate IL-6 expression, ultimately inhibiting tumor metastasis. In this project, our aim is to study how high mCRC cells induce M2-type polarization and how bufalin, via the SRC-3/IL-6 pathway, can inhibit CRC metastasis. This research will provide a theoretical foundation for understanding the anti-CRC effect of bufalin.

Ion-Selective Micropipette Sensor for In Vivo Monitoring of Sodium Ion with Crown Ether-Encapsulated Metal-Organic Framework Subnanopores.

In vivo sensing of the dynamics of ions with high selectivity is essential for gaining molecular insights into numerous physiological and pathological processes. In this work, we report an ion-selective micropipette sensor (ISMS) through the integration of functional crown ether-encapsulated metal-organic frameworks (MOFs) synthesized in situ within the micropipette tip. The ISMS features distinctive sodium ion (Na+) conduction and high selectivity toward Na+ sensing. The selectivity is attributed to the synergistic effects of subnanoconfined space and the specific coordination of 18-crown-6 toward potassium ions (K+), which largely increase the steric hindrance and transport resistance for K+ to pass through the ISMS. Furthermore, the ISMS exhibits high stability and sensitivity, facilitating real-time monitoring of Na+ dynamics in the living rat brain during spreading of the depression events process. In light of the diversity of crown ethers and MOFs, we believe this study paves the way for a nanofluidic platform for in vivo sensing and neuromorphic electrochemical sensing.

SnS/SnS2 Heterostructures Embedded in Hierarchical Porous Carbon as Polysulfides Immobilizer for High-Performance Lithium-Sulfur Batteries.

Driven by the strong adsorptive and catalytic ability of metal sulfides for soluble polysulfides, it is considered as a potential mediator to resolve the problems of shuttle effect and slow reaction kinetics of polysulfides in lithium-sulfur (Li-S) batteries. However, their further development is limited by poor electrical conductivity and bad long-term durability. Herein, one type of new catalyst composed of SnS/SnS2 heterostructures on hierarchical porous carbon (denoted as SnS/SnS2-HPC) by a simple hydrothermal method is reported and used as an interlayer coating on the conventional separator for blocking polysulfides. The SnS/SnS2-HPC integrates the advantages of a porous conductive network for promoting the transport of electrons and an enhanced electrocatalyst for accelerating polysulfides conversion. As a result, such a cell coupled with a SnS/SnS2-HPC interlayer exhibits a long-term lifespan of 1200 cycles. This work provides a new cell configuration by using heterostructures with a built-in electric field formed from a p-n heterojunction to improve the performance of Li-S batteries.

High-Entropy Metal Oxide-Coated Carbon Cloth as Catalysts for Long-Life Li-S Batteries.

Lithium-sulfur (Li-S) batteries with high specific energy density, low cost, and environmental friendliness of sulfur have been regarded as a competitive alternative to replace lithium-ion batteries. However, the shuttle effect and the sluggish conversion rate of lithium polysulfides (LiPSs) have seriously limited the practical application of Li-S batteries. Herein, high-entropy oxides grown on the carbon cloth (CC/HEO) are synthesized by a simple and ultrafast solution combustion method for the sulfur cathode. The as-prepared composites possess abundant HEO active sites for strong interaction with LiPSs, which can significantly promote redox kinetics. Besides, the carbon fiber substrate not only ensures high electrical conductivity but also accommodates large volume change, leading to a stable sulfur electrochemistry. Benefiting from the rational design, the Li-S batteries with CC/HEO as cathode skeleton exhibits good cyclability with a capacity decay rate of 0.057% per cycle after 1000 cycles at 2 C. More importantly, the Li-S batteries with 4.3 mg cm-2 high sulfur loading can still retain a high capacity retention of 78.2% after 100 cycles.

A binding-triggered hybridization chain reaction cascade multi-site activated CRISPR/Cas12a signal amplification strategy for sensitive detection of α-synuclein.

