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At present, amorphous glasses that can give blue light, green light, and yellow light emission upon ultraviolet excitation have achieved good commercial prospect, but lacking of the high-efficiency cyan luminescence is still a challenging problem. To fill the lack of cyan light emission in the current white light LED technology spectrum excited by ultraviolet light, the effect of the substitution of CaO for SrO and BaO, and that of SrO for BaO on the optical properties, structure, DSC, and CIE (Commission International de L'Eclairage) coordinates of Bi ions-doped borosilicate glasses were systematically studied in this work. The emission spectra results reveal that the emission position of Bi ions-doped borosilicated glasses is observed from 482 nm to 492 nm when CaO is gradually replaced by SrO, from 482 nm to 502 nm when CaO is gradually replaced by BaO. In one word, the luminescent peak position of the Bi ions-doped borosilicate glass can be easily tuned by altering the concentration of basicity-earth oxide modifier, and the cyan light emission can be finally achieved. • Cyan emission with center at 482–502 nm regions can be tuned in Bi ions doped borosilicate glasses modified by MO. • The excitation wavelength is well located in the near ultraviolet range. • The glass shows excellent stability evaluated by thermal temperature data. [ABSTRACT FROM AUTHOR]

Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC 50 values of 1.43 and 0.94 μM in NCI–H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8 , but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI–H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer. [Display omitted] • A potent and selective PROTAC degrader of NSD3 was designed, synthesized and evaluated. • Compound 8 decreased NSD3-associated genes and H3K36me3. • Compound 8 induced lung cancer cell growth arrest and apoptosis. • Compound 8 inhibited proliferation and clone formation in lung cancer cells. • A single dose of compound 8 effectively reduced NSD3 in xenograft tumor tissue in mice. [ABSTRACT FROM AUTHOR]

[Display omitted] The stability of methane hydrate depends on not only temperature and pressure but also the salinity of the environment where the methane hydrate exists. The variation in the stability of methane hydrate due to the change in salinity induces mechanical response in micro scale of the methane hydrate-bearing sediments (MHBS). However, it is really heard to quantitatively analyze this effect by controlling salinity of the MHBS in micro scale experiment. Therefore, our study applies Distinct Element Method to investigate the micro-scale mechanical response subject to the salinity variation. An existing contact model for cemented soils is extended to explicitly include the effects of salinity on bond strength and modulus, which are verified by experimental data. Using the proposed thermo-hydro-mechanical-chemical contact model, we conducted a series of case studies to investigate macroscopic and microscopic mechanical responses during three different stress paths, i.e. isotropic, triaxial and constant stress ratio tests. The results show that as the salinity increases, the shear strength and stiffness decrease while the deformation and bond breakage ratio accelerate. The results are valuable to develop constitutive models for MHBS and have safe exploitation of MH resources in the future. [ABSTRACT FROM AUTHOR]

• An on-machine noncontact scanning method for high-gradient surface is presented. • Segmented motion is designed considering steepness angle and planning deviations. • The chromatic confocal probe is integrated into the diamond turning machine. Inspecting a high-gradient freeform surface is a challenging task in manufacturing automation due to its complexity of the surface and high-aspect-ratio. On-machine measurement has shown remarkable achievements in ultra-precision manufacturing. In this paper, an on-machine noncontact scanning method using chromatic confocal probe for high-gradient freeform surface is proposed. First, a coordinate sampling model of scanning based on an ultra-precision diamond turning machine is established. Then, the steepness angle is defined to guide the scanning curves distribution, and global mesh scanning lines are generated by controlling planning deviations. Segmented motion trajectory of the probe is designed considering the vector direction of optical axis and sensor offset error. Finally, the scanning parameters are determined and the NC inspection program is generated. The proposed method can make a balance between accuracy and efficiency. Its effectiveness is verified by the on-machine inspection experiments. [ABSTRACT FROM AUTHOR]

• The welding current is the most important parameter for the features. • The regression model performs well and its maximum relative error is about 9%. • Five features were selected to express the shape of the dynamic resistance signal. In this paper, relevant twenty features were extracted from the dynamic resistance signal of the welding operation and subsequent mathematical models incorporating the qualifying features were developed to investigate the relationship among dynamic resistance, welding quality and welding parameters based on the stepwise regression method. The results of the analysis of variance indicated the peak point location t 1 , the initial resistance value r 0 , and the first slope k 1 had little correlation with welding process parameters. The welding current is the most significant factor affecting the dynamic resistance signal, followed by welding time and electrode pressure. The welding current has significant effects on all the extracted features, while the electrode pressure only affects seven features. The model utilizing the features of r mean , r e , r α , r β and r med was developed to predict the welding quality. r mean is the most significant factor in the model whose maximum relative error is less than 10%. [ABSTRACT FROM AUTHOR]

Cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) act as significant roles in many physiological processes, and their abnormal proliferation will cause multiple diseases including Alzheimer's disease, Parkinson's disease, Cardiovascular disease, atherosclerosis, and soft tissue damage. However, It is challenging work to develop a efficient method for differentiating and detecting GSH, Cys and Hcy because of their significant similarity in structures and functions. In this work, a smart fluorescent probe FBCN based on curcumin was rationally devised and developed by etherifying the phenol hydroxyl group on FBC with NBD-Cl, which emitted strong green at 516 nm. FBCN distinguished Hcy from Cys/GSH with naked eyes based on the color variation of probe solution in sunlight. Meanwhile, GSH induced the powerful fluorescence quenching of probe solution, but the fluorescence color of FBCN solution transformed from green to luminous yellow accompanied with emission wavelength redshifted from 516 nm to 540 nm or 553 nm in the existence of Hcy and Cys, respectively. Probe FBCN had outstanding sensitivity and anti-interference, low detection limit (56.5 nM, 77.7 nM, and 288 nM corresponded to Cys, Hcy, and GSH, respectively), short response time (the response time of FBCN to Cys, Hcy and GSH was 1 min, 2 min and 5 min, respectively). The DFT calculation and HRMS had verified the sensing mechanism of FBCN to biothiols. In addition, the probe was successfully utilized to detect three biothiols levels in living cell and zebrafish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanodrug delivery systems (NDDS) have been proposed to improve the targeting and bioavailability of chemotherapy drugs. The approach of drug loading via physical adsorption is facile to operate; however, there exists a risk of premature leakage. Coupling the drug molecules with the carrier through chemical reactions can guarantee the stability of the drug delivery process, yet the preparation procedure is relatively intricate. In this research, a kind of Prussian blue nanocage (PB Cage) was fabricated, and the phase change material, 1-pentadecanol, was used as the gating material to solidify 5-fluorouracil (5-FU) inside the nanocage. Upon irradiation with near-infrared (NIR) light, the temperature of the PB Cage can rise rapidly. When the temperature exceeds 43 °C, 1-pentadecanol undergoes a solid-liquid phase transition and subsequently releases 5-FU to inhibit DNA synthesis. Meanwhile, the photothermal therapy (PTT) mediated by the PB Cage is also capable of ablating tumor cells. The NDDS constructed based on PB has achieved the precise release of 5-FU triggered by NIR light, which may avoid side effects on normal tissues. Moreover, the combination of chemotherapy and photothermal therapy can efficaciously suppress the proliferation of tumor cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: Laparoscopic hepatectomy (LH) has become a common surgery for the treatment of liver tumor. To evaluate the surgical quality of laparoscopic hepatectomy under the context of precision surgery with Textbook outcome (TO), a comprehensive and holistic assessment approach., Methods: A total of 1056 patients who underwent laparoscopic hepatectomy from May 2016 and December 2022 were enrolled in the study. All the patients were performed hepatectomy. The rate of TO and factors associated with achieving TO were examined., Results: Among the 1056 patients, 75 % patients achieved TO. The main reason limited patients achieving textbook outcomes was prolonged length of hospital stay (LOS). The univariate analysis indicated that age>65, ASA classification ≥3, liver cirrhosis, tumor size > 3 cm, tumor number ≥2, type of primary cancer, and IWATE DSS were significantly associated with non-achievement of TO. The multivariate analysis indicated that the ASA classification ≥3 and advanced difficulty level in IWATE DSS independent factors associated with achieving TO. Reaching TO can significantly prolong the postoperative recurrence time and overall survival time of hepatocellular carcinoma patients., Conclusion: In the context of precision surgery, 75 % patients undergoing laparoscopic hepatectomy achieved a TO. Patients who achieved TO had significantly improved survival., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To achieve precise grasping and spreading of irregular sheet-like soft objects (such as leather) by robots, this study addresses several challenges, including the irregularity of leather edges and the ambiguity of feature recognition points. To tackle these issues, this paper proposes an innovative method that involves alternately grasping the lowest point twice and using planar techniques to effectively spread the leather. We improved the YOLOV8 algorithm by incorporating the BIFPN network structure and the WIOU loss function, and trained a dedicated dataset for the lowest grasping points and planar grasping points, thereby achieving high-precision recognition. Additionally, we determined the optimal posture for grasping the lowest point and constructed an experimental platform, successfully conducting multiple rounds of leather grasping and spreading experiments with a success rate of 72%. Through an in-depth analysis of the failed experiments, this study reveals the limitations of the current methods and provides valuable guidance for future research., (© 2024. The Author(s).)

The relatively poor mechanical properties of extruded modified double base (EMDB) propellants limit their range of applications. To overcome these drawbacks, a novel method was proposed to introduce glycidyl azide polymer-based energetic thermoplastic elastomers (GAP-ETPE) with bonding groups into the propellant adhesive. The influence of the molecular structure of three kinds of elastomers on the mechanical properties of the resultant propellant was analyzed. It was found that the mechanical properties of the propellant with 3% CBA-ETPE (a type of GAP-ETPE that features chain extensions using N-(2-Cyanoethyl) diethanolamine and 1,4-butanediol) were improved at both 50 °C and -40 °C compared to a control propellant without GAP-ETPE. The elongation and impact strength of the propellant at -40 °C were 7.49% and 6.58 MPa, respectively, while the impact strength and maximum tensile strength of the propellant at 50 °C reached 21.1 MPa and 1.19 MPa, respectively. In addition, all three types of GAP-ETPE improved the safety of EMDB propellants. The friction sensitivity of the propellant with 3% CBA-ETPE was found to be 0%, and its characteristic drop height H 50 was found to be 39.0 cm; 126% higher than the traditional EMDB propellant. These results provide guidance for studies aiming to optimize the performance of EMDB propellants.

Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the "3-RBD-up" conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses., (© 2024. The Author(s).)

Viscosity is a crucial indicator of the cellular microenvironment, which can affect the normal level of cellular metabolism. Aberrant levels of viscosity can result in the emergence of a variety of physiological problems including diabetes, Parkinson's disease, inflammation, etc . Therefore, it is crucial to exploit effective assays that can detect viscosity levels in living cells and organisms. Three new nitrogen-containing heterocyclic fluorescent probes, CNO, CNN and CNNB, were designed and prepared by coupling curcumin with isoxazole, pyrazole, and phenylpyrazole rings, respectively. The fluorescence response properties of these probes to the viscosity level were analyzed in parallel. All the probes, CNO, CNN and CNNB, exhibited a significantly enhanced fluorescence response to viscosity in a broad pH range with excellent photostability, sensitivity and anti-interference ability. The sensing mechanisms of these probes for viscosity were verified by DFT calculations. In addition, these probes were successfully employed for detecting viscosity levels in living HeLa cells and zebrafish. This research compares the viscosity-responsive capabilities of curcumin-based fluorescent probes containing different nitrogen-containing heterocyclic structures, and provides a new design strategy and guidance for developing curcumin-based fluorescent probes for viscosity analysis.

N 6 -methyladenosine (m 6 A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m 6 A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions., Competing Interests: Declaration of interests S.X., X.H., W.D., Y.H., and X.C. are named as inventors on a pending patent application (CN202210956384.9, submitted to the Chinese Patent Office) related to the work described., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hydrogen peroxide (H 2 O 2 ) is involved in many important tasks in normal cell metabolism and signaling. However, abnormal levels of H 2 O 2 are associated with the occurrence of several diseases. Therefore, it is important to develop a new method for the detection of H 2 O 2 in vivo and in vitro . A turn-off sensor, 2,2-difluoro-4,6-bis(3-methoxy-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)styryl)-2 H -1,3,2-dioxaborine (DFCB), based on curcumin was developed for the detection of H 2 O 2 . The DFCB, an orange-emitting sensor, was constructed by employing 2,2-difluoro-4,6-bis(4-hydroxy-3-methoxystyryl)-2 H -1,3,2-dioxaborine (DFC) as the main carrier, and 2-(4-bromomethylphenyl)-4,4,5,5-tetramethyl-1,3,2-doxaborolane as the recognition site. The recognition group on the DFCB sensor could be completely cleaved by H 2 O 2 to generate the intermediate DFC, which would lead to a colorimetric change from bright orange to light blue accompanying by a significantly quenched fluorescence, which could be seen by the naked eye. This sensor exhibited a highly specific fluorescence response to H 2 O 2 , in preference to other relevant species, with an excellent anti-interference performance. The sensor DFCB also possessed some advantages including a wide pH response range (6-11), a broad linear range (0-300 μM), and a low detection limit (1.31 μM). The sensing mechanism of the DFCB sensor for H 2 O 2 was verified by HRMS analysis, 1 H-NMR titration and DFT calculations. In addition, the use of the DFCB sensor was compatible with the fluorescence imaging of H 2 O 2 in living cells and zebrafish.

Smart hydrogels that can adsorb both anionic and cationic dyes and have excellent mechanical properties have not been reported yet, despite bright prospect in dye adsorption. The emergence of polyampholyte made it possible for the preparation of novel hydrogels. PMAD (copolymer of AM, AA and DMC) is a novel thermo-responsive hydrogel based on polyampholyte, whereas poor mechanical properties limit its application. Herein, we designed a novel polysaccharide crosslinker, which integrates chemical-crosslinking network and physical-entanglements to fabricate PMAD hydrogels. Chemical-crosslinking network maintains the shape of hydrogel as backbone, whereas physical-entanglements enhance the energy-dissipation capacity by disentangle upon deformation. Synergistic effect of the above structure improves the fracture strength and elongation of PMAD by nearly 4700% and 900%, respectively. Moreover, the hydrogel can be used as controllable adsorption material towards both cationic and anionic dyes, which could greatly increase adsorption capacity after reaching the critical temperature due to its unique temperature-sensitive characteristics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The understanding of mechanical behavior in magnesium aluminate spinel ( M g A l 2 O 4 ) at the nanoscale lays a foundation for its material removal mechanism in ultraprecision machining. Nanoindentation tests are carried out in the interior and boundary of spinel grain with different loads. An obvious indentation size effect exhibits in both of these areas. First, the nano-hardness and elastic modulus decrease, followed by stabilization due to an increase of pressure. The measured elastic modulus, hardness, and fracture toughness of the grain interior are 277.7±8.4 G P a , 19.79±0.83 G P a , and 1.12±0.02 M P a ⋅ m 1/2 , respectively. Deformation of spinel transits from elastic to plastic at approximately 0.8 mN load, which corresponds to the discontinuous steps of load-displacement curves. By comparing the fracture toughness and the residual indent morphology, the grain boundary exhibits lower brittleness than the grain interior. Radial cracks form on the grain surface as indentation load exceeds 29 mN, whose propagation is influenced by the loading conditions and the grain boundary effect.

Streptococcus pyogenes Cas9 (SpCas9) has become a powerful genome editing tool, but has a limited range of recognizable protospacer adjacent motifs (PAMs) and shows off-target effects. To address these issues, we present a rational approach to optimize the xCas9 mutant derived from SpCas9 by directed evolution. Firstly, energy minimization with the Rosetta program was applied to optimize the three-dimensional structure of Cas9 to obtain the lowest energy conformation. Subsequently, combinatorial mutations were designed based on the mutations sites of xCas9 acquired during the directed evolution. Finally, optimal mutants were selected from the designed mutants by free energy ranking and subjected to experimental verification. A new mutant yCas9 (262A/324R/409N/480K/543D/694L/1219T) with multiple PAM recognition ability and low off-target effects was obtained and verified by DNA cleavage experiments. This mutant recognizes the NG, GAA and GAT PAMs and shows low off-target DNA cleavage activity guided by mismatched sgRNA, thus provides a gene editing tool with potential applications in biomedical field. Furthermore, we performed molecular dynamics simulations on the structures of SpCas9, xCas9 and yCas9 to reveal the mechanisms of their PAM recognition and off-target effects. These may provide theoretical guidance for further optimization and modification of CRISPR/Cas9 proteins.

Effective treatment or vaccine is not yet available for combating SARS coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic. Recent studies showed that two drugs, Camostat and Nafamostat, might be repurposed to treat COVID-19 by inhibiting human TMPRSS2 required for proteolytic activation of viral spike (S) glycoprotein. However, their molecular mechanisms of pharmacological action remain unclear. Here, we perform molecular dynamics simulations to investigate their native binding sites on TMPRSS2. We revealed that both drugs could spontaneously and stably bind to the TMPRSS2 catalytic center, and thereby inhibit its proteolytic processing of the S protein. Also, we found that Nafamostat is more specific than Camostat for binding to the catalytic center, consistent with reported observation that Nafamostat blocks the SARS-CoV-2 infection at a lower concentration. Thus, this study provides mechanistic insights into the Camostat and Nafamostat inhibition of the SARS-CoV-2 infection, and offers useful information for COVID-19 drug development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

The CRISPR/Cas9 system, originally derived from the prokaryotic adaptive immune system, has been developed as efficient genome editing tools. It enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA, and the Cas9 protein, which has endonuclease activity, will cut a double strand break at specific locus. However, Cas9 is a foreign protein in mammalian cells, and the potential risks associated with its introduction into mammalian cells are not fully understood. In this study, we performed pull-down and mass spectrometry (MS) analysis of Streptococcus pyogenes Cas9 (SpyCas9) interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the nucleolus. Interestingly, we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal (NoDS). Compared with wild-type (WT) Cas9, NoDS-mutated variants of Cas9 (mCas9) are less stable, although their gene editing activity is minimally affected. Overexpression of WT Cas9, but not mCas9, causes general effects on transcription and protein translation in the host cell. Overall, identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo , and the removal of NoDS in Cas9 may enhance its safety for future clinical use., (© 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.)