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1.
Sci Rep ; 14(1): 12605, 2024 06 01.
Article in English | MEDLINE | ID: mdl-38824246

ABSTRACT

The diagnostic value of contrast-enhanced ultrasound combined with ultrasound elastography for benign and malignant thyroid nodules is still controversial, so we used meta-analysis to seek controversial answers. The PubMed, OVID, and CNKI databases were searched according to the inclusion and exclusion criteria. The literature was selected from the establishment of each database to February 2024. The QUADAS-2 tool assessed diagnostic test accuracy. SROC curves and Spearman's correlation coefficient were made by Review Manager 5.4 software to assess the presence of threshold effects in the literature. Meta-Disc1.4 software was used for Cochrane-Q and χ2 tests, which be used to evaluate heterogeneity, with P-values and I2 indicating heterogeneity levels. The appropriate effect model was selected based on the results of the heterogeneity test. Stata18.0 software was used to evaluate publication bias. The diagnostic accuracy of contrast-enhanced ultrasound combined with ultrasound elastography for benign and malignant thyroid nodules was evaluated by calculating the combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, DOR, and area under the SROC curve. A total of 31 studies included 3811 patients with 4718 nodules were analyzed. There is no heterogeneity caused by the threshold effect, but there is significant non-threshold heterogeneity. Combined diagnostic metrics were: sensitivity = 0.93, specificity = 0.91, DOR = 168.41, positive likelihood ratio = 10.60, and negative likelihood ratio = 0.07. The SROC curve area was 0.97. Contrast-enhanced ultrasound and elastography show high diagnostic accuracy for thyroid nodules, offering a solid foundation for early diagnosis and treatment.Trial registration. CRD42024509462.


Subject(s)
Contrast Media , Elasticity Imaging Techniques , Thyroid Nodule , Ultrasonography , Humans , Thyroid Nodule/diagnostic imaging , Thyroid Nodule/pathology , Elasticity Imaging Techniques/methods , Ultrasonography/methods , Diagnosis, Differential , Sensitivity and Specificity , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/pathology , Thyroid Neoplasms/diagnosis
2.
Molecules ; 29(10)2024 May 13.
Article in English | MEDLINE | ID: mdl-38792150

ABSTRACT

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.


Subject(s)
Complement Factor B , Molecular Structure , Complement Factor B/antagonists & inhibitors
3.
NanoImpact ; 34: 100512, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38768902

ABSTRACT

Titanium dioxide nanoparticles (TiO2 NPs) have been widely employed in various industry fields, which makes consumers concerned about their health impact. Our previous work displayed that TiO2 NPs participated in the mitigation of TNBS-induced colitis, but the mechanism is still unknown. This work aimed to explore the role of oxidative stress and NF-κB pathway in the effect of TiO2 NPs on TNBS-induced colitis. The results showed that TiO2 NPs administration reduced the DAI score of colitis mice after TNBS enema. TiO2 NPs did not alter oxidative stress status (GSH/GSSG), but repaired the gut dysbacteriosis and inhibited the canonical NF-κB pathway activation in TNBS-induced colitis mice, manifested as a decrease in pathogenic bacteria and an increase in beneficial bacteria, as well as down-regulation of toll-like receptors (TLRs), IKKα, IKKß, p65 and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and IFN-γ) in mRNA level, and the increased transcription of anti-inflammatory cytokines (IL-10, TGF-ß, and IL-12), along with the declined protein level of TNF-α in TiO2 NPs treated colitis mice. The present study suggested that oral TiO2 NPs administration inhibited the canonical NF-κB pathway activation by repairing gut dysbacteriosis, which made a predominant role in alleviating colitis. These findings provided a new perspective for exploring the safety of TiO2 NPs.


Subject(s)
Colitis , NF-kappa B , Signal Transduction , Titanium , Trinitrobenzenesulfonic Acid , Titanium/pharmacology , Animals , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Mice , NF-kappa B/metabolism , Signal Transduction/drug effects , Metal Nanoparticles , Male , Oxidative Stress/drug effects , Cytokines/metabolism , Nanoparticles
4.
Mater Horiz ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38748488

