Design, synthesis and biological evaluation of novel 3C-like protease inhibitors as lead compounds against SARS-CoV-2.

Background: The epidemic caused by SARS-CoV-2 swept the world in 2019. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in viral replication, and its inhibition could inhibit viral replication. Materials & methods: The virtual screen based on receptor-ligand pharmacophore models and molecular docking were conducted to obtain the novel scaffolds of the 3CLpro. The molecular dynamics simulation was also carried out. All compounds were synthesized and evaluated in biochemical assays. Results: The compound C2 could inhibit 3CLpro with a 72% inhibitory rate at 10 µM. The covalent docking showed that C2 could form a covalent bond with the Cys145 in 3CLpro. Conclusion: C2 could be a potent lead compound of 3CLpro inhibitors against SARS-CoV-2.

Research on the tilt-to-length coupling noise suppression method inside the gravitational wave detection telescope.

As an integral component of the laser interferometry measurement system, the tilt-to-length (TTL) coupling noise inside the telescope stands out as a critical noise factor that requires meticulous consideration. In the TianQin project, the non-geometric TTL-coupled noise inside the telescope should be less than 0.22 pm/Hz1/2. Additionally, the wavefront aberration RMS at the small pupil of the telescope needs to be better than 0.0065 λ. These requirements set for the telescope are exceptionally stringent. To address this challenge, this study aims to relax the wavefront aberration requirements by mitigating non-geometric TTL coupling noise, while ensuring the non-geometric TTL coupling noise remains below 0.22 pm/Hz1/2. By controlling the coupling aberration proportion, the wavefront aberration RMS at the small pupil of the telescope can be relaxed to 0.014 λ. Alternatively, optimizing the Gaussian beam waist radius can relax the wavefront aberration RMS to 0.016 λ. By simultaneously utilizing two optimization methods, the wavefront aberration at the small pupil of the telescope can be reduced to 0.033 λ, resulting in an impressive success rate of 91.15% in meeting the noise requirements.

Dynamic flyer in barrel imaging via high intensity short-pulse laser.

The thin flyer is a small-scale flying object, which is well known as the core functional element of the initiator. Understanding how flyers perform has been a long-standing issue in detonator science. However, it remains a significant challenge to explore how the flyer is formed and functions in the barrel of the initiator via tabletop devices. In this study, we present dynamic and unprecedented images of flyer in barrel via high intensity short-pulse laser. Advanced radiography, coupled with a high-intensity picosecond laser X-ray source, has enabled the provision of state-of-the-art radiographs in a single-shot experiment for observing micron-scale flyer formation in a hollow cylinder in nanoseconds. The flyer was clearly visible in the barrel and was accelerated and restricted differently from that without the barrel. This first implementation of a tabletop X-ray source provided a new approach for capturing dynamic photographs of small-scale flying objects, which were previously reported to be accessible only via an X-ray phase-contrast imaging system at the advanced photon source. These efforts have led to a significant improvement of radiographic capability and a greater understanding of the mechanisms of "burst" of exploding foil initiators for this application.

Five undescribed cyclopeptides from Cordyceps militaris.

Ustiloxins I-M (1-5), five undescribed cyclopeptides bearing a 15-membered macrocyclic skeleton, were isolated from Cordyceps militaris. The structures of 1 and 5 were identified by spectroscopic and crystallographic methods, whereas the structures of 2-4 were assigned by spectroscopic and computational approaches. Biological evaluation of all the compounds toward human triple-negative breast cancer cells revealed that compounds 4 and 5 are toxic with IC50 values of 64.29 µM and 28.89 µM, respectively.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

The integrate profiling of single-cell and spatial transcriptome RNA-seq reveals tumor heterogeneity, therapeutic targets, and prognostic subtypes in ccRCC.

Clear-cell renal cell carcinoma (ccRCC) is the most common type of RCC; however, the intratumoral heterogeneity in ccRCC remains unclear. We first identified markers and biological features of each cell cluster using bioinformatics analysis based on single-cell and spatial transcriptome RNA-sequencing data. We found that gene copy number loss on chromosome 3p and amplification on chromosome 5q were common features in ccRCC cells. Meanwhile, NNMT and HILPDA, which are associated with the response to hypoxia and metabolism, are potential therapeutic targets for ccRCC. In addition, CD8+ exhausted T cells (LAG3+ HAVCR2+), CD8+ proliferated T cells (STMN+), and M2-like macrophages (CD68+ CD163+ APOC1+), which are closely associated with immunosuppression, played vital roles in ccRCC occurrence and development. These results were further verified by whole exome sequencing, cell line and xenograft experiments, and immunofluorescence staining. Finally, we divide patients with ccRCC into three subtypes using unsupervised cluster analysis. and generated a classifier to reproduce these subtypes using the eXtreme Gradient Boosting algorithm. Our classifier can help clinicians evaluate prognosis and design personalized treatment strategies for ccRCC. In summary, our work provides a new perspective for understanding tumor heterogeneity and will aid in the design of antitumor therapeutic strategies for ccRCC.

Technology-supported behavior change interventions for reducing sodium intake in adults: a systematic review and meta-analysis.

The effects of technology-supported behavior change interventions for reducing sodium intake on health outcomes in adults are inconclusive. Effective intervention characteristics associated with sodium reduction have yet to be identified. A systematic review and meta-analysis were conducted, searching randomized controlled trials (RCTs) published between January 2000 and April 2023 across 5 databases (PROSPERO: CRD42022357905). Meta-analyses using random-effects models were performed on 24-h urinary sodium (24HUNa), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Subgroup analysis and meta-regression of 24HUNa were performed to identify effective intervention characteristics. Eighteen RCTs involving 3505 participants (51.5% female, mean age 51.6 years) were included. Technology-supported behavior change interventions for reducing sodium intake significantly reduced 24HUNa (mean difference [MD] -0.39 gm/24 h, 95% confidence interval [CI] -0.50 to -0.27; I2 = 24%), SBP (MD -2.67 mmHg, 95% CI -4.06 to -1.29; I2 = 40%), and DBP (MD -1.39 mmHg, 95% CI -2.31 to -0.48; I2 = 31%), compared to control conditions. Interventions delivered more frequently (≤weekly) were associated with a significantly larger effect size in 24HUNa reduction compared to less frequent interventions (>weekly). Other intervention characteristics, such as intervention delivery via instant messaging and participant-family dyad involvement, were associated with larger, albeit non-significant, effect sizes in 24HUNa reduction when compared to other subgroups. Technology-supported behavior change interventions aimed at reducing sodium intake were effective in reducing 24HUNa, SBP, and DBP at post-intervention. Effective intervention characteristics identified in this review should be considered to develop sodium intake reduction interventions and tested in future trials, particularly for its long-term effects.

Designer Lithium Reservoirs for Ultralong Life Lithium Batteries for Grid Storage.

The minimization of irreversible active lithium loss stands as a pivotal concern in rechargeable lithium batteries, particularly in the context of grid-storage applications, where achieving the utmost energy density over prolonged cycling is imperative to meet stringent demands, notably in terms of life cost. Departing from conventional methodologies advocating electrode prelithiation and/or electrolyte additives, a new paradigm is proposed here: the integration of a designer lithium reservoir (DLR) featuring lithium orthosilicate (Li4SiO4) and elemental sulfur. This approach concurrently addresses active lithium consumption through solid electrolyte interphase (SEI) formation and mitigates minor yet continuous parasitic reactions at the electrode/electrolyte interface during extended cycling. The remarkable synergy between the Li-ion conductive Li4SiO4 and the SEI-favorable elemental sulfur enables customizable compensation kinetics for active lithium loss throughout continuous cycling. The introduction of a minute quantity of DLR (3 wt% Li4SiO4@S) yields outstanding cycling stability in a prototype pouch cell (graphite||LiFePO4) with an ampere-hour-level capacity (≈2.3 Ah), demonstrating remarkable capacity retention (≈95%) even after 3000 cycles. This utilization of a DLR is poised to expedite the development of enduring lithium batteries for grid-storage applications and stimulate the design of practical, implantable rechargeable batteries based on related cell chemistries.

Immune-related long noncoding RNA zinc finger protein 710-AS1-201 promotes the metastasis and invasion of gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal system. ZNF710 is a transcription factor (TF), and zinc finger protein 710 (ZNF710)-AS1-201 is an immune-related long noncoding RNA (lncRNA) that is upregulated in GC cells. AIM: To assess the correlation between ZNF710-AS1-201 and immune microenvironment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells. METHODS: We obtained data from The Cancer Genome Atlas and Wujin Hospital. We assessed cell growth, migration, invasion, and programmed cell death using cell counting kit-8, EdU, scratch, Transwell, and flow cytometry assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify the potential downstream targets of ZNF710-AS1-201. RESULTS: In GC tissues with low ZNF710-AS1-201 expression, immunoassays detected significant infiltration of various antitumor immune cells, such as memory CD8 T cells and activated CD4 T cells. In the low-expression group, the half-maximal inhibitory concentrations (IC50s) of 5-fluorouracil, cisplatin, gemcitabine, and trametinib were lower, whereas the IC50s of dasatinib and vorinostat were higher. The malignant degree of GC was higher and the stage was later in the high-expression group. Additionally, patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates. In vitro, the overexpression of ZNF710-AS1-201 greatly enhanced growth, metastasis, and infiltration while suppressing cell death in HGC-27 cells. In contrast, the reduced expression of ZNF710-AS1-201 greatly hindered cell growth, enhanced apoptosis, and suppressed the metastasis and invasion of MKN-45 cells. The expression changes in ZNF710 were significant, but the corresponding changes in isocitrate dehydrogenase-2, Semaphorin 4B, ARHGAP10, RGMB, hsa-miR-93-5p, and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201, as determined by qRT-PCR. CONCLUSION: Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells. It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC. Nevertheless, it is still necessary to determine the specific targets of the ZNF710 TF.

Structurally diverse phthalides from fibrous roots of Ligusticum chuanxiong Hort. and their biological activities.

Falonolide A (1) and B (2), two novel polyyne hybrid phthalides resulting from unprecedented carbon skeleton polymerized by Z-ligustilide and falcarindiol, along with six new related phthalides (3-8), were isolated from Ligusticum chuanxiong Hort. Their structures were elucidated by spectroscopic analysis, computer-assisted structure elucidation (CASE) analysis, DP4+ probability analysis and electronic circular dichroism (ECD) calculations. A plausible biosynthetic pathway for 1-8 was proposed, and the production mechanism of 2 was revealed by density functional theory (DFT) method. Compounds 4 and 6 exhibited significant vasodilatory activity with EC50 of 8.00 ± 0.86 and 6.92 ± 1.02 µM, respectively. Compound 4 also displayed significant inhibitory effect of NO production with EC50 value of 8.82 ± 0.30 µM. Based on the established compounds library, structure-activity relationship analysis of phthalides was explored to provide insights into the drug development of vasodilators and anti-flammatory.

Optimized design of a gravitational wave telescope system based on pupil aberration.

The telescope is vital for accurate gravitational wave detection in the TianQin project. It must meet criteria like a geometric tilt-to-length (TTL) coupling noise c o e f f i c i e n t≤0.02√2n m/µr a d and wavefront R M S≤λ/30. Analyzing the pupil aberration's impact on geometric TTL noise, we devised an optimization method using the chief ray spot diagram's standard deviation. Implementing this in Zemax with a ZPL macro, we designed an optical system meeting TianQin's requirements. The system has a maximum geometric TTL noise coefficient of 0.0250 nm/µrad over the science FOV and a wavefront RMS of 0.0111λ, confirming the method's feasibility.

Analysis of alignment requirements for off-axis resonant cavity based on coupling efficiency.

The optical path length stability of the off-axis four-reflection telescope is one of the key technical indicators for the TianQin gravitational wave detection system. In the MHz observation band, the telescope must exhibit an optical path length stability of 0.4p m/H z 1/2. As a feasible solution, the optical path length stability measurement of the off-axis four-reflection telescope based on the Pound-Drever-Hall (PDH) technique imposes stringent requirements on the alignment of the off-axis resonant cavity (ORC). Taking the off-axis two-reflection prototype as the research object, we propose a Monte Carlo analysis-based method for ORC alignment precision analysis. By considering misalignment as an intermediate function, we establish a relationship between the coupling efficiency of the ORC and the wavefront aberration of the telescope. The research results show that by considering the combined effects of multiple misalignment couplings of the primary and secondary mirrors, when the detected telescope wavefront aberration is better than 0.068λ (λ=1064n m) with a probability of 98%, the ORC coupling efficiency can achieve greater than 40% with a probability of 97.13%, which can be used as the main reference indicator for system misalignment analysis. This method simplifies the alignment difficulty of the target under test and can provide alignment reference for subsequent resonant cavities with internal off-axis telescopes.

Photochromism and single-component white light emission from a metalloviologen complex based on 1,5-naphthyridine.

Metalloviologens, as emerging electron-transfer photochromic compounds, have shown intriguing properties such as radiochromism, photochromism and photoconductance. However, only a limited number of them have been reported so far. Exploration of new metalloviologens is strongly desired. Herein, we report a new solvothermally synthesized metalloviologen complex [CdCl2(ND)2]n (1, ND = 1,5-naphthalenes) that exhibits photochromic and intrinsic white light emission properties. Density functional theory calculation results reveal that the photochromism could be assigned to photoinduced electron transfer from chlorine atoms to ND molecules. The photoinduced charge-separated states are heat/air stable, attributed to the delocalization of ND and strong intermolecular π-π interactions. Besides, complex 1 consistently emits intrinsic white light when excited with 340-370 nm UV light, achieving high color rendering index (CRI) values (82.54-94.04). By adjusting the excitation wavelength, both "warm" and "cold" white light emission can be produced, making it suitable for the application of a white light emitting diode (WLED). Thus, this work demonstrates that the ND-based metalloviologen is not only helpful in producing photochromism, but also beneficial for creating white-light emission.

Discovery of Covalent Lead Compounds Targeting 3CL Protease with a Lateral Interactions Spiking Neural Network.

Covalent drugs exhibit advantages in that noncovalent drugs cannot match, and covalent docking is an important method for screening covalent lead compounds. However, it is difficult for covalent docking to screen covalent compounds on a large scale because covalent docking requires determination of the covalent reaction type of the compound. Here, we propose to use deep learning of a lateral interactions spiking neural network to construct a covalent lead compound screening model to quickly screen covalent lead compounds. We used the 3CL protease (3CL Pro) of SARS-CoV-2 as the screen target and constructed two classification models based on LISNN to predict the covalent binding and inhibitory activity of compounds. The two classification models were trained on the covalent complex data set targeting cysteine (Cys) and the compound inhibitory activity data set targeting 3CL Pro, respected, with good prediction accuracy (ACC > 0.9). We then screened the screening compound library with 6 covalent binding screening models and 12 inhibitory activity screening models. We tested the inhibitory activity of the 32 compounds, and the best compound inhibited SARS-CoV-2 3CL Pro with an IC50 value of 369.5 nM. Further assay implied that dithiothreitol can affect the inhibitory activity of the compound to 3CL Pro, indicating that the compound may covalently bind 3CL Pro. The selectivity test showed that the compound had good target selectivity to 3CL Pro over cathepsin L. These correlation assays can prove the rationality of the covalent lead compound screening model. Finally, covalent docking was performed to demonstrate the binding conformation of the compound with 3CL Pro. The source code can be obtained from the GitHub repository (https://github.com/guzh970630/Screen_Covalent_Compound_by_LISNN).

Isolation and target identification of anti-renal fibrosis compounds from Cordyceps militaris.

Four undescribed compounds including one aromatic glucoside derivative, cordyceglycoside A (1), one new isoleucine derivative inner salt, cordycepisosalt A (2), a rare four-membered lactam, cinerealactam B (3), and one sesquiterpene derivative, cordycepsetp A (4), together with six known compounds were isolated from Cordyceps militaris. The structures including absolute configurations of these new compounds, were unambiguously elucidated by spectroscopic data analysis and single crystal X-ray diffraction. Biological evaluation of compounds 1-4 showed that 3 displays anti-renal fibrotic activities in TGF-ß1 induced NRK-52e cells. Furthermore, DARTS coupled with LC-MS/MS analysis was used to identify candidate target proteins for 3. Subsequently, C1qbp knockdown using siRNA allowed us to validate the target protein of 3.

A Diffusive Artificial Synapse Based on Charged Metal Nanoparticles.

We show that a diffusive memristor with analogue switching characteristics can be achieved in a layer of gold nanoparticles (AuNPs) functionalized with charged self-assembled monolayers (deprotonated 11-mercaptoundecanoic acid). The nanoparticle core and the anchored stationary charges are jammed within the layer while the mobile counterions [N(CH3)4+] can respond to the electric field and spontaneously diffuse back to the initial positions upon removal of the field. This metal nanoparticle device is set-step free, energy consumption efficient, mechanically flexible, and analogous to bio-Ca2+ dynamics and has tunable conductance modulation capabilities at the counterion concentrations. The gradual resistive switching behavior enables us to implement several important synaptic functions such as potentiation/depression, spike voltage-dependent plasticity, spike duration-dependent plasticity, spike frequency-dependent plasticity, and paired-pulse facilitation. Finally, on the basis of the paired-pulse facilitation characteristics, the metal nanoparticle diffusive artificial synapse is used for edge extraction with exhibits excellent performance.

Proper doses of brassinolide enhance somatic embryogenesis in different competent Korean pine cell lines during embryogenic callus differentiation.

