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Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essential. Here, we identified that an underappreciated serine/threonine kinase, cyclin-dependent kinase-like 3 (CDKL3), crucially drives rapid cell cycle progression and cell growth in cancers. With regard to mechanism, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of cyclin-dependent kinase 4 (CDK4) by direct phosphorylation on T172 to sustain [G.sub.1] phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized, and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes acquired resistance to CDK4/6 inhibitor. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presents an integrated paradigm of cancer cell cycle regulation and suggests CDKL3 targeting as a feasible approach in cancer treatment., Introduction The cell cycle consists of multiple modules and machineries to regulate cell division in a precise manner (1, 2). A complete cell cycle is composed of [G.sub.1], S, [G.sub.2], [...]

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The quantum confinement effect is an effective strategy to broaden the bandgaps of quasi-2D perovskites for achieving efficient blue perovskite light-emitting diodes (PeLEDs). However, reducing the quantum well (QW) width in quasi-2D PEA2Csn−1PbnBr3n+1 perovskites always induces a disordered QW distribution, which is detrimental to its electroluminescent performance. We disclose that low-n quasi-2D perovskites tend to freely distort octahedra forming γ-phase perovskites due to the lattice mismatch brought by small-size Cs+ ions. The short-chain ligand ethylammonium (EA) is then used to suppress the distortion of [PbBr6]4− octahedra by partially entering the A-site interspace as a larger cation. The quasi-2D perovskites prepared with the mixed EA/PEA ligands exhibit a narrow diffraction peak with little octahedral distortion, uniform QW distribution and efficient energy transfer process. The sky-blue PeLEDs prepared with the proposed strategy of mixed EA/PEA ligands achieve a remarkable external quantum efficiency of 14.14%. [ABSTRACT FROM AUTHOR]

With the continuous development of manned space technology, higher requirements have been proposed for solid rocket motors. The ignition process of solid rocket motors affects the reliability, stability and safety of their operation. The ignition powder, cover opening pressure and grain length‐diameter ratio are the main factors affecting the ignition process. Therefore, the influence of different factors on the ignition process of solid rocket motors is studied with numerical simulations. Based on the finite volume method, the ignition process of a solid rocket motor is modelled and experimentally verified. Then, the pressure and temperature distribution characteristics during the ignition delay, flame propagation and gas filling times are analysed. Finally, the effects of different ignition powders, cover opening pressures and length‐diameter ratios on the ignition process are compared and analysed. The results show that the model has high prediction accuracy. When the ignition powder is 6 g, the maximum combustion temperature of solid rocket motor increases from 2590 K to 2620 K between 0.1 ms and 0.44 ms. Between 0.44 ms and 3.18 ms, intermittent flame propagation and pressure oscillations occur. In the gas filling time, the flow field gradually stabilizes. Increasing the ignition powder mass is beneficial to the ignition process, but the disadvantages of pressure oscillations should be considered. Increasing the cover opening pressure enhances the ignition process, while increasing the length‐diameter ratio increases the ignition pressure building time. The study results provide technical support for the structural design of solid rocket motors. [ABSTRACT FROM AUTHOR]

The main building of Zone II of Zhanjiang Bay Laboratory R&D Building adopts a steel frame–core tube shear wall structure system, with a 53.4 m large-span and heavy-load-transfer truss on the fourth floor. In order to propose the optimal construction and installation scheme for the large-span and heavy-load-transfer truss, the simplified model, single model, and 3D model are utilized to compare Scheme 1 with rigid connection and Scheme 2 with elastic connection and rigid connection. After completing the construction of the underground layer and towers on both sides, in Scheme 1, the fourth-floor transfer truss is directly connected to the towers on both sides in a rigid manner. Subsequently, the support at the bottom of the transfer truss is removed, allowing for layer-by-layer construction. The transfer truss remains rigidly connected to both side towers throughout. On the other hand, in Scheme 2, initially, the transfer truss is connected to both side towers through upper chords and diagonal bars before being constructed upwards until reaching the sixth floor. Once formed as a whole with two floors above using large diagonal tie rods, lower chords of the large-span and heavy-load-transfer truss are then connected with another diagonal bar to establish a rigid connection between the transfer truss and towers; thereafter, upward construction continues. Following completion of constructing a seven-story large diagonal tie rod, whereupon removal of support at the bottom of the conversion truss occurs, subsequent layer-by-layer construction takes place accordingly. It has been observed that employing Scheme 2 can enhance stress distribution within core barrel shear walls as well as transfer trusses while ensuring deflection and stress levels meet requirements for the large-span and heavy-load-transfer truss, thereby rendering structural stress more rationalized, leading to significantly improved overall safety. [ABSTRACT FROM AUTHOR]