ABSTRACT

The emergence of flexible fabric-based pneumatic actuators (FPAs) with pre-programmable motion capabilities, enhanced security and versatile interaction features significantly advances the construction of sophisticated soft robotic systems, owing to their enhanced security and versatile interaction features. Despite these promising attributes, the commercial viability of FPA products faces a considerable amount of challenges, primarily stemming from the scarcity of highly deformable fabric structures and the availability of industrial fabrication approaches. Taking inspiration from the anisotropic nature of lobster antennae, we propose a scalable and economical strategy to fabricate functional FPAs using nonwoven fabric material with superior mechanical anisotropy. This innovative method involves the adoption of tunable inelastic constrained wires sewn onto extensible nonwoven fabrics with regular wrinkles. This nonwoven fabric-based pneumatic actuator (NFPA) demonstrates specific motion profiles with curvature of over 0.6 cm-1 and output forces of over 140 cN under adjustable pressure conditions. Guided by the constrained wire combinations, NFPA enables diverse programmable motions like spiraling, assistance, and grasping. Furthermore, NFPA incorporated with specific sensors exhibits significant potential in wearable devices with real-time environmental detection for rehabilitation applications. Our work contributes a distinctive insight into the design of programmable NFPAs and enlightens an arena toward versatile soft robotic applications.

5.
Hepatol Int ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38740699

ABSTRACT

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

6.
Molecules ; 29(10)2024 May 08.
Article in English | MEDLINE | ID: mdl-38792047

ABSTRACT

Compound 7-16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT2A receptor antagonist and inverse agonist for treating Parkinson's disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7-16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7-16/[14C]7-16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7-16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7-16 was at least 74.7%. 7-16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7-16 deserves further development as a new treatment drug for PDP.


Subject(s)
Microsomes, Liver , Parkinson Disease , Humans , Animals , Rats , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Microsomes, Liver/metabolism , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Male , Serotonin 5-HT2 Receptor Agonists/pharmacology
7.
Molecules ; 29(10)2024 May 19.
Article in English | MEDLINE | ID: mdl-38792257

ABSTRACT

Glioblastoma multiforme, a highly aggressive and lethal brain tumor, is a substantial clinical challenge and a focus of increasing concern globally. Hematological toxicity and drug resistance of first-line drugs underscore the necessity for new anti-glioma drug development. Here, 43 anthracenyl skeleton compounds as p53 activator XI-011 analogs were designed, synthesized, and evaluated for their cytotoxic effects. Five compounds (13d, 13e, 14a, 14b, and 14n) exhibited good anti-glioma activity against U87 cells, with IC50 values lower than 2 µM. Notably, 13e showed the best anti-glioma activity, with an IC50 value up to 0.53 µM, providing a promising lead compound for new anti-glioma drug development. Mechanistic analyses showed that 13e suppressed the MDM4 protein expression, upregulated the p53 protein level, and induced cell cycle arrest at G2/M phase and apoptosis based on Western blot and flow cytometry assays.


Subject(s)
Antineoplastic Agents , Apoptosis , Glioblastoma , Tumor Suppressor Protein p53 , Humans , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Tumor Suppressor Protein p53/metabolism , Cell Line, Tumor , Apoptosis/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Anthracenes/pharmacology , Cell Proliferation/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Proto-Oncogene Proteins/metabolism , Cell Cycle Proteins/metabolism
8.
IEEE Trans Haptics ; PP2024 May 27.
Article in English | MEDLINE | ID: mdl-38801696

ABSTRACT

The objective of this study was to investigate the influence of roughened surface features on the perceived hardness of various materials. Thirteen participants used a visual analog scale to evaluate the hardness of ten 3D-printed specimens by sliding a fingertip on them. The specimens had two types of surface features: flat and smooth, or with microscopic rectangular gratings. They were fabricated from two types of plastic with different Young's moduli-2.46 and 9.35 MPa. We found that both surface pattern and mechanical hardness significantly contributed to the perceived hardness of a material individually and without interaction. The roughened surfaces with rectangular gratings were judged to be harder than the flat and smooth surfaces of the same material. Among the parameters of the rectangular gratings, the groove width or periodic surface wavelength significantly contributed to the perceived hardness. Although the root cause of this phenomenon is unknown, friction caused by surface roughness is considered a potential mediator that influences the perceived hardness. The findings of this study can facilitate the manipulation of softness perception through surface design.

9.
Biochem Pharmacol ; 225: 116310, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38788960

ABSTRACT

Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a damage response signal transduction sensor, and its therapeutic potential in tumor cells needs to be precisely investigated. Herein, we identified a new axis that could be targeted by ATR inhibitors to decrease the DNA-dependent protein kinase catalytic subunit (DNAPKcs), downregulate the expression of the retinoblastoma (RB), and drive G1/S-phase transition. Four-way DNA Holliday junctions (FJs) assembled in this process could trigger S-phase arrest and induce lethal chromosome damage in RB-positive triple-negative breast cancer (TNBC) cells. Furthermore, these unrepaired junctions also exerted toxic effects to RB-deficient TNBC cells when the homologous recombination repair (HRR) was inhibited. This study proposes a precise strategy for treating TNBC by targeting the DDR and extends our understanding of ATR and HJ in tumor treatment.

