Potent inhibitors targeting cyclin-dependent kinase 9 discovered via virtual high-throughput screening and absolute binding free energy calculations.

Due to the crucial regulatory mechanism of cyclin-dependent kinase 9 (CDK9) in mRNA transcription, the development of kinase inhibitors targeting CDK9 holds promise as a potential treatment strategy for cancer. A structure-based virtual screening approach has been employed for the discovery of potential novel CDK9 inhibitors. First, compounds with kinase inhibitor characteristics were identified from the ZINC15 database via virtual high-throughput screening. Next, the predicted binding modes were optimized by molecular dynamics simulations, followed by precise estimation of binding affinities using absolute binding free energy calculations based on the free energy perturbation scheme. The binding mode of molecule 006 underwent an inward-to-outward flipping, and the new binding mode exhibited binding affinity comparable to the small molecule T6Q in the crystal structure (PDB ID: 4BCF), highlighting the essential role of molecular dynamics simulation in capturing a plausible binding pose bridging docking and absolute binding free energy calculations. Finally, structural modifications based on these findings further enhanced the binding affinity with CDK9. The results revealed that enhancing the molecule's rigidity through ring formation, while maintaining the major interactions, reduced the entropy loss during the binding process and, thus, enhanced binding affinities.

Genome-wide identification and analysis of the WRKY gene family and low-temperature stress response in Prunus sibirica.

BACKGROUND: WRKY transcription factors are a prominent gene family in plants, playing a crucial role in various biological processes including development, metabolism, defense, differentiation, and stress response. Although the WRKY gene family has been extensively studied and analysed in numerous plant species, research on Prunus sibirica's WRKY genes (PsWRKY) remains lacking. RESULTS: This study analysed the basic physicochemical properties, phylogeny, gene structure, cis-acting elements, and Gene ontology (GO) annotation of PsWRKY gene family members using bioinformatics methods based on the whole-genome data of P. sibirica. In total, 55 WRKYs were identified in P. sibirica and were heterogeneously distributed on eight chromosomes. Based on the phylogenetic analysis, these WRKYs were classified into three major groups: Group I, Group II (II-a, II-b, II-c, II-d, II-e), and Group III. Members of different subfamilies have different cis-acting elements, conserved motifs, and intron-exon structures, indicating functional heterogeneity of the WRKY family. Prediction of subcellular localisation indicated that PsWRKYs were mainly located in the nucleus. Twenty pairs of duplicated genes were identified, and segmental duplication events may play an important role in PsWRKY gene family expansion. Analysis of the Ka/Ks ratio showed that the PsWRKY family's homologous genes were primarily purified by selection. Additionally, GO annotation analysis showed that the WRKY gene family was mainly involved in responses to stimuli, immune system processes, and reproductive processes. Furthermore, quantitative real-time PCR (qRT-PCR) analysis showed that 23 PsWRKYs were highly expressed in one or more tissues (pistils and roots) and PsWRKYs showed specific expression patterns under different low-temperature stress conditions. CONCLUSIONS: Our results provide a scientific basis for the further exploration and functional validation of WRKYs in P. sibirica.

Low-Concentration Redox-Electrolytes for High-Rate and Long-Life Zinc Metal Batteries.

The uncontrolled zinc electrodeposition and side reactions severely limit the power density and lifespan of Zn metal batteries. Herein, the multi-level interface adjustment effect is realized with low-concentration redox-electrolytes (0.2 m KI) additives. The iodide ions adsorbed on the zinc surface significantly suppress water-induced side reactions and by-product formation and enhance the kinetics of zinc deposition. The distribution of relaxation times results reveal that iodide ions can reduce the desolvation energy of hydrated zinc ions and guide the deposition of zinc ions due to their strong nucleophilicity. As a consequence, the Zn||Zn symmetric cell achieves superior cycling stability (>3000 h at 1 mA cm-2 , 1 mAh cm-2 ) accompanied by a uniform deposition and a fast reaction kinetics with a low voltage hysteresis (<30 mV). Additionally, coupled with an activated carbon (AC) cathode, the assembled Zn||AC cell delivers a high-capacity retention of 81.64% after 2000 cycles at 4 A g-1 . More importantly, the operando electrochemical UV-vis spectroscopies show that a small number of I3 - can spontaneously react with the dead zinc as well as basic zinc saltsand regenerate iodide ions and zinc ions; thus, the Coulombic efficiency of each charge-discharge process is close to 100%.

Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.

Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors-such as endothelin-1-and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SKCA/IKCA expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.

Limb loading enhances skill transfer between augmented and physical reality tasks during limb loss rehabilitation.

BACKGROUND: Virtual and augmented reality (AR) have become popular modalities for training myoelectric prosthesis control with upper-limb amputees. While some systems have shown moderate success, it is unclear how well the complex motor skills learned in an AR simulation transfer to completing the same tasks in physical reality. Limb loading is a possible dimension of motor skill execution that is absent in current AR solutions that may help to increase skill transfer between the virtual and physical domains. METHODS: We implemented an immersive AR environment where individuals could operate a myoelectric virtual prosthesis to accomplish a variety of object relocation manipulations. Intact limb participants were separated into three groups, the load control (CGLD; [Formula: see text]), the AR control (CGAR; [Formula: see text]), and the experimental group (EG; [Formula: see text]). Both the CGAR and EG completed a 5-session prosthesis training protocol in AR while the CGLD performed simple muscle training. The EG attempted manipulations in AR while undergoing limb loading. The CGAR attempted the same manipulations without loading. All participants performed the same manipulations in physical reality while operating a real prosthesis pre- and post-training. The main outcome measure was the change in the number of manipulations completed during the physical reality assessments (i.e. completion rate). Secondary outcomes included movement kinematics and visuomotor behavior. RESULTS: The EG experienced a greater increase in completion rate post-training than both the CGAR and CGLD. This performance increase was accompanied by a shorter motor learning phase, the EG's performance saturating in less sessions of AR training than the CGAR. CONCLUSION: The results demonstrated that limb loading plays an important role in transferring complex motor skills learned in virtual spaces to their physical reality analogs. While participants who did not receive limb loading were able to receive some functional benefit from AR training, participants who received the loading experienced a greater positive change in motor performance with their performance saturating in fewer training sessions.

A Covalent Organic Framework as a Long-life and High-Rate Anode Suitable for Both Aqueous Acidic and Alkaline Batteries.

Aqueous rechargeable batteries are prospective candidates for large-scale grid energy storage. However, traditional anode materials applied lack acid-alkali co-tolerance. Herein, we report a covalent organic framework containing pyrazine (C=N) and phenylimino (-NH-) groups (HPP-COF) as a long-cycle and high-rate anode for both acidic and alkaline batteries. The HPP-COF's robust covalent linkage and the hydrogen bond network between -NH- and water molecules collectively improve the acid-alkaline co-tolerance. More importantly, the hydrogen bond network promotes the rapid transport of H+ /OH- by the Grotthuss mechanism. As a result, the HPP-COF delivers a superior capacity and cycle stability (66.6 mAh g-1 @ 30 A g-1 , over 40000 cycles in 1 M H2 SO4 electrolyte; 91.7 mAh g-1 @ 100 A g-1 , over 30000 cycles @ 30 A g-1 in 1 M NaOH electrolyte). The work opens a new direction for the structural design and application of COF materials in acidic and alkaline batteries.

Effects of Macroautophagy and Mitophagy on the Pathogenicity of Fusarium graminearum.

Fusarium graminearum is the main pathogen of Fusarium head blight (FHB), which causes huge economic losses every year. In this study, an attempt was made to control FHB from the point of view of the physiological behavior of the pathogen itself. Autophagic inhibitors and activators were used, and the pathogenicity-related indices of F. graminearum were measured. The results showed that under nitrogen-rich conditions, macroautophagy inhibition and activation greatly reduced the mycelium weight to 0.28 and 0.25 g/ml at 24 h, which were 17.82 and 24.77% lower than that of the control treatment, respectively. Mitophagy inhibition also significantly decreased the mycelium weight (P < 0.05). Conidial yield was found to be affected by factors related to autophagy occurrence. It was found that both autophagy inhibition and activation could reduce the conidiation of F. graminearum. The toxin contents in wheat medium of macroautophagy activation treatments were 0.678, 0.190, 0.402, and 0.195 µg/g when cultured for 8 and 24 h under 0% N and 100% N conditions, respectively, which were significantly higher than those of the control treatments (P < 0.05). The infection length was measured to characterize the infectivity of F. graminearum, and we found that the length was short under macroautophagy activation conditions. However, mitophagy did not seem to affect the infectivity of F. graminearum. In summary, the above results indicate that macroautophagy and mitophagy inhibition could reduce the pathogenicity of F. graminearum, which may provide a new perspective for management of plant fungal diseases.