Somatic embryogenesis of Korean pine (Pinus koraiensis Sieb. Et Zucc.), an ecologically and econimically very important conifer species, was hindered by the gradually weakens and fast runaway of the embryogenicity and embryo competence of the embryogenic callus. Brassinolide (BL) has shown the enhancing capability of somatic embryo regeneration. For checking the function of BL in this issue, we applied different concentrations of BL to Korean pine callus materials exhibiting different embryogenic capacities and subsequently monitored the physiological alterations and hormone dynamics of the embryogenic callus. Our study revealed that calli with different embryogenic strengths responded differently to different concentrations of BL, but the effect after the addition of BL was very uniform. The addition of BL during the proliferation phase of embryogenic callus may help to stimulate the biological activity of callus during the proliferation process and improve the level of cell metabolism, which is accompanied by a reduction in storage substances. BL could reduce the level of endogenous auxin IAA in embryogenic callus and increase the level of abscisic acid to regulate cell division and differentiation. In addition, the MDA content in the callus was significantly decreased and the activity of antioxidant enzymes was significantly increased after the addition of BL. During the proliferation of embryogenic callus, BL was added to participate in the metabolism of phenylpropane in the cells and to increase the activity of phenylalanine ammonia-lyase and the content of lignin in the cells. We deduced that the proper doses of BL for Korean pine embryogenic callus culture were as follow: calli with low, high and decreasing embryogenicity were subcultured after the addition of 0.75 mg/L, 0.35 mg/L, 2.00 mg/L BL, respectively, during proliferation culture stage.

Elemental partitioning-mediated crystalline-to-amorphous phase transformation under quasi-static deformation.

The transformation induced plasticity phenomenon occurs when one phase transforms to another one during plastic deformation, which is usually diffusionless. Here we present elemental partitioning-mediated crystalline-to-amorphous phase transformation during quasi-static plastic deformation, in an alloy in form of a Cr-Ni-Co (crystalline)/Zr-Ti-Nb-Hf-Ni-Co (amorphous) nanolaminated composite, where the constitute elements of the two phases have large negative mixing enthalpy. Upon plastic deformation, atomic intermixing occurs between adjacent amorphous and crystalline phases due to extensive rearrangement of atoms at the interfaces. The large negative mixing enthalpy among the constituent elements promotes amorphous phase transformation of the original crystalline phase, which shows different composition and short-range-order structure compared with the other amorphous phase. The reduced size of the crystalline phase shortens mean-free-path of dislocations, facilitating strain hardening. The enthalpy-guided alloy design based on crystalline-to-amorphous phase transformation opens up an avenue for the development of crystal-glass composite alloys with ultrahigh strength and large plasticity.

Study on the Physical and Rheological Characterisation of Low-Density Polyethylene (LDPE)/Recycled Crumb Rubber (RCR) on Asphalt Binders.

Recycled crumb rubber (RCR) is considered a reliable asphalt modifier and a solution to the problem of scrap tyre recycling. RCR-modified asphalt (RCRMA) typically has good low-temperature performance and storage stability. However, the pre-treatment of crumb rubber (CR) impairs its physical properties, resulting in poor high-temperature performance, which limits the industrial application of RCRMA. In this study, low-density polyethylene (LDPE) composite RCR was used to modify asphalt, and LDPE/RCR-composite-modified asphalt (L-RCRMA) was produced to compensate for the deficiencies in the high-temperature performance of RCRMA. The comprehensive physical properties of L-RCRMA were elucidated using tests such as the conventional properties, rotational viscosity, and rheological tests. The results showed that the incorporation of LDPE improved the high-temperature stability and rutting resistance of the asphalt, but an excessive amount of LDPE impaired the low-temperature performance and storage stability of L-RCRMA. Therefore, it is necessary to control the amount of LDPE to balance the performance of the asphalt. On this basis, we recommend a dosage of 20% for RCR and 1.5% for LDPE.

Mantidisflavin A: A Riboflavin Derivative Featuring a 6/6/6/5/5 Skeleton from the Egg Cases of the Insect Tenodera sinensis Saussure and Its Anti-Renal Fibrosis Activity.

Mantidisflavin A (1) was isolated from the egg cases of the Tenodera sinensis Saussure. It exhibits an unprecedented 6/6/6/5/5 skeleton, accompanied by the formation of two additional fused heterocycles through a novel C-C bond and an oxygen bridge on riboflavin backbone. The structure of 1 was identified by spectroscopic and computational methods. To assess the inhibitory effect against renal fibrosis, compound 1 was evaluated in TGF-ß1-induced rat kidney epithelial cells, and the results were compared to those of its precursor, riboflavin.