10.
Nat Commun ; 15(1): 4631, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38821971

ABSTRACT

Although long-read sequencing enables the generation of complete genomes for unculturable microbes, its high cost limits the widespread adoption of long-read sequencing in large-scale metagenomic studies. An alternative method is to assemble short-reads with long-range connectivity, which can be a cost-effective way to generate high-quality microbial genomes. Here, we develop Pangaea, a bioinformatic approach designed to enhance metagenome assembly using short-reads with long-range connectivity. Pangaea leverages connectivity derived from physical barcodes of linked-reads or virtual barcodes by aligning short-reads to long-reads. Pangaea utilizes a deep learning-based read binning algorithm to assemble co-barcoded reads exhibiting similar sequence contexts and abundances, thereby improving the assembly of high- and medium-abundance microbial genomes. Pangaea also leverages a multi-thresholding algorithm strategy to refine assembly for low-abundance microbes. We benchmark Pangaea on linked-reads and a combination of short- and long-reads from simulation data, mock communities and human gut metagenomes. Pangaea achieves significantly higher contig continuity as well as more near-complete metagenome-assembled genomes (NCMAGs) than the existing assemblers. Pangaea also generates three complete and circular NCMAGs on the human gut microbiomes.


Subject(s)
Algorithms , Gastrointestinal Microbiome , Genome, Microbial , Metagenome , Metagenomics , Humans , Metagenome/genetics , Metagenomics/methods , Gastrointestinal Microbiome/genetics , High-Throughput Nucleotide Sequencing/methods , Deep Learning , Computational Biology/methods , Sequence Analysis, DNA/methods , Genome, Bacterial
11.
Eur J Radiol ; 176: 111512, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38788609

ABSTRACT

OBJECTIVE: To evaluate the effectiveness of a decision tree that integrates conventional ultrasound (CUS) with two different strain imaging (SI) techniques for diagnosing breast lesions, and to analyze the factors contributing to false negative (FN) and false positive (FP) in the decision tree's outcomes. MATERIALS AND METHODS: Imaging and clinical data of 796 cases in the training set and 351 cases in the validation set were prospectively collected. A decision tree model that combines two types of SI and CUS was constructed, and its diagnostic performance was analyzed. Univariate analysis and multivariate analysis were applied to identify independent risk factors associated with FP and FN results of the decision tree model. RESULTS: Size, shape, margin, vascularity, the types of internal calcifications, EI score and VTI pattern were found to be significantly independently associated with the diagnosis of benign and malignant breast lesions. Therefore, size, shape, margin, vascularity, EI score and VTI pattern were used to construct decision tree models. The Tree (EI+VTI) model had the highest AUC. Both in the training and validation groups, the AUC of Tree (EI+VTI) was significantly higher compared with that of EI, VTI, and BI-RADS (all, P < 0.05). Orientation, posterior acoustic features and the types of internal calcifications were significantly positively associated with misdiagnosis results of Tree (EI+VTI) in evaluation of breast lesions (all P < 0.05). CONCLUSION: The diagnostic model based on a decision tree that integrates two distinct types of SI with CUS enhances the diagnostic accuracy of each method when used individually. This integration lowers the misdiagnosis rate, potentially assisting radiologists in more effective lesion assessments. When applying the decision tree model, attention should be paid to the orientation, posterior acoustic features, and the types of internal calcifications of the lesions.

12.
Cell Mol Life Sci ; 81(1): 226, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38775844

ABSTRACT

Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.


Subject(s)
Cell Proliferation , Cholestanetriol 26-Monooxygenase , Cholesterol , Hydroxycholesterols , Melanoma , Neoplastic Stem Cells , Vemurafenib , Vemurafenib/pharmacology , Vemurafenib/therapeutic use , Humans , Melanoma/drug therapy , Melanoma/pathology , Melanoma/metabolism , Melanoma/genetics , Hydroxycholesterols/metabolism , Hydroxycholesterols/pharmacology , Animals , Cell Proliferation/drug effects , Cholestanetriol 26-Monooxygenase/metabolism , Cholestanetriol 26-Monooxygenase/genetics , Cholesterol/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Cell Line, Tumor , Mice , Drug Resistance, Neoplasm/drug effects , Signal Transduction/drug effects , Cell Movement/drug effects , Xenograft Model Antitumor Assays
13.
Front Robot AI ; 11: 1383732, 2024.
Article in English | MEDLINE | ID: mdl-38774468

