OVAR-BPnet: A General Pulse Wave Deep Learning Approach for Cuffless Blood Pressure Measurement.

Pulse wave analysis, a non-invasive and cuffless approach, holds promise for blood pressure (BP) measurement in precision medicine. In recent years, pulse wave learning for BP estimation has undergone extensive scrutiny. However, prevailing methods still encounter challenges in grasping comprehensive features from pulse waves and generalizing these insights for precise BP estimation. In this study, we propose a general pulse wave deep learning (PWDL) approach for BP estimation, introducing the OVAR-BPnet model to powerfully capture intricate pulse wave features and showcasing its effectiveness on multiple types of pulse waves. The approach involves constructing population pulse waves and employing a model comprising an omni-scale convolution subnet, a Vision Transformer subnet, and a multilayer perceptron subnet. This design enables the learning of both single-period and multi-period waveform features from multiple subjects. Additionally, the approach employs a data augmentation strategy to enhance the morphological features of pulse waves and devise a label sequence regularization strategy to strengthen the intrinsic relationship of the subnets' output. Notably, this is the first study to validate the performance of the deep learning approach of BP estimation on three types of pulse waves: photoplethysmography, forehead imaging photoplethysmography, and radial artery pulse pressure waveform. Experiments show that the OVAR-BPnet model has achieved advanced levels in both evaluation indicators and international evaluation criteria, demonstrating its excellent competitiveness and generalizability. The PWDL approach has the potential for widespread application in convenient and continuous BP monitoring systems.

Risk of hepatocellular carcinoma occurrence after antiviral therapy for patients with chronic hepatitis C Infection: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The risk of hepatocellular carcinoma (HCC) occurrence following antiviral therapy in patients with chronic hepatitis C (CHC) remains unclear. The current study aims to compare: (1) the HCC occurrence rate following sustained virological response (SVR) versus non-response (NR); (2) the HCC occurrence rate following direct-acting antiviral (DAA) therapy versus interferon (IFN)-based therapy, and (3) the HCC occurrence rate in SVR patients with or without cirrhosis. METHODS: A search was performed for articles published between January 2017 and July 2022. Studies were included if they assessed HCC occurrence rate in CHC patients following anti-HCV therapy. Random effects meta-analysis was used to synthesize the results from individual studies. RESULTS: A total of 23 studies including 29,395 patients (IFN-based = 6, DAA = 17; prospective = 10, retrospective = 13) were included in the review. HCC occurrence was significantly lower in CHC with SVR (1.54 per 100 person-years (py, 95% CI 1.52, 1.57) than those in non-responders (7.80 py, 95% CI 7.61, 7.99). Stratified by HCV treatment regimens, HCC occurrence following SVR was 1.17 per 100 py (95% CI 1.11, 1.22) and 1.60 per 100 py (95% CI 1.58, 1.63) in IFN- and DAA treatment-based studies. HCC occurrence was 0.85 per 100 py (95% CI 0.85, 0.86) in the non-cirrhosis population and rose to 2.47 per 100 py (95% CI 2.42, 2.52) in the cirrhosis population. Further meta-regression analysis showed that treatment types were not associated with a higher HCC occurrence rate, while cirrhosis status was an important factor of HCC occurrence rate. CONCLUSION: HCC occurrence was significantly lower in the SVR population than in the NR population. HCC risk following SVR occurred three times more frequently in patients with cirrhosis than patients without cirrhosis. However, we found no significant difference in HCC occurrence risk following SVR between DAA and IFN therapies. CLINICAL TRIAL NUMBER: CRD42023473033.

Critically evaluated key points on hereditary medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).

Polydopamine bridging encapsulated laccase on MOF-based mixed-matrix membrane for selective dye/salt separation.

Mixed-matrix membranes (MMMs) exhibit significant potential for dye/salt separation. However, overcoming the "trade-off" between permeability and selectivity, as well as membrane fouling, remains a formidable task. In this work, a biocatalytic membrane was prepared using polydopamine (PDA) as a "bridge" connecting the metal-organic framework (MOF)-based MMM and immobilized laccase. The MOF-based MMM featured an interconnected MOF anchoring on the polyvinylidene fluoride (PVDF) skeleton structure, effectively mitigating the "trade-off" phenomenon and enabling efficient separation of dyes and salts. Enzyme-MOF was in situ grown on the MOF-based MMM via coordination reactions between PDA and metal ion, effectively degrading the adhesion of organic pollutants and fouling, ensuring the long-term stable operation of the membrane. The Lac-MOF@PDA MMM exhibited excellent water permeability of 142.4 L·m-2·h-1, 100 % rejection for dye, and less than 10 % rejection for NaCl. Furthermore, the separation mechanism of Lac-MOF@PDA MMM was systematically investigated, and the results suggested a synergistic combination of rejection, adsorption and catalysis processes. This biocatalytic membrane with multiple sieving and biological catalysis is expected to pave a promising way for efficient wastewater treatment applications.

A Soft Inductive Bimodal Sensor for Proprioception and Tactile Sensing of Soft Machines.

The somatosensory system is crucial for living beings to survive and thrive in complex environments and to interact with their surroundings. Similarly, rapidly developed soft robots need to be aware of their own posture and detect external stimuli. Bending and force sensing are key for soft machines to achieve embodied intelligence. Here, we present a soft inductive bimodal sensor (SIBS) that uses the strain modulation of magnetic permeability and the eddy-current effect for simultaneous bidirectional bending and force sensing with only two wires. The SIBS is made of a flexible planar coil, a porous ferrite film, and a soft conductive film. By measuring the inductance at two different frequencies, the bending angle and force can be obtained and decoupled. Rigorous experiments revealed that the SIBS can achieve high resolution (0.44° bending and 1.09 mN force), rapid response, excellent repeatability, and high durability. A soft crawling robot embedded with one SIBS can sense its own shape and interact with and respond to external stimuli. Moreover, the SIBS is demonstrated as a wearable human-machine interaction to control a crawling robot via wrist bending and touching. This highlights that the SIBS can be readily implemented in diverse applications for reliable bimodal sensing.

Bioinformatics Analysis and Experimