Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy-based virtual screening and machine learning evaluation.

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Supramolecular Radical Electronics.

Supramolecular radical chemistry is an emerging area bridging supramolecular chemistry and radical chemistry, and the integration of radicals into the supramolecular architecture offers a new dimension for tuning their structures and functions. Although various efforts have been devoted to the fabrication of supramolecular junctions, the charge transport characterization through the supramolecular radicals remained unexplored due to the challenges in creating supramolecular radicals at the single-molecule level. Here, we demonstrate the fabrication and charge transport investigation of a supramolecular radical junction using the electrochemical scanning tunneling microscope-based break junction (EC-STM-BJ) technique. We found that the conductance of a supramolecular radical junction was more than 1 order of magnitude higher than that of a supramolecular junction without a radical and even higher than that of a fully conjugated oligophenylenediamine molecule with a similar length. The combined experimental and theoretical investigations revealed that the radical increased the binding energy and decreased the energy gap in the supramolecular radical junction, which leads to the near-resonant transport through the supramolecular radical. Our work demonstrated that the supramolecular radical can provide not only strong binding but also efficient electrical coupling between building blocks, which provides new insights into supramolecular radical chemistry and new materials with supramolecular radicals.

Room-temperature logic-in-memory operations in single-metallofullerene devices.

In-memory computing provides an opportunity to meet the growing demands of large data-driven applications such as machine learning, by colocating logic operations and data storage. Despite being regarded as the ultimate solution for high-density integration and low-power manipulation, the use of spin or electric dipole at the single-molecule level to realize in-memory logic functions has yet to be realized at room temperature, due to their random orientation. Here, we demonstrate logic-in-memory operations, based on single electric dipole flipping in a two-terminal single-metallofullerene (Sc2C2@Cs(hept)-C88) device at room temperature. By applying a low voltage of ±0.8 V to the single-metallofullerene junction, we found that the digital information recorded among the different dipole states could be reversibly encoded in situ and stored. As a consequence, 14 types of Boolean logic operation were shown from a single-metallofullerene device. Density functional theory calculations reveal that the non-volatile memory behaviour comes from dipole reorientation of the [Sc2C2] group in the fullerene cage. This proof-of-concept represents a major step towards room-temperature electrically manipulated, low-power, two-terminal in-memory logic devices and a direction for in-memory computing using nanoelectronic devices.

The Evolution of the Charge Transport Mechanism in Single-Molecule Break Junctions Revealed by Flicker Noise Analysis.

The electronic noise characterization of single-molecule devices provides insights into the mechanisms of charge transport. In this work, it is reported that flicker noise can serve as an indicator of the time-dependent evolution of charge transport mechanisms in the single-molecule break junction process. By introducing time-frequency analysis, the authors find that flicker noise components of the molecule junction show time evolution behavior in the dynamic break junction process. A further investigation of the power-law dependence of flicker with conductance during the dynamic break junction process reveals that the mechanism of charge transport transits from the through-space transport to the through-bond transport, and is dominated by through-space transport again when the junction is about to rupture. The authors' results provide a flicker noise-based way to characterize the time-dependent evolution of charge transport mechanisms in single-molecule break junctions.

The Glaesserella parasuis phosphoglucomutase is partially required for lipooligosaccharide synthesis.

Lipooligosaccharides (LOSs) are virulence determinants of Glaesserella parasuis, a pathogen of the respiratory tract of pigs. We previously reported that disruption of the galU or galE gene in G. parasuis results in increased sensitivity to porcine serum, indicating that the galactose catabolism pathway is required for polysaccharide formation in G. parasuis. Here, we evaluated the role of the HAPS_0849 gene in LOS synthesis. The G. parasuis SC096 HAPS_0849 mutant produced a highly truncated LOS molecule, although a small fraction of intact LOS was still observed, and this mutant was found to be more sensitive to serum than the parental strain. HAPS_0849 was overexpressed and purified for biochemical assays, and this protein exhibited phosphoglucomutase (PGM) activity. Heterologous expression of a pgm gene from Escherichia coli in the HAPS_0849 mutant led to restoration of the wild-type LOS glycoform, further demonstrating the PGM function of HAPS_0849 in G. parasuis. The autoagglutination and biofilm formation ability of this strain were also investigated. Disruption of HAPS_0849 led to an increased tendency to autoagglutinate and form more biofilms, and these enhanced phenotypes were observed in the absence of glucose. In addition, LOSs from HAPS_0849, galU and lgtB mutants had similar truncated glycoforms, while LOSs from the galE and lex-1 mutants exhibited another type of defective LOS pattern. These findings imply that HAPS_0849 may function upstream of GalU in the generation of glucose 1-phosphate. In conclusion, our results preliminarily described the functions of HAPS_0849 in G. parasuis, and this gene was partially required for LOS synthesis.

Comparative study on numerical simulation of temperature field of farm house with different roof forms.

In recent years, the issue of energy consumption in farm buildings has received much attention. The roofs of farm buildings in Northwest China have a variety of roof forms. This paper presents the implementation of first fully confirmed the indoor thermal environment of different roof construction was significantly effected by periodic thermogenesis. In order to determine the indoor temperature distribution of the farmhouse in summer in Ningxia Hui Autonomous Region, we provided the heat transfer coefficient data of the farmhouse envelope, also detailed in the manuscript. Model of Thermal Mass Transport enables fast and accurately simulates the indoor temperature distribution of farmhouses with different roof forms on the same day, taking into account the climate zone of the region. This is despite the phase delay time of indoor temperatures for different roof forms caused by periodic initial temperature boundaries ranged from 1.55 to 2.78 h , and the phase delay angle ranged from 23.25 ∘ to 41.7 ∘ . Extensive simulated results revealed individual variability in the role of roof form, demonstrating indoor temperatures in farmhouses corresponding to different climatic zones. In addition, by analyzing and discussing the indoor temperature phase delay angle and delay time for each type of roof forms, statistical results identified the advantages of Non-equal-sloped roof as a local farmhouse roof.

Tailoring raloxifene into single-component molecular crystals possessing multilevel stimuli-responsive room-temperature phosphorescence.

Simultaneously achieving room-temperature phosphorescence (RTP) and multiple-stimuli responsiveness in a single-component system is of significance but remains challenging. Crystallization has been recognized to be a workable strategy to fulfill the above task. However, how the molecular packing mode affects the intersystem crossing and RTP lifetime concurrently remains unclear so far. Herein, four economic small-molecular compounds, analogues of the famous drug raloxifene (RALO), are facilely synthesized and further explored as neat single-component and stimuli-responsive RTP emitters via crystallization engineering. Thanks to their simple structures and high ease to crystallize, these raloxifene analogues function as models to clarify the important role of molecular packing in the RTP and stimuli-responsiveness properties. Thorough combination of the single-crystal structure analysis and theoretical calculations clearly manifests that the tight antiparallel molecular packing mode is the key point to their RTP behaviors. Interestingly, harnessing the controllable and reversible phase transitions of the two polymorphs of RALO-OAc driven by mechanical force, solvent vapor, and heat, a single-component multilevel stimuli-responsive platform with tunable emission color is established and further exploited for optical information encryption. This work would shed light on the rational design of multi-stimuli responsive RTP systems based on single-component organics.

Near-infrared AIEgens with high singlet-oxygen yields for mitochondria-specific imaging and antitumor photodynamic therapy.

AIE-active photosensitizers (PSs) are promising for antitumor therapy due to their advantages of aggregation-promoted photosensitizing properties and outstanding imaging ability. High singlet-oxygen (1O2) yield, near-infrared (NIR) emission, and organelle specificity are vital parameters to PSs for biomedical applications. Herein, three AIE-active PSs with D-π-A structures are rationally designed to realize efficient 1O2 generation, by reducing the electron-hole distribution overlap, enlarging the difference on the electron-cloud distribution at the HOMO and LUMO, and decreasing the ΔEST. The design principle has been expounded with the aid of time-dependent density functional theory (TD-DFT) calculations and the analysis of electron-hole distributions. The 1O2 quantum yields of AIE-PSs developed here can be up to 6.8 times that of the commercial photosensitizer Rose Bengal under white-light irradiation, thus among the ones with the highest 1O2 quantum yields reported so far. Moreover, the NIR AIE-PSs show mitochondria-targeting capability, low dark cytotoxicity but superb photo-cytotoxicity, and satisfactory biocompatibility. The in vivo experimental results demonstrate good antitumor efficacy for the mouse tumour model. Therefore, the present work will shed light on the development of more high-performance AIE-PSs with high PDT efficiency.

Bionic Tactile-Gustatory Receptor for Object Identification Based on All-Polymer Electrochemical Transistor.

Human sensory receptors enable the real world to be perceived effortlessly. Hence, massive efforts have been devoted to the development of bionic receptors capable of identifying objects. Unfortunately, most of the existing devices are limited to single sensory emulation and are established on solid-state electronic technologies, which are incompatible with the biological reactions occurring in electrolyte media. Here, an iontronic tactile-gustatory receptor using an all-polymer electrochemical transistor (AECT) is presented. The sensor is biocompatible with the operation voltage of 0.1 V, which is 1 to 2 orders lower than those of reported values. By this study, one receptor is able to accurately recognize various objects perceived by the human tactile and gustatory system without complex circuitry. Additionally, to promote its further application, flexible AECT arrays with channel length of 2 µm and density of 104 167 transistors cm-2 (yield of 97%) are fabricated, 1 to 5 orders higher than those of related works. Finally, a flexible integrated network for electrocardiogram recording is successfully constructed. This study moves a step forward toward state-of-the-art bionic sensors.

Van der Waals Multilayer Heterojunction for Low-Voltage Organic RGB Area-Emitting Transistor Array.

Organic light-emitting transistors (OLETs) have garnered considerable attention from academy and industry due to their potential applications in next-generation display technologies, multifunctional devices, and organic electrically pumped lasers. However, overcoming the trade-offs among power consumption, external quantum efficiency (EQE), and uniform area emission remains a long-standing issue for OLETs. Herein, a van der Waals multilayer heterojunction methodology is proposed to enhance the layer-to-layer interfacial interaction and contact, resulting in better dipole shielding, carrier transport, exciton recombination, and current density distribution. The prepared multilayer heterojunction OLET (MLH-OLET) array shows uniform and bright RGB area emission and low operating voltage (<30 V among the lowest applied voltage of reported lateral LETs). Additionally, a high brightness under area emission of 1060 cd m-2 , a high EQE value of 0.85%, and a high loop stability (over 380 cycles, outperforming state-of-the-art OLETs) indicate that the proposed multilayer heterojunction is obviously superior to the reported lateral device configuration. The van der Waals multilayer heterojunction developed for the preparation of OLET arrays sufficiently meets the low-voltage, high-performance, and low-cost requirements of future display technologies.

Low-Voltage Intrinsically Stretchable Organic Transistor Amplifiers for Ultrasensitive Electrophysiological Signal Detection.

Stretchability is a prerequisite for electronic skin devices. However, state-of-the-art stretchable thin-film transistors do not possess sufficiently low operating voltages and good stability, significantly limiting their use in real-world biomedical applications. Herein, a van der Waals-controlling elastomer/carbon quantum dot interfacial polarization methodology is proposed to form a hybrid polymer dielectric with 620% tensile strain and large-area film uniformity (>A4 paper size). Using the hybrid polymer dielectrics, the prepared intrinsically stretchable organic thin-film transistors demonstrate a low operating voltage below 5 V, 100% strain tolerance, and excellent operational stability, as well as a high on-current/off-current ratio of 105 and a steep subthreshold slope of 500 mV dec-1 . Based on this device technology, an amplifier with a high gain of 90 V V-1 among the highest values of reported stretchable transistors is realized. This amplifier is at the first time applied to detect human electrophysical signals with an output signal amplitude of over 0.2 V, which even outperforms other types of the state-of-the-art organic amplifiers for human electrophysiology monitoring. This stretchable device technology sufficiently meets the safety and portability requirements of wearable biomedical applications, opening a new opportunity to e-skin with signal control and amplification capabilities.

Confidence set-membership state estimation for LPV systems with inexact scheduling variables.

In this paper, a confidence set-membership state estimator is proposed for a class of polytopic linear parameter varying (LPV) systems with inexact scheduling variables. The set-bounded and Gaussian uncertainties are considered simultaneously in the process disturbances and measurement noises. The purpose of the proposed estimator is to achieve a confidence set of the state with given confidence level. Based on the polytopic LPV uncertain enclosure model, the set-bounded/Gaussian uncertainties of the state are given by using the worst case strategy. The size of the confidence set is minimized to get the optimal gain for the estimator. Meanwhile, the constrained zonotope is adopted to represent set-bounded uncertainties for more accurate results. Finally, a vehicle example is given to illustrate the effectiveness of proposed methods.

Preparation and performance characterization of a new dust suppressant with a cross-linked network structure for use in open-pit coal mines.

In an effort to control dust pollution in open-air environments such as pit coal mines and coal transportation systems, a new dust suppressant with a cross-linked network structure was prepared. Graft copolymerization of soy protein isolate (SPI) and methacrylic acid (MAA), using potassium persulfate (KPS) as the initiator and hexametaphosphoric acid (SHMP) as the cross-linking agent, formed the network structure. The optimal MAA/SPI mass ratio for the dust suppressant was determined through a single-factor experiment to be 3:4, with 0.8 and 0.2 g of SHMP and KPS, respectively. The grafting reaction required 30 min at 60 °C. Scanning electron microscopy, energy-dispersive x-ray spectroscopy, Fourier-transform infrared spectroscopy, and differential scanning calorimetry were used to characterize the structure and application performance of the dust suppressant. The experimental results showed that the graft copolymerization reaction successfully formed the desired cross-linked network, and that when the cross-linked network material was sprayed on coal dust, it formed a dense, solidified shell, which effectively resisted wind erosion and served as a dust suppressant. The average reduction of the total suspended particulate matter of an open-air coal pile reached 79.95%, demonstrating effective dust suppression.

σ-σ Stacked supramolecular junctions.

Intermolecular charge transport plays an essential role in organic electronic materials and biological systems. To date, experimental investigations of intermolecular charge transport in molecular materials and electronic devices have been restricted to conjugated systems in which π-π stacking interactions are involved. Herein we demonstrate that the σ-σ stacking interactions between neighbouring non-conjugated molecules offer an efficient pathway for charge transport through supramolecular junctions. The conductance of σ-σ stacked molecular junctions formed between two non-conjugated cyclohexanethiol or single-anchored adamantane molecules is comparable to that of π-π stacked molecular junctions formed between π-conjugated benzene rings. The current-voltage characteristics and flicker noise analysis demonstrate the existence of stacked molecular junctions formed between the electrode pairs and exhibit the characteristics of through-space charge transport. Density functional theory calculations combined with the non-equilibrium Green's function method reveal that efficient charge transport occurs between two molecules configured with σ-σ stacking interactions.

Spatially nanoconfined N-type polymer semiconductors for stretchable ultrasensitive X-ray detection.

Polymer semiconductors are promising candidates for wearable and skin-like X-ray detectors due to their scalable manufacturing, adjustable molecular structures and intrinsic flexibility. Herein, we fabricated an intrinsically stretchable n-type polymer semiconductor through spatial nanoconfinement effect for ultrasensitive X-ray detectors. The design of high-orientation nanofiber structures and dense interpenetrating polymer networks enhanced the electron-transporting efficiency and stability of the polymer semiconductors. The resultant polymer semiconductors exhibited an ultrahigh sensitivity of 1.52 × 104 µC Gyair-1 cm-2, an ultralow detection limit of 37.7 nGyair s-1 (comparable to the record-low value of perovskite single crystals), and polymer film X-ray imaging was achieved at a low dose rate of 3.65 µGyair s-1 (about 1/12 dose rate of the commercial medical chest X-ray diagnosis). Meanwhile, the hybrid semiconductor films could sustain 100% biaxial stretching strain with minimal degeneracy in photoelectrical performances. These results provide insights into future high-performance, low-cost e-skin photoelectronic detectors and imaging.

The Characterization of Electronic Noise in the Charge Transport through Single-Molecule Junctions.

With the goal of creating single-molecule devices and integrating them into circuits, the emergence of single-molecule electronics provides various techniques for the fabrication of single-molecule junctions and the investigation of charge transport through such junctions. Among the techniques for characterization of charge transport through molecular junctions, electronic noise characterization is an effective strategy with which issues from molecule-electrode interfaces, mechanisms of charge transport, and changes in junction configurations are studied. Electronic noise analysis in single-molecule junctions can be used to identify molecular conformations and even monitor reaction kinetics. This review summarizes the various types of electronic noise that have been characterized during single-molecule electrical detection, including the functions of random telegraph signal (RTS) noise, flicker noise, shot noise, and their corresponding applications, which provide some guidelines for the future application of these techniques to problems of charge transport through single-molecule junctions.

The Performance and Mechanism of the Green Explosion Suppressant SGA for Coal Dust Explosion Suppression.

In recent years, coal processing is developing rapidly, but there are often hidden safety hazards such as coal dust explosions during coal processing. In order to ensure safe production and avoid coal dust explosion accidents, a carrier with unique micro-mesoporous structure (SG) based waste molecular sieves was prepared. After that, the carrier was loaded with (NH4)2C2O4(A) uniformly by ultrasound, which acted as an activity component for the first time. A novel micro-mesoporous coal dust explosion suppressant (SGA) is obtained. The law influence of different compositions of suppressant on the flame propagation of explosion was investigated. The results showed that the best ratio of waste molecular sieve, zirconium dioxide, and (NH4)2C2O4 of the suppressant is 1:7:2. The suppression performance increases with the increase of the addition of suppressant. When the addition amount is 70 wt %, the explosion loses the ability to continue to expand. Finally, combining the suppression performance with characterization results, the physical and chemical synergistic suppression mechanism is proposed, which reveals the reason why the suppressant has efficient suppression performance. The study could realize the green reuse of waste molecular sieves and provide guarantees for safe production of the coal processing industry.

Electric field-induced switching among multiple conductance pathways in single-molecule junctions.

Here, we report the switching among multiple conductance pathways achieved by sliding the scanning tunneling microscope tip among different binding sites under different electric fields. With an increase in the electric field, high molecular conductance states appear, suggesting the formation of different configurations in single-molecule junctions. The switch can be operated in situ and reversibly, which is also confirmed by the apparent conductance conversion in I-V measurements. Theoretical simulations also agree well with the experimental results, which implies that the electric field enables the possibility to trigger switching in single-molecule junctions.

Discovery of phenyl-linked symmetric small molecules as inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction.

Programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is one of the most promising targets in the field of immune checkpoint blockade therapy. Beginning with our exploration of linkers and structure-activity relationship research, we found that the aromatic ring could replace the linker and aryl group to maintain the satisfactory activity of classic triaryl scaffold inhibitor. Based on previous studies, we designed and synthesized a series of C2-symmetric phenyl-linked compounds, and further tail optimization afforded the inhibitors, which displayed promising inhibitory activity against the PD-1/PD-L1 interaction with IC50 value at the single nanomolar range (C13-C15). Further cell-based PD-1/PD-L1 blockade bioassays indicated that these C2-symmetric molecules could significantly inhibit the PD-1/PD-L1 interaction at the cellular level and restore T cells' immune function at the safety concentrations. The discovery of these phenyl-linked symmetric small molecules showed the potential of simplified-linker and C2-symmetric strategy and provided a basis for developing symmetric small molecule inhibitors of PD-1/PD-L1 interaction. Moreover, C13 and C15 performed stable binding modes to PD-L1 dimeric after computational docking and dynamic simulation, which may serve as a good starting point for further development.

Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors.

Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.