Alpha-synuclein (α-syn) is closely related to the pathological process of Parkinson's disease (PD). Sensitive detection of α-syn is important for the early diagnosis and disease progression monitoring of PD. Herein, we report a binding-triggered hybridization chain reaction (HCR) cascade multi-site activated CRISPR/Cas12a signal amplification strategy for sensitive detection of α-syn. In this method, antibody-DNA capture probes recognized α-syn and bound with it to increase the local effective concentrations of two DNA strands, promoting their hybridization to form a split HCR trigger. Then the trigger initiated an HCR to generate a long double-stranded structure which contained abundant periodically repeated Cas12a/crRNA target sequences. Finally, the Cas12a/crRNA recognized the target sequence in HCR products and then the cleavage activity toward fluorescent reporters was activated, leading to the recovery of appreciable fluorescence signals. Our method provided a detection limit as low as 9.33 pM and exhibited satisfactory applicability in human serum samples. In summary, this study provides a homogeneous strategy for convenient, sensitive, and accurate detection of α-syn, showing great potential in the early diagnosis of PD.

Antioxidant mechanism, spectroscopic and pharmacological properties of four flavonoids: DFT, docking and molecular dynamics.

Myricetin (1), quercetin (2), kaempferol (3) and kaempferide (4) were flavonoids with phenolic hydroxyl groups. The antioxidant and pharmacological mechanisms of them were investigated in detail. The lowest hydroxyl dissociation enthalpies of 1, 2, 3 and 4 were calculated by DFT, respectively. The hydroxyl dissociation enthalpies of the four flavonoids at the O2 site are the highest. By analyzing the intramolecular hydrogen bonds and HOMO-LUMO orbitals of the four flavonoids, the reasons for their divergence of hydroxyl dissociation enthalpies and antioxidant mechanisms were further investigated. The UV-vis and IR spectra of four flavonoids were compared. The interactions about electrostatic attraction, p-π conjugation and hydrogen bond combined the flavonoid with the target protein closely. The root mean square deviation of peroxisome proliferator-activated receptor γ combined with 1, 2 and 3 increased, while that of PPARγ combined with 4 decreased.

DPM2 serve as novel oncogene and prognostic marker transactivated by ESR1 in breast cancer.

Breast cancer (BRCA) is the most common malignancies worldwide with increasing rate. Dolichol phosphate mannose synthase (DPMS) is a critical mannosyltransferase involved in the posttranslational modification of proteins. At present, there is limited knowledge regarding the function of DPMS in breast cancer. In this study, silica analysis in multiple datasets found that dolichyl-phosphate mannosyltransferase subunit 2 (DPM2) is an unfavorable prognostic marker, suggesting its oncogenic role. Cell counting kit-8 and apoptosis assays show that DPM2-silenced cancer cells exhibit decreased growth potential and enhanced cell death rate. Further, transwell and wound healing assays show reduced invasion and migration capabilities in DPM2 knockdown groups, xenograft nude mice model demonstrated smaller tumor volume in DPM2 silenced BC cells. Then, the underlying downstream mechanism of DPM2 in BC was predicted and analyzed, highlighting classical tumorigenic pathways like JAK/STAT signaling pathway and oxidative phosphorylation activated in the cancer group. Finally, ChIP-seq analysis, expression correlation analysis, inhibitor treatment, and dual luciferase assays show that DPM2 is transcriptionally activated by estrogen receptor1 (ESR1). The results show that high expression of DPM2 mRNA is significantly correlated with shorter overall survival (OS) and disease-free survival (DFS) in breast cancer patients, and in vitro knockdown of DPM2 can significantly inhibit the malignant phenotypes of cells, including proliferation, invasion, migration, and apoptosis. These results suggest that DPM2 may play an important role in breast cancer. Altogether, we first uncovered the tumorigenic and prognostic role of DPM2 in breast cancer, cellular assays, and bioinformatics analysis highlighted DPM2 as oncogene via inhibited cancer-related signaling pathways in breast cancer. Besides, DPM2 is transcriptionally activated by ESR1, the signaling axis of ESR1/DPM2 provides a new strategy for BC-targeted therapy.

Design, synthesis, and biological evaluation of naphthoylamide derivatives as inhibitors of STAT3 phosphorylation.

The phosphorylation of STAT3 plays a critical physiological role in the proliferation of rectal cancer. Hence, inhibiting STAT3 phosphorylation is an effective anticancer approach. In this work, we designed a novel 5-R'-1-naphthylmethylamide scaffold as a small molecule inhibitor of STAT3 phosphorylation. The results showed that 3D and 4D have exceptional inhibitory ability against three different colorectal cancer (CRC) cell lines, and can induce apoptosis of CRC cells by inhibiting STAT3 phosphorylation, while having no killing effect on normal human cells. 3D and 4D can inhibit STAT3 phosphorylation in a time- and concentration-dependent manner, and also inhibit the nuclear translocation of interleukin (IL)-6-induced STAT3. In the in vivo tumor model research, 4D significantly reduced the tumor volume of mice and had no drug toxicity on other organ tissues. Furthermore, molecular docking studies revealed that 3D and 4D had greater binding free energy when interacting with the STAT3 SH2 structural domain, and could establish H-π interaction modes. Dynamic simulation studies indicated that both compounds were able to bind tightly to STAT3.

Superior Strong and Tough Nacre-Inspired Materials by Interlayer Entanglement.

Natural materials teach that mechanical dissipative interactions relieve the conflict between strength and toughness and enable fabrication of strong yet tough artificial materials. Replicating natural nacre structure has yielded rich biomimetic materials; however, stronger interlayer dissipation still waits to be exploited to extend the performance limits of artificial nacre materials. Here, we introduce strong entanglement as a new artificial interlayer dissipative mechanism and fabricate entangled nacre materials with superior strength and toughness, across molecular to nanoscale nacre structures. The entangled graphene nacre fibers achieved high strength of 1.2 GPa and toughness of 47 MJ/m3, and films reached 1.5 GPa and 25 MJ/m3. Experiments and simulations reveal that strong entanglement can effectively dissipate interlayer energy to relieve the conflict between strength and toughness, acting as natural folded proteins. The strong interlayer entanglement opens up a new path for designing stronger and tougher artificial materials to mimic but surpass natural materials.

Optimizing Molecular Crystallinity and Suppressing Electron-Phonon Coupling in Completely Non-Fused Ring Electron Acceptors for Organic Solar Cells.

High open-circuit voltage (Voc) organic solar cells (OSCs) have received increasing attention because of their promising application in tandem devices and indoor photovoltaics. However, the lack of a precise correlation between molecular structure and stacking behaviors of wide band gap electron acceptors has greatly limited its development. Here, we adopted an asymmetric halogenation strategy (AHS) and synthesized two completely non-fused ring electron acceptors (NFREAs), HF-BTA33 and HCl-BTA33. The results show that AHS significantly enhances the molecular dipoles and suppresses electron-phonon coupling, resulting in enhanced intramolecular/intermolecular interactions and decreased nonradiative decay. As a result, PTQ10 : HF-BTA33 realizes a power conversion efficiency (PCE) of 11.42 % with a Voc of 1.232 V, higher than that of symmetric analogue F-BTA33 (PCE=10.02 %, Voc=1.197 V). Notably, PTQ10 : HCl-BTA33 achieves the highest PCE of 12.54 % with a Voc of 1.201 V due to the long-range ordered π-π packing and enhanced surface electrostatic interactions thereby facilitating exciton dissociation and charge transport. This work not only proves that asymmetric halogenation of completely NFREAs is a simple and effective strategy for achieving both high PCE and Voc, but also provides deeper insights for the precise molecular design of low cost completely NFREAs.

Time-ordering japonica/geng genomes analysis indicates the importance of large structural variants in rice breeding.

Temperate japonica/geng (GJ) rice yield has significantly improved due to intensive breeding efforts, dramatically enhancing global food security. However, little is known about the underlying genomic structural variations (SVs) responsible for this improvement. We compared 58 long-read assemblies comprising cultivated and wild rice species in the present study, revealing 156 319 SVs. The phylogenomic analysis based on the SV dataset detected the putatively selected region of GJ sub-populations. A significant portion of the detected SVs overlapped with genic regions were found to influence the expression of involved genes inside GJ assemblies. Integrating the SVs and causal genetic variants underlying agronomic traits into the analysis enables the precise identification of breeding signatures resulting from complex breeding histories aimed at stress tolerance, yield potential and quality improvement. Further, the results demonstrated genomic and genetic evidence that the SV in the promoter of LTG1 is accounting for chilling sensitivity, and the increased copy numbers of GNP1 were associated with positive effects on grain number. In summary, the current study provides genomic resources for retracing the properties of SVs-shaped agronomic traits during previous breeding procedures, which will assist future genetic, genomic and breeding research on rice.

Quantum metric and metrology with parametrically-driven Tavis-Cummings models.

We study the quantum metric in a driven Tavis-Cummings model, comprised of multiple qubits interacting with a quantized photonic field. The parametrical driving of the photonic field breaks the system's U(1) symmetry down to a Z2 symmetry, whose spontaneous breaking initiates a superradiant phase transition. We analytically solved the eigenenergies and eigenstates, and numerically simulated the system behaviors near the critical point. The critical behaviors near the superradiant phase transition are characterized by the quantum metric, defined in terms of the response of the quantum state to variation of the control parameter. In addition, a quantum metrological protocol based on the critical behaviors of the quantum metric near the superradiant phase transition is proposed, which enables greatly the achievable measurement precision.

Observation of a Superradiant Phase Transition with Emergent Cat States.

Superradiant phase transitions (SPTs) are important for understanding light-matter interactions at the quantum level, and play a central role in criticality-enhanced quantum sensing. So far, SPTs have been observed in driven-dissipative systems, but the emergent light fields did not show any nonclassical characteristic due to the presence of strong dissipation. Here we report an experimental demonstration of the SPT featuring the emergence of a highly nonclassical photonic field, realized with a resonator coupled to a superconducting qubit, implementing the quantum Rabi model. We fully characterize the light-matter state by Wigner matrix tomography. The measured matrix elements exhibit quantum interference intrinsic of a photonic mesoscopic superposition, and reveal light-matter entanglement.

The effect of different combinations of physical activity and natural environment videos on children's attention levels between class breaks.

BACKGROUND: Physical activity intervention and watching natural environment videos have been proven to improve young children's attention levels. However, evidence comparing the improvement effects of different combinations of the two activities has rarely been reported. By comparing the differences in the improvement effects of four combinations of physical activities and watching natural environment videos on young children's attention levels, this study can enrich the evidence in this research field and also provide a reference for arranging effective intervention methods for children's attention recovery between classes. METHOD: A total of 152 children aged 4 to 6 years were recruited and randomly divided into four intervention groups: (1) physical activity intervention first and thereafter watching a natural environment video group (activity + video group), (2) watching a natural environment video first and thereafter the physical activity intervention group (video + activity group), (3) physical activity-based group, and (4) natural environment video-based group. Physical activity involved 4 min of moderate-intensity basic physical fitness combination training. The subjects wore the Pico Neo pioneer version of the VR glasses all-in-one machine to watch a natural environment video. Thereafter, population sociological variables and daily physical activity levels were investigated. Auditory and visual sustained attention tests were performed before and after intervention in each group. RESULT: The auditory attention post-test scores of the four groups showed an improvement trend compared with the pretest scores. In particular, the activity + video group (F = 10.828; ɳp2 = 0.226; p = 0.002) and natural environment video-based group (F = 9.452; ɳp2 = 0.203; p = 0.004) have the best improvement effect. For visual attention, only the activity + video group showed a significant improvement trend (F = 4.287; ɳp2 = 0.104; p = 0.045), while the other three groups showed a downward trend in scores. CONCLUSIONS: Among the different intervention combinations, the physical activity intervention first and watching natural environment videos thereafter group has the best effect on improving children's attention during recess. Physical activity interventions at the end of recess adversely affect young children's visual attention levels at the beginning of the class. Therefore, this study recommends that children should not engage in physical activity interventions in the second half of the class break. Lastly, the current research recommends presenting the content of physical activity interventions first and further improving their attention thereafter by watching natural environment videos.

Highly-Efficient Ion Gating through Self-Assembled Two-Dimensional Photothermal Metal-Organic Framework Membrane.

Biological ion channels regulate the ion flow across cell membrane via opening or closing of the pores in response to various external stimuli. Replicating the function of high ion gating effects with artificial porous materials has been challenging. Herein, we report that the self-assembled two-dimensional metal-organic framework (MOF) membrane can serve as an excellent nanofluidic platform for smart regulation of ion transport. The MOF membrane with good photothermal performance exhibits extremely high ion gating ratio (up to 104 ), which is among the highest values in MOF membrane nanochannels for light-controlled ion gating reported so far. By repeatedly turning on and off the light, the nanofluidic device shows outstanding stability and reversibility that can be applied in the remote light-switching system. This work may spark promising applications of MOF membrane with variety of stimuli responsive properties in ion sieving, biosensing, and energy conversion.

Light-Regulated Nanofluidic Ionic Diodes with Heterogeneous Channels Stemming from Asymmetric Growth of Metal-Organic Frameworks.

Nanofluidic ionic diodes have attracted much attention, because of the unique property of asymmetric ion transport and promising applications in molecular sensing and biosensing. However, it remains a challenge to fabricate diode-like nanofluidic system with molecular-size pores. Herein, we report a new and facile approach to construct nanofluidic ionic diode by in situ asymmetric growth of metal-organic frameworks (MOFs) in nanochannels. We implement microwave-assisted strategy to obtain asymmetric distribution of MOFs in porous anodic aluminum oxide with barrier layer on one side. After etching the barrier layer and modifying with positively charged molecules, the nanofluidic device possesses asymmetric geometry and surface charge, performing the ionic current rectification (ICR) behavior in different electrolyte concentrations. Moreover, the ICR ratio is readily regulated with visible light illumination mainly due to the enhancement of surface charge of MOFs, which is further confirmed by finite element simulation. This study provides a reliable way to build the nanofluidic platform for investigating the asymmetric ion transport through the molecular-size pores, which is envisaged to be important for molecular sensing based on ICR with molecular-size pores.

Metal-Organic Framework Membrane Nanopores as Biomimetic Photoresponsive Ion Channels and Photodriven Ion Pumps.

Biological ion channels and ion pumps with sub-nanometer sizes modulate ion transport in response to external stimuli. Realizing such functions with sub-nanometer solid-state nanopores has been an important topic with wide practical applications. Herein, we demonstrate a biomimetic photoresponsive ion channel and photodriven ion pump using a porphyrin-based metal-organic framework membrane with pore sizes comparable to hydrated ions. We show that the molecular-size pores enable precise and robust optoelectronic ion transport modulation in a broad range of concentrations, unparalleled with conventional solid-state nanopores. Upon decoration with platinum nanoparticles to form a Schottky barrier photodiode, photovoltage across the membrane is generated with "uphill" ion transport from low concentration to high concentration. These results may spark applications in energy conversion, ion sieving, and artificial photosynthesis.

Nature and Value of Freely Dissolved EPS Ecosystem Services: Insight into Molecular Coupling Mechanisms for Regulating Metal Toxicity.

Extracellular polymeric substances (EPSs) dispersed in natural waters play a significant role in relieving impacts to microbial survival associated with heavy metal release, yet little is known about the association of freely dissolved EPS ecosystem services with metal transformation in natural waters. Here, we demonstrate that dispersive EPSs mitigate the metal toxicity to microbial cells through an associative coordination reaction. Microtitrimetry coupled with fluorescence spectroscopy ascribes the combination of freely dissolved EPSs from Escherichia coli (E. coli) with Cu2+/Cd2+ to a coordination reaction associated with chemical static quenching. Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and computational chemistry confirm that carboxyl residues in protein-like substances of the EPSs are responsible for the coordination. Frontier molecular orbitals (MOs) of a deprotonated carboxyl integrate with the occupied d orbitals of Cu2+ and/or d, s orbitals of Cd2+ to form metal-EPS complexes. Microcosmic systems show that because the metal-EPS complexes decrease cellular absorbability of metals, E. coli survivals increase by 4.3 times for Cu2+ and 1.6 times for Cd2+, respectively. Based on bonding energies for six metals-EPS coordination, an associative toxic effect further confirms that increased bonding energies facilitate retardation of metals in the EPS matrix, protecting against E. coli apoptosis.

An improved subtraction model applied in supercritical fluid chromatography to characterise polar stationary phases.

Herein, an improved subtraction model was proposed to characterise the polar stationary phases in supercritical fluid chromatography (SFC). Fifteen stationary phases were selected, including two types of aromatic columns, Waters Torus and Viridis series columns, as well as silica and amino columns. Ethylbenzene and Torus 1-AA were defined as the reference solute and column, respectively. Identifying the interaction with the maximum contribution to retention in SFC separation and using it as the initial term is a key step in modelling. The dipole, or induced dipole interaction (θ'P), replaced the hydrophobic interaction (η'H) as the starting term. The improved model was expressed as logα=η'H+ß'A+α'B+κ'C+θ'P+ε'E+σ'S, where the term ε'E indicated that anion exchange interaction was intentionally supplemented. A 7-step modelling process, including bidirectional fitting and residual analysis, was proposed. The obtained column parameters had reasonable physical significance, with the adjusted determination coefficient (R2adj) greater than 0.999 and the standard error (SE) less than 0.029. Methodological validation was further performed using the other four columns and 12 solutes that were not involved in the modelling. The result revealed good predictions of solutes' retention, as demonstrated by R2adj from 0.9923 to 0.9979 and SE from 0.0636 to 0.1088. This study indicated the feasibility of using the improved subtraction model to characterise polar stationary phases in SFC, with the most crucial being the determination of an initial term, followed by the addition of a new descriptor and the selection of an appropriate reference column. The study expanded the application scope of the subtraction model in SFC, which will help gain an in-depth understanding of the SFC separation mechanism.

Advancements in the Understanding of Small-Cell Neuroendocrine Cervical Cancer: Where We Stand and What Lies Ahead.

Small-cell neuroendocrine cervical carcinoma (SCNCC) is a rare yet aggressive gynecological malignancy associated with dismal clinical outcomes. Its rarity has led to a limited number of retrospective studies and an absence of prospective research, posing significant challenges for evidence-based treatment approaches. As a result, most gynecologic oncology centers have limited experience with this tumor, emphasizing the urgent need for a comprehensive review and summary. This article systematically reviews the pathogenesis, immunohistochemical and molecular characteristics, prognostic factors, and clinical management of gynecologic SCNCC. We specifically focused on reviewing the distinct genomic characteristics of SCNCC identified via next-generation sequencing technologies, including loss of heterozygosity (LOH), somatic mutations, structural variations (SVs), and microRNA alterations. The identification of these actionable genomic events offers promise for discovering new molecular targets for drug development and enhancing therapeutic outcomes. Additionally, we delve deeper into key clinical challenges, such as determining the optimal treatment modality between chemoradiation and surgery for International Federation of Gynecology and Obstetrics (FIGO) stage I phase patients within a precision stratification framework, as well as the role of targeted therapy within the homologous recombination (HR) pathway, immune checkpoint inhibitors (ICIs), and prophylactic cranial irradiation (PCI) in the management of SCNCC. Finally, we anticipate the utilization of multiple SCNCC models, including cancer tissue-originated spheroid (CTOS) lines and patient-derived xenografts (PDXs), to decipher driver events and develop individualized therapeutic strategies for clinical application.