ABSTRACT

In traditional cardiac ultrasound diagnostics, the process of planning scanning paths and adjusting the ultrasound window relies solely on the experience and intuition of the physician, a method that not only affects the efficiency and quality of cardiac imaging but also increases the workload for physicians. To overcome these challenges, this study introduces a robotic system designed for autonomous cardiac ultrasound scanning, with the goal of advancing both the degree of automation and the quality of imaging in cardiac ultrasound examinations. The system achieves autonomous functionality through two key stages: initially, in the autonomous path planning stage, it utilizes a camera posture adjustment method based on the human body's central region and its planar normal vectors to achieve automatic adjustment of the camera's positioning angle; precise segmentation of the human body point cloud is accomplished through efficient point cloud processing techniques, and precise localization of the region of interest (ROI) based on keypoints of the human body. Furthermore, by applying isometric path slicing and B-spline curve fitting techniques, it independently plans the scanning path and the initial position of the probe. Subsequently, in the autonomous scanning stage, an innovative servo control strategy based on cardiac image edge correction is introduced to optimize the quality of the cardiac ultrasound window, integrating position compensation through admittance control to enhance the stability of autonomous cardiac ultrasound imaging, thereby obtaining a detailed view of the heart's structure and function. A series of experimental validations on human and cardiac models have assessed the system's effectiveness and precision in the correction of camera pose, planning of scanning paths, and control of cardiac ultrasound imaging quality, demonstrating its significant potential for clinical ultrasound scanning applications.

14.
Cancer Gene Ther ; 2024 May 22.
Article in English | MEDLINE | ID: mdl-38778089

ABSTRACT

Circular RNAs (circRNAs) represent a class of covalently closed, single-stranded RNAs and have been linked to cancer progression. N6-methyladenosine (m6A) methylation is a ubiquitous RNA modification in cancer cells. Increasing evidence suggests that m6A can mediate the effects of circRNAs in cancer biology. In contrast, the post-transcriptional systems of m6A and circRNA in the progression of endometrial cancer (EC) remain obscure. The current study identified a novel circRNA with m6A modification, hsa_circ_0084582 (circCHD7), which was upregulated in EC tissues. Functionally, circCHD7 was found to promote the proliferation of EC cells. Mechanistically, circCHD7 interacted with insulin-like growth factor 2 mRNA-binding protein (IGF2BP2) to amplify its enrichment. Moreover, circCHD7 increased the mRNA stability of platelet-derived growth factor receptor beta (PDGFRB) in an m6A-dependent manner, thereby enhancing its expression. In addition, the circCHD7/IGF2BP2/PDGFRB axis activated the JAK/STAT signaling pathway and promoted EC cell proliferation. In conclusion, these findings provide new insights into the regulation of circRNA-mediated m6A modification, and the new "circCHD7-PDGFRB" model of regulation offers new perspectives on circCHD7 as a potential target for EC therapy.

15.
Eur J Med Chem ; 272: 116466, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38704938

ABSTRACT

P-glycoprotein (Pgp) modulators are promising agents for overcoming multidrug resistance (MDR) in cancer chemotherapy. In this study, via structural optimization of our lead compound S54 (nonsubstrate allosteric inhibitor of Pgp), 29 novel pyxinol amide derivatives bearing an aliphatic heterocycle were designed, synthesized, and screened for MDR reversal activity in KBV cells. Unlike S54, these active derivatives were shown to transport substrates of Pgp. The most potent derivative 4c exhibited promising MDR reversal activity (IC50 of paclitaxel = 8.80 ± 0.56 nM, reversal fold = 211.8), which was slightly better than that of third-generation Pgp modulator tariquidar (IC50 of paclitaxel = 9.02 ± 0.35 nM, reversal fold = 206.6). Moreover, the cytotoxicity of this derivative was 8-fold lower than that of tariquidar in human normal HK-2 cells. Furthermore, 4c blocked the efflux function of Pgp and displayed high selectivity for Pgp but had no effect on its expression and distribution. Molecular docking revealed that 4c bound preferentially to the drug-binding domain of Pgp. Overall, 4c is a promising lead compound for developing Pgp modulators.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Amides , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Molecular Docking Simulation , Humans , Drug Resistance, Multiple/drug effects , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects
16.
J Am Chem Soc ; 146(20): 13797-13804, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38722223

ABSTRACT

Hydrides are promising candidates for achieving room-temperature superconductivity, but a formidable challenge remains in reducing the stabilization pressure below a megabar. In this study, we successfully synthesized a ternary lanthanum borohydride by introducing the nonmetallic element B into the La-H system, forming robust B-H covalent bonds that lower the pressure required to stabilize the superconducting phase. Electrical transport measurements confirm the presence of superconductivity with a critical temperature (Tc) of up to 106 K at 90 GPa, as evidenced by zero resistance and Tc shift under an external magnetic field. X-ray diffraction and transport measurements identify the superconducting compound as LaB2H8, a nonclathrate hydride, whose crystal structure remains stable at pressures as low as ∼ half megabar (59 GPa). Stabilizing superconductive stoichiometric LaB2H8 in a submegabar pressure regime marks a substantial advancement in the quest for high-Tc superconductivity in polynary hydrides, bringing us closer to the ambient pressure conditions.

17.
ACS Omega ; 9(12): 13704-13713, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38559999

ABSTRACT

The integration of low-dimensional nanomaterials with microscale architectures in flexible pressure sensors has garnered significant interest due to their outstanding performance in healthcare monitoring. However, achieving high sensitivity across different magnitudes of external pressure remains a critical challenge. Herein, we present a high-performance flexible pressure sensor crafted from biomimetic hibiscus flower microstructures coated with silver nanowires. When compared with a flat electrode, these microstructures as electrodes display significantly enhanced sensitivity and an extended stimulus-response range. Furthermore, we utilized an ionic gel film as the dielectric layer, resulting in an enhancement of the overall performance of the flexible pressure sensor through an increase in interfacial capacitance. Consequently, the capacitive pressure sensor exhibits an extraordinary ultrahigh sensitivity of 48.57 [Kpa]-1 within the pressure range of 0-1 Kpa, 15.24 [Kpa]-1 within the pressure range of 1-30 Kpa, and 3.74 [Kpa]-1 within the pressure range of 30-120 Kpa, accompanied by a rapid response time (<58 ms). The exceptional performance of our flexible pressure sensor serves as a foundation for its numerous applications in healthcare monitoring. Notably, the flexible pressure sensor excels not only in detecting subtle physiological signals such as finger and wrist pulse signals, vocal cord vibrations, and breathing intensity but also demonstrates excellent performance in monitoring higher pressures, such as plantar pressure. We foresee that this flexible pressure sensor possesses significant potential in the field of wearable electronics.

18.
J Am Chem Soc ; 146(15): 10753-10766, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38578841

ABSTRACT

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.


Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Proteolysis Targeting Chimera , Antineoplastic Agents/pharmacology , Sulfatases , Proteolysis , Peptides , Ubiquitin-Protein Ligases
19.
Front Neurol ; 15: 1367854, 2024.
Article in English | MEDLINE | ID: mdl-38606275

ABSTRACT

Stroke is the second leading cause of death worldwide, with ischemic stroke accounting for a significant proportion of morbidity and mortality among stroke patients. Ischemic stroke often causes disability and cognitive impairment in patients, which seriously affects the quality of life of patients. Therefore, how to predict the recovery of patients can provide support for clinical intervention in advance and improve the enthusiasm of patients for rehabilitation treatment. With the popularization of imaging technology, the diagnosis and treatment of ischemic stroke patients are often accompanied by a large number of imaging data. Through machine learning and Deep Learning, information from imaging data can be used more effectively. In this review, we discuss recent advances in neuroimaging, machine learning, and Deep Learning in the rehabilitation of ischemic stroke.

20.
Sensors (Basel) ; 24(7)2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38610521

ABSTRACT

Most lower limb rehabilitation robots are limited to specific training postures to adapt to stroke patients in multiple stages of recovery. In addition, there is a lack of attention to the switching functions of the training side, including left, right, and bilateral, which enables patients with hemiplegia to rehabilitate with a single device. This article presents an exoskeleton robot named the multistage hemiplegic lower-limb rehabilitation robot, which has been designed to do rehabilitation in multiple training postures and training sides. The mechanism consisting of the thigh, calf, and foot is introduced. Additionally, the design of the multi-mode limit of the hip, knee, and ankle joints supports delivering therapy in any posture and training sides to aid patients with hemiplegia in all stages of recovery. The gait trajectory is planned by extracting the gait motion trajectory model collected by the motion capture device. In addition, a control system for the training module based on adaptive iterative learning has been simulated, and its high-precision tracking performance has been verified. The gait trajectory experiment is carried out, and the results verify that the trajectory tracking performance of the robot has good performance.


Subject(s)
Hemiplegia , Robotics , Humans , Lower Extremity , Foot , Gait
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