Hypoxia inhibits HUNK kinase activity to induce epithelial-mesenchymal transition.

Hypoxia is a common hallmark of cancer and plays a crucial role in promoting epithelial-mesenchymal transition (EMT). Hormonally Upregulated Neu-associated Kinase (HUNK) regulates EMT through its kinase activity. However, whether hypoxia is involved in HUNK-mediated EMT is incompletely understood. This study unveils an association between HUNK kinase activity and hypoxia in colorectal cancer (CRC). Importantly, hypoxia does not alter the expression levels of HUNK, but directly affects the phosphorylation levels of downstream proteins with indication of HUNK activity. Functionally, the upregulation of migration, invasion, and expression of EMT markers in CRC cells under hypoxic conditions can be attributed, in part, to the downregulation of HUNK-mediated phosphorylation of downstream proteins. These findings highlight the intricate relationship between HUNK, hypoxia and the molecular mechanisms of cancer EMT. Understanding these mechanisms may provide valuable insights into therapeutic targets for inhibiting cancer metastasis.

Anion Solvation Reconfiguration Enables High-Voltage Carbonate Electrolytes for Stable Zn/Graphite Cells.

Conventional carbonate solvents with low HOMO levels are theoretically compatible with the low-cost, high-voltage chemistry of Zn/graphite batteries. However, the nucleophilic attack of the anion on carbonates induces an oxidative breakdown at high potentials. Here, we restore the inherent anodic stability of carbonate electrolytes by designing a micro-heterogeneous anion solvation network. Based on the addition of a strongly electron-donating solvent, trimethyl phosphate (TMP), the oxidation-vulnerable anion-carbonate affinities are decoupled because of the preferential sequestration of anions into solvating TMP domains around the metal cations. The hybridized electrolytes elevate the electrochemical window of carbonate electrolytes by 0.45 V and enable the operation of Zn/graphite dual-ion cells at 2.80 V with a long cycle life (92 % capacity retention after 1000 cycles). By inheriting the non-flammability from TMP and the high ion-transport kinetics from the carbonate systems, this facile strategy provides cells with the additional benefits of fire retardancy and high-power capability.

Nonlinear filter based decision feedback equalizer for optical communication systems.

Nonlinear impairments in optical communication system have become a major concern of optical engineers. In this paper, we demonstrate that utilizing a nonlinear filter based Decision Feedback Equalizer (DFE) with error detection capability can deliver a better performance compared with the conventional linear filter based DFE. The proposed algorithms are tested in simulation using a coherent 100 Gb/sec 16-QAM optical communication system in a legacy optical network setting.

Synthesis and biological evaluation of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety as potent antitumor agents.

A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50 = 0.31 µM) with IC50 values ranging from 0.24 to 0.92µM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50 = 0.41 µM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity.

CarsiDock: a deep learning paradigm for accurate protein-ligand docking and screening based on large-scale pre-training.

The expertise accumulated in deep neural network-based structure prediction has been widely transferred to the field of protein-ligand binding pose prediction, thus leading to the emergence of a variety of deep learning-guided docking models for predicting protein-ligand binding poses without relying on heavy sampling. However, their prediction accuracy and applicability are still far from satisfactory, partially due to the lack of protein-ligand binding complex data. To this end, we create a large-scale complex dataset containing ∼9 M protein-ligand docking complexes for pre-training, and propose CarsiDock, the first deep learning-guided docking approach that leverages pre-training of millions of predicted protein-ligand complexes. CarsiDock contains two main stages, i.e., a deep learning model for the prediction of protein-ligand atomic distance matrices, and a translation, rotation and torsion-guided geometry optimization procedure to reconstruct the matrices into a credible binding pose. The pre-training and multiple innovative architectural designs facilitate the dramatically improved docking accuracy of our approach over the baselines in terms of multiple docking scenarios, thereby contributing to its outstanding early recognition performance in several retrospective virtual screening campaigns. Further explorations demonstrate that CarsiDock can not only guarantee the topological reliability of the binding poses but also successfully reproduce the crucial interactions in crystalized structures, highlighting its superior applicability.

HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1.

Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

A PF6 - -Permselective Polymer Electrolyte with Anion Solvation Regulation Enabling Long-Cycle Dual-Ion Battery.

Graphitic carbon that allows reversible anion (de)intercalation is a promising cathode material for cost-efficient and high-voltage dual-ion batteries (DIBs). However, one notorious but overlooked issue is the incomplete interfacial anion desolvation, which not only reduces the oxidative stability of electrolytes, but also results in solvent co-intercalation into graphite layers. Here, an "anion-permselective" polymer electrolyte with abundant cationic quaternary ammonium motif is developed to weaken the PF6 - -solvent interaction and thus facilitates PF6 - desolvation. This strategy significantly inhibits solvent co-intercalation as well as enhances the oxidation resistance of electrolyte, ensuring the structural integrity of graphite. As a result, the as-assembled graphite||Li cell achieves a superior cyclability with an average Coulombic efficiency of 99.0% (vs 95.7% for baseline electrolyte) and 87.1% capacity retention after 2000 cycles even at a high cutoff potential of 5.4 V versus Li+ /Li. Besides, this polymer also forms a robust cathode electrolyte interface, working together to enable a long-life DIB. This strategy of tuning anion coordination environment provides a promising solution to regulate solvent co-intercalation chemistry for DIBs.

DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) patients are highly angiogenic and treated by targeted therapies against VEGFA/VEGFR signaling pathway. However, tumors with such targeted therapies remain a significant clinic challenge. Understanding the underlying mechanism against angiogenesis is highly desired. Here, we demonstrated that the lncRNA DMDRMR serves as a sponge of miR-378a-5p to increase EZH2 and SMURF1 expression, thus promoting EZH2-mediated transcriptional repression of DAB2IP and SMURF1-mediated degradation of DAB2IP. Consequently, this axis activates VEGFA/VEGFR2 signaling pathway, resulting in angiogenesis and resistance of tumor cells to sunitinib in ccRCC. Moreover, the competing endogenous RNA regulatory axis of DMDRMR is clinically relevant to ccRCC pathogenesis and prognosis of patients with ccRCC. Our results support that the DMDRMR/miR-378a-5p/DAB2IP axis may serve as a novel target for combination diagnosis or therapy of ccRCC patients. Our findings may have highly clinical relevance for future translation to develop the targeted therapies for patients with ccRCC.

DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression.

Aberrant N 6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.

Frontier Orbital Energy-Customized Ionomer-Based Polymer Electrolyte for High-Voltage Lithium Metal Batteries.

The development of gel polymer electrolytes (GPEs) is considered to be an effective strategy to drive practical applications of high-voltage lithium metal batteries (HLMBs). However, rare GPEs that can satisfy the demands of HLMBs have been developed because of the limited compatibility with lithium anodes and high-voltage cathodes simultaneously. Herein, a novel strategy for constructing polymer matrixes with a customized frontier orbital energy for GPEs is proposed. The as-investigated polymer matrix (P(CUMA-NPF6))-based GPE (P(CUMA-NPF6)-GPE) obtained via in situ random polymerization delivers a wide voltage window (0-5.6 V vs Li+/Li), large lithium-ion transference number (tLi+, 0.61), and superior electrode/electrolyte interface compatibility. It is to be noted that such a tLi+ of P(CUMA-NPF6)-GPE, which is one of the largest tLi+ among high-voltage GPEs in a fair comparison, results from the high dissociation of lithium salts and effective anion immobilization abilities of P(CUMA-NPF6). Ultimately, the as-assembled HLMB delivers more enhanced cycle performance than its counterpart of commercial liquid electrolytes. It is also demonstrated that P(CUMA-NPF6) can scavenge the active PF5 intermediate generated in the electrolyte at the anode side, thus suppressing the PF5-mediated decomposition reaction of carbonates. This work will enlighten the rational structure design of GPEs for HLMBs.

A High-Energy 5 V-Class Flexible Lithium-Ion Battery Endowed by Laser-Drilled Flexible Integrated Graphite Film.

Due to its highly in-plane oriented crystal structure, the flexible graphite film (GF) possesses excellent electrochemical corrosion resistance, high planar electrical conductivity, and considerable mechanical strength. In this work, the laser-drilled integrated graphite film (porous-GF, PGF) is unprecedentedly used as a key to fabricate a high-performance high-energy 5 V-class flexible PGF/PGF-LiNi0.5Mn1.5O4 full cell, where the flexible PGF is a self-standing flexible graphite anode for lithium-ion intercalation/deintercalation and a high-voltage resistance cathode current collector. This unique design based on the flexible PGF will endow the future flexible batteries with excellent characteristics of thin, lightweight, simple fabrication, and high energy. More encouragingly, unlike previously reported flexible electrodes using carbon nanomaterials as the nonmetal current collector, the mass production and processability of the flexible GF and PGF are feasible with the aid of commercially available roll-to-roll laser drilling technology.

[Structural regulation by calcium ion in preparing cross-linked enzyme aggregates].

We studied the effect of calcium ion on particle size and pore structure of cross-linked enzyme aggregates (CLEAs) of glucose oxidase, with activity and stability of the enzyme as evaluation criteria. With calcium ion to prepare CLEA significantly decreased particle sizes of CLEAs whilst the pore structures of CLEAs gradually disappeared with the increase of calcium concentration. When glucose oxidase was precipitated at 0.1 mmol/L Ca²âº, glucose oxidase in CLEA showed the definitive pore structure. Moreover, glucose oxidase activity in CLEA with Ca²âº was 1.69 times higher than that without Ca²âº. Even at Ca²âº as high as 1.0 mmol/L, glucose oxidase activity in CLEA was 42% higher than that of CLEA without Ca²âº. Furthermore, CLEA prepared with 0.1 mmol/L Ca²âº not only exhibited higher substrate conversion and operational stability, but also increased the maximum reaction speed. Therefore, calcium ion improved the performance of glucose oxidase in CLEAs.

Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 µM) and 16b (procaspase-3 EC50 = 0.25 µM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 µM to 0.98 µM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 µM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

Sarcopenia and sarcopenic obesity among men aged 80 years and older in Beijing: prevalence and its association with functional performance.

AIM: Sarcopenia and sarcopenic obesity are significant associative factors for functional impairment related to aging. The main aim of the present study was to investigate the prevalence of sarcopenia and sarcopenic obesity, and their associations with functional status among men aged 80 years and older in Beijing. METHODS: A total of 75 young healthy volunteers, and 101 older men aged 80 years and older participated in the present study. Demographic characteristics, anthropometry, skeletal muscle mass measured by dual X-ray absorptiometry (DXA), 6-m gait speed and handgrip strength were collected. Relative appendicular skeletal muscle index (RASM) and percentage skeletal muscle index (SMI) were obtained. RESULTS: Overall, the prevalence of sarcopenia was 45.7% by using RASM. By the weight-adjusted skeletal muscle index definition (SMI), the prevalence of sarcopenia was 53.2%. The prevalence of sarcopenic obesity was lower by using RASM than SMI (4.9% vs 11.5%, P < 0.05). When we compared the sarcopenia prevalence (%) in obese participants, it was also remarkably lower by using RASM (40.0%) than SMI (95.0%). By using either RASM or SMI, gait speed was of no significant difference among the pure sarcopenia group, pure obese group and sarcopenic obesity group (0.76 ± 0.27 vs 0.82 ± 0.37 vs 0.82 ± 0.27 m/s, P > 0.05, by RASM; 0.75 ± 0.25 vs 0.92 ± 0.27 vs 0.82 ± 0.35 m/s, P > 0.05 by SMI), respectively. Multiple linear regression analyses showed that thigh skeletal muscle mass was positively correlated with gait speed independently (ß = 0.221, P = 0.011), and total body fat (ß = -0.216, P = 0.002) and age (ß = -0.524, P = 0.000) were negatively correlated with gait speed independently. CONCLUSIONS: The prevalence of sarcopenia is high either based on RASM or SMI among Chinese men aged 80 years and older. Functional limitations were significantly associated with older age, skeletal muscle mass and total body fat.