The electrochemical N2 reduction reaction (ENRR), driven by renewable electricity and run under ambient conditions, offers a promising sustainable avenue for carbon‐neutral NH3 production. Yet, to efficiently bind and activate the inert N2 remains challenge. Herein, effective and stable electrochemical NH3 synthesis on Sm(OH)3 via enhanced adsorption of hydrogen and dinitrogen by dual integration of sulfur dopants and oxygen vacancies (VO) is reported. The resulting S‐doped lanthanide electrocatalyst attains both a good NH3 yield rate, exceeding 21 μgNH3 h−1 mgcat.−1, and an NH3 faradaic efficiency of over 29% at −0.3 V (vs reversible hydrogen electrode) in an H‐type cell using a neutral electrolyte, figures of merit that are largely maintained after 2 days of consecutive polarization. Density functional theory calculations show that the adsorption energy barrier of N2 on S‐Sm(OH)3(VO) is greatly lowered by the introduction of VO. In addition, the S sites improve the adsorption of hydrogen produced via the Volmer reaction, which is conducive to the formation of the *N–NH intermediate (i.e., the potential determining step, PDS) on adjacent Sm sites, and thereby significantly promotes the reaction kinetics of ENRR. The PDS free energy for the catalyst is comparable with the values at the peak of the ENRR volcano plots of leading transition metal catalyst surfaces. [ABSTRACT FROM AUTHOR]

The electrochemical N2 reduction reaction (ENRR), driven by renewable electricity and run under ambient conditions, offers a promising sustainable avenue for carbon‐neutral NH3 production. Yet, to efficiently bind and activate the inert N2 remains challenge. Herein, effective and stable electrochemical NH3 synthesis on Sm(OH)3 via enhanced adsorption of hydrogen and dinitrogen by dual integration of sulfur dopants and oxygen vacancies (VO) is reported. The resulting S‐doped lanthanide electrocatalyst attains both a good NH3 yield rate, exceeding 21 μgNH3 h−1 mgcat.−1, and an NH3 faradaic efficiency of over 29% at −0.3 V (vs reversible hydrogen electrode) in an H‐type cell using a neutral electrolyte, figures of merit that are largely maintained after 2 days of consecutive polarization. Density functional theory calculations show that the adsorption energy barrier of N2 on S‐Sm(OH)3(VO) is greatly lowered by the introduction of VO. In addition, the S sites improve the adsorption of hydrogen produced via the Volmer reaction, which is conducive to the formation of the *N–NH intermediate (i.e., the potential determining step, PDS) on adjacent Sm sites, and thereby significantly promotes the reaction kinetics of ENRR. The PDS free energy for the catalyst is comparable with the values at the peak of the ENRR volcano plots of leading transition metal catalyst surfaces. [ABSTRACT FROM AUTHOR]

Development of low‐cost and high‐efficiency electrocatalysts for overall water splitting is of great significance in the sustainable hydrogen economy. Herein, Fe1.2(CoNi)1.8Sex medium‐entropy metal selenides (MESes) nanoparticles are prepared via the selenylation of metal‐organic frameworks (MOFs) precursors. The optimal Fe1.2(CoNi)1.8Se6 MESe exhibits an outstanding electrocatalytic performance in alkaline media, offering low overpotentials of 66 and 216 mV at 10 mA cm−2 for the hydrogen evolution reaction and oxygen evolution reaction, respectively. A full electrolysis apparatus with Fe1.2(CoNi)1.8Se6 MESe as both cathode and anode displays an excellent performance, achieving 10 mA cm−2 at a potential of 1.55 V. Furthermore, density functional theory calculations demonstrate that the formation of MESe enhances the surface charge density and brings the d‐band center closer to Fermi level, as compared with that of the MOF precursor. Overall, the proposed strategy of medium‐entropy materials presents a low‐cost approach to fabricate energy storage and conversion devices. [ABSTRACT FROM AUTHOR]

Earthquake prediction is a long-standing problem in seismology that has garnered attention from the scientific community and the public. Despite ongoing efforts to understand the physical mechanisms of earthquake occurrence, there is no convincing physical or statistical model for predicting large earthquakes. Machine learning methods, such as random forest and long short-term memory (LSTM) neural networks, excel at identifying patterns in large-scale databases and offer a potential means to improve earthquake prediction performance. Differing from physical and statistical approaches to earthquake prediction, we explore whether small earthquakes can be used to predict large earthquakes within the framework of machine learning. Specifically, we attempt to answer two questions for a given region: (1) Is there a likelihood of a large earthquake (e.g., M ≥ 6.0) occurring within the next year? (2) What is the maximum magnitude of an earthquake expected to occur within the next year? Our results show that the random forest method performs best in classifying large earthquake occurrences, while the LSTM method provides a rough estimation of earthquake magnitude. We conclude that small earthquakes contain information relevant to predicting future large earthquakes and that machine learning provides a promising avenue for improving the prediction of earthquake occurrences. [ABSTRACT FROM AUTHOR]

Green solvent processing of perovskite light‐emitting diodes (PeLEDs) is a necessity for their future commercialization. However, the almost insoluble nature of perovskites in most green solvents strongly impedes the progress of green solvent‐processed PeLEDs. Here, a novel green solvent triethylene glycol (TEG) is used as the processing solvent for perovskites. TEG has better solubility for perovskite precursors than most reported green solvents. Moreover, it is found that the low vapor pressure of TEG solvent and stable precursor solution render a much wider time window for the so‐called antisolvent treatment than that of perovskite precursor solution in commonly dimethyl sulfoxide. High‐quality perovskite film can be readily synthesized with the antisolvent treatment at a time window of 70–100 s, and the resultant green PeLEDs demonstrate nearly identical light‐emitting efficiencies. Together with further interface modification, the optimized green PeLEDs processed with TEG exhibit an external quantum efficiency of 20.4% and a maximal luminance over 38000 cd m−2. It is the first successful attempt to fabricate high‐efficiency PeLEDs utilizing green solvent and is enlightening for the development of high‐performance PeLEDs prepared with eco‐friendly solvents. [ABSTRACT FROM AUTHOR]

Although π‐conjugated two dimensional (2D) covalent organic frameworks (COFs) have been extensively reported, developing fully π‐conjugated 3D COFs is still an extremely difficult problem due to the lack of fully π‐conjugated 3D linkers. We synthesize a fully conjugated 3D COF (BUCT‐COF‐1) by designing a saddle‐shaped building block of aldehyde‐substituted cyclooctatetrathiophene (COThP)‐CHO. As a consequence of the fully conjugated 3D network, BUCT‐COF‐1 demonstrates ultrahigh Hall electron mobility up to ≈3.0 cm2 V−1 s−1 at room temperature, which is one order of magnitude higher than the current π‐conjugated 2D COFs. Temperature‐dependent conductivity measurements reveal that the charge carriers in BUCT‐ COF‐1 exhibit the band‐like transport mechanism, which is entirely different from the hopping transport phenomena observed in common organic materials. The findings indicate that fully conjugated 3D COFs can achieve electron delocalization and charge‐transport pathways within the whole 3D skeleton, which may open up a new frontier in the design of organic semiconducting materials. [ABSTRACT FROM AUTHOR]

The rapidly evolving field of immunotherapy has attracted great attention in the field of cancer research and already revolutionized the clinical practice standard for treating cancer. Genetically engineered T cells expressing either T cell receptors or chimeric antigen receptors represent novel treatment modalities and are considered powerful weapons to fight cancer. The immune checkpoint blockade, which harnesses the negative control signaling behind the anti‐tumor immune response with therapeutic antibodies by blocking cytotoxic T lymphocyte‐associated protein 4 or the programmed cell death 1 pathways are another mainstream direction for cancer immunotherapy. In addition to cytotoxic T cells, other immune cell types such as nature killer cells and macrophages also possess the ability to eradicate cancer cells, which may serve as the basis to develop novel cancer immunotherapies. The advent of cutting‐edge genome editing technology, especially clustered regularly interspaced palindromic repeats (CRISPR)‐based tools, has greatly expedited many biomedical research areas, including cancer immunology and immunotherapy. In this review, the contribution of current CRISPR techniques to basic and translational cancer immunology research is discussed, and the future for cancer immunotherapy in the age of CRISPR is predicted. [ABSTRACT FROM AUTHOR]

An efficient two-step method to allocate power for orthogonal frequency division multiplexing-based full-duplex (FD) two-way communication links is proposed in this letter. We try to maximize sum data rate of the two-way link by allocating available power over each subcarrier at both FD transceivers with imperfect self-interference cancellation. This sum-rate optimization problem is formulated under total power constraint. In order to solve this problem, we first consider a one-subcarrier problem and derive the closed-form solution for power allocation. Based on this result, the multi-carrier optimization problem can be solved by our proposed two-step method. First, we allocate total power to each subcarrier optimally, and then we solve the power allocation problem for each subcarrier. Compared with direct dual decomposition method, numerical results indicate that our two-step method can obtain the same two-way link performance, however, with much lower computational complexity. [ABSTRACT FROM PUBLISHER]

The recent outbreak of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a severe threat to the global public health and economy, however, effective drugs to treat COVID-19 are still lacking. Here, we employ a deep learning-based drug repositioning strategy to systematically screen potential anti-SARS-CoV-2 drug candidates that target the cell entry mechanism of SARS-CoV-2 virus from 2635 FDA-approved drugs and 1062 active ingredients from Traditional Chinese Medicine herbs. In silico molecular docking analysis validates the interactions between the top compounds and host receptors or viral spike proteins. Using a SARS-CoV-2 pseudovirus system, we further identify several drug candidates including Fostamatinib, Linagliptin, Lysergol and Sophoridine that can effectively block the cell entry of SARS-CoV-2 variants into human lung cells even at a nanomolar scale. These efforts not only illuminate the feasibility of applying deep learning-based drug repositioning for antiviral agents by targeting a specified mechanism, but also provide a valuable resource of promising drug candidates or lead compounds to treat COVID-19. • A host-directed drug repurposing targeting the cell entry mechanism of SARS-CoV-2. • Three independent deep learning methods for drug repurposing. • Thousands of approved drugs and natural compounds for repurposing. • Validation of top drug candidates by molecular docking and virus entry assay. [ABSTRACT FROM AUTHOR]

With the rapid urbanization in China, directly buried municipal pipelines have been gradually replaced by urban utility tunnels due to a serious shortage of urban underground spaces and weak disaster prevention of traditional municipal pipelines. The urban utility tunnels normally contain electricity pipelines, natural gas pipelines, heat pipelines, sewer pipelines, etc. If a natural gas pipeline leaks, a fire and explosion might occur and lead to serious consequences. In this study, the characteristics of gas explosion in a natural gas compartment of urban utility tunnel are investigated based on FLACS (Flame Acceleration Simulator) simulations. The results revealed that the flame profile undergoes two unstable flame stages. When the ignition position is set at the middle area (100.25, 1.2, 1.4 m) of the 200 m-long natural gas compartment, the maximum overpressure of the gas explosion in the 200 m-long natural gas compartment is 25.17 bar, which is the largest maximum overpressure under all gas explosion simulation setups. It is also found that the length of the natural gas compartment and different ignition positions have slight effects on the maximum overpressure. This study could provide technical support for structural strength design and division of the fireproofing area of the natural gas compartment in the utility tunnel, which is of great significance to improve urban safety during sustainable development. [ABSTRACT FROM AUTHOR]