The association of functional polymorphisms in genes expressed in endothelial cells and smooth muscle cells with the myocardial infarction.

BACKGROUND: The association of platelet endothelial cell adhesion molecule 1 (PECAM1), hypoxia-inducible factor 1 subunit alpha (HIF1A), and KIAA1462 in myocardial infarction (MI) was investigated. The study included 401 Han Chinese MI patients and 409 controls. Three tag single-nucleotide polymorphisms (SNPs)-PECAM1 rs1867624, HIF1A rs2057482, and KIAA1462 rs3739998-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. A systematic review and meta-analysis of studies including 3314 cases and 2687 controls on the association of 5 HIF1A SNPs and the overall risk of MI or coronary artery disease (CAD) was performed. RESULTS: The rs1867624 variants were associated with high TG concentrations (p = 0.040) and the rs2057482 variants were associated with decreased HDL-C in MI patients compared with the control group (p = 0.003). Rs2057482 SNP interacted with age to influence TC levels. The SNP of rs3739998 interacted with sex and hypertension to modulate CRE and TG levels, respectively (p < 3.04E-5-0.002). No association between the three SNPs and susceptibility to MI was found (p > 0.05 for all). In the meta-analysis of HIF1A, the rs11549465 C > T and rs10873142 T > C polymorphisms, but not rs2057482, rs11549467, and rs41508050, were correlated with overall MI or CAD risk. CONCLUSIONS: Taken together, this study provides additional evidence that genetic variation of the PECAM1 rs1867624 and HIF1A rs2057482 can mediate lipid levels in MI patients.

Continuous Movement Mechanism of Oil Droplets Adhered on Surfaces with Different Wettability in the Flow Field.

In this aticle, the continuous movement patterns and characteristic parameters of oil droplets on surfaces with different wettability immersed in a laminar flow field were observed, and the change rules of the geometric parameters of oil droplets under different experimental conditions were obtained. Then, the factors influencing the continuous moving behaviors of the oil droplets were analyzed, and the continuous movement velocity of the oil droplets under different experimental conditions was demonstrated. On this basis, the change law of the continuous movement velocity of oil droplets with the flow velocity was discussed. In addition, the coupling effect of the oil drops' height, surface properties, and water flow velocity on the continuous movement of oil droplets was studied, and the critical conditions for the continuous movement were obtained. According to the critical conditions, the mathematical model which described the law of continuous motion of the oil droplets adhered on surfaces with different wettability in the laminar flow field was established. The quantitative relationships among the average continuous moving velocity of oil droplets, physical properties, geometric parameters, water flow velocity, and surface wettability were obtained, which defined the necessary conditions for the uniform and accelerated movement of oil droplets, providing an important basis for choices of suitable surface wettability and flow field conditions in practical engineering applications.

Migration and Adherence of Oil Droplets on Surfaces with Different Wettability in a Laminar Flow Field.

In this article, the rising trajectories of oil droplets near the substrates of small channels in the laminar flow field were observed using a high-speed camera. Chemical modifications were made on the surfaces of the brass sheets to change the surface properties, and the controllable regulation of the superoleophilic-superoleophobic wettability gradient was achieved. The adhesion behaviors of the oil droplets on surfaces with different wettabilities at different flow velocities were observed as well. According to the adhesion behaviors of oil droplets on surfaces with different wettabilities, a mathematical model was established to analyze water film thinning and the adherence of oil droplets on the wall in the laminar flow field. Then the quantitative relationships among the adhesion times tf of oil droplets on different wetting surfaces, oil and water properties, and surface wettability were acquired.

A Virtual Force Algorithm-Lévy-Embedded Grey Wolf Optimization Algorithm for Wireless Sensor Network Coverage Optimization.

The random placement of a large-scale sensor network in an outdoor environment often causes low coverage. In order to effectively improve the coverage of a wireless sensor network in the monitoring area, a coverage optimization algorithm for wireless sensor networks with a Virtual Force-Lévy-embedded Grey Wolf Optimization (VFLGWO) algorithm is proposed. The simulation results show that the VFLGWO algorithm has a better optimization effect on the coverage rate, uniformity, and average moving distance of sensor nodes than a wireless sensor network coverage optimization algorithm using Lévy-embedded Grey Wolf Optimizer, Cuckoo Search algorithm, and Chaotic Particle Swarm Optimization. The VFLGWO algorithm has good adaptability with respect to changes of the number of sensor nodes and the size of the monitoring area.

Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway.

BACKGROUND/AIMS: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erbα mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erbα expression in macrophages remains unclarified. METHODS: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erbα expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erbα agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5- diphenyltetrazolium bromide assay. RESULTS: Ang II suppressed Rev-erbα mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor γ (PPARγ). Consistent with Rev-erbα expression regulated by Ang II, the liver X receptor α (LXRα) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXRα significantly increased or decreased Rev-erbα expression regulated by Ang II, respectively. This suggests that LXRα is involved in the effect of Ang II on Rev-erbα expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II-induced MMP-9 protein expressions in two types of macrophages. CONCLUSION: Ang II downregulates Rev-erbα expression in THP-1 macrophages via the AT1R/LXRα pathway.

Polarization-insensitive 2 × 2 thermo-optic Mach-Zehnder switch on silicon.

A polarization-insensitive 2×2 thermo-optic Mach-Zehnder switch (MZS) on silicon is proposed and demonstrated experimentally by utilizing silicon-on-insulator (SOI) nanophotonic waveguides with a 340-nm-thick silicon core layer. The present MZS consists of two 2×2 3 dB multimode interference (MMI) couplers, which are designed to be polarization-insensitive by choosing the core width optimally. Meanwhile, the MZS arms are designed with square SOI nanophotonic waveguides with a cross section of 340 nm×340 nm in order to achieve polarization-insensitive phase shift. The fabricated silicon MZS has an excess loss of 1∼4 dB and an extinction ratio of >20 dB in the C-band (1530∼1565 nm) for both TM and TE polarizations.

Silicon-based hybrid demultiplexer for wavelength- and mode-division multiplexing.

A silicon-based hybrid demultiplexer for wavelength-division multiplexing (WDM) and mode-division multiplexing (MDM) is proposed and demonstrated by integrating an M-channel-mode demultiplexer and N-channel WDM filters based on microring resonators (MRRs) with box-like responses. For the mode demultiplexer, the 2k-th output port is connected with the (2k+1)-th output port through the bus waveguide for the k-th MRR array, so that each MRR-based optical filter works bi-directionally and provides two drop ports. As an example, a 32-channel hybrid MDM-WDM demultiplexer is realized by integrating a 4-channel mode demultiplexer based on dual-core adiabatic tapers and two bi-directional MRR-based WDM filters with eight wavelength-channels. For the fabricated hybrid demultiplexer, the excess loss is 0.5-5 dB, the intermode cross talk is -16.5 to -23.5 dB, and the cross talks between the adjacent and nonadjacent wavelength channels are about -25 dB and -35 dB, respectively.

Investigation of glyphosate resistance levels and target-site based resistance (TSR) mechanisms in Conyza canadensis (L.) from apple orchards around areas of Bohai seas and Loess Plateau in China.

The resistance levels to glyphosate and target-site based resistance mechanisms in susceptible (S) and resistant (R) Conyza canadensis (L.) populations, which were collected from apple orchards around areas of Bohai seas and Loess Plateau in China, were investigated. Among forty C. canadensis populations, eighteen populations (45%) were still susceptible; fourteen populations (35%) evolved low resistance levels resistance to glyphosate with resistance index (RI) of 2.02 to 3.90. In contrast, eight populations (20%) evolved medium resistance levels with RI of 4.35 to 8.38. The shikimic acid concentrations in R populations were highly negative relative with the glyphosate resistance levels in C. canadensis, the Pearson correlation coefficient was -0.82 treated by glyphosate at 1.8mg/L. Three 5-enoylpyruvylshikimate 3'-phosphate synthase genes (EPSPS1, EPSPS2 and EPSPS3) were cloned in all S and glyphosate-resistant C. canadensis populations. No amino acid substitution was identified at site of 102 and 106 in three EPSPS genes, which were reported to confer glyphosate resistance in other weed species. The relative expression level of EPSPS mRNA in R populations (SD07, LN05, SHX06 and SD09) was 4.5 to 13.2 times higher than in S biotype. The Pearson correlation coefficient between EPSPS expression levels and RI was 0.79, which indicated the over expression of EPSPS mRNA may cause these R populations evolve higher resistance level to glyphosate.

A class-A GPCR solubilized under high hydrostatic pressure retains its ligand binding ability.

The effect of high hydrostatic pressure (HHP) on the solubilization of a class-A G protein-coupled receptor, the silkmoth pheromone biosynthesis-activating neuropeptide receptor (PBANR), was investigated. PBANR was expressed in expresSF+ insect cells as a C-terminal fusion protein with EGFP. The membrane fraction was subjected to HHP treatment (200MPa) at room temperature for 1-16h in the presence of 0-2.0% (w/v) n-dodecyl-ß-D-maltopyranoside (DDM). The solubilization yield of PBANR-EGFP in the presence of 0.6% (w/v) DDM increased to ~1.5-fold after 1h HHP treatment. Fluorescence-detection size-exclusion chromatography demonstrated that the PBANR-EGFP ligand binding ability was retained after HHP-mediated solubilization. The PBANR-EGFP solubilized with 1.0% DDM under HHP at room temperature for 6h retained ligand binding ability, whereas solubilization in the absence of HHP treatment resulted in denaturation.

On-chip reconfigurable optical add-drop multiplexer for hybrid wavelength/mode-division-multiplexing systems.

A silicon-based on-chip reconfigurable optical add-drop multiplexer (ROADM) is presented for hybrid wavelength-division-multiplexing-mode-division-multiplexing systems. The present ROADM consists of a four-channel mode demultiplexer, four wavelength-selective thermo-optic switches based on microring resonators, and a four-channel mode multiplexer. With the present ROADM, one can add/drop one of wavelength channels of any mode to/from the multimode bus waveguide successfully with an excess loss of 2-5 dB and an extinction ratio of ∼20 dB over a wavelength range of 1525-1555 nm.

Monolithically integrated reconfigurable add-drop multiplexer for mode-division-multiplexing systems.

An integrated reconfigurable optical add-drop multiplexer (ROADM) for mode-division-multiplexing systems is proposed and demonstrated for the first time, to the best of our knowledge. The present ROADM with four mode-channels is composed of a four-channel mode demultiplexer, four identical 2×2 thermo-optic Mach-Zehnder switches (MZSs), and a four-channel mode multiplexer, which are integrated monolithically on silicon. All the devices are designed for operation with TM polarization. The ROADM can add/drop any one of the mode channels freely by thermally turning on/off the corresponding MZS. For the added/dropped mode-channels, the excess loss is 1-5 dB, and the extinction ratio is 15-20 dB in the wavelength range of 1535-1565 nm.

Experimental demonstration of simultaneous mode and polarization-division multiplexing based on silicon densely packed waveguide array.

A silicon mode and polarization-division multiplexing scheme based on a densely packed waveguide array structured as a bus waveguide is introduced. A short adiabatic taper is adopted for (de)multiplexing. Such a structure shows theoretical insertion losses that are <0.05 dB and crosstalk that is <-20 dB over a wide wavelength band for all five supported modes. The structures for (de)multiplexing are fabricated and characterized experimentally. A device, which consists of a multiplexer, a 50-µm-long straight-bus waveguide, and a demultiplexer, exhibits insertion losses that are <0.6 dB and crosstalk that is <-15 dB over an 80 nm wavelength band. The demonstrated (de)multiplexer has a total length of 60 µm, and the bus waveguide has an effective width of 1.58 µm.

A novel mode of ferric ion coordination by the periplasmic ferric ion-binding subunit FbpA of an ABC-type iron transporter from Thermus thermophilus HB8.

Crystal structures of FbpA, the periplasmic ferric ion-binding protein of an iron-uptake ABC transporter, from Thermus thermophilus HB8 (TtFbpA) have been solved in apo and ferric ion-bound forms at 1.8 and 1.7 Šresolution, respectively. The latter crystal structure shows that the bound ferric ion forms a novel six-coordinated complex with three tyrosine side chains, two bicarbonates and a water molecule in the metal-binding site. The results of gel-filtration chromatography and dynamic light scattering show that TtFbpA exists as a monomer in solution regardless of ferric ion binding and that TtFbpA adopts a more compact conformation in the ferric ion-bound state than in the apo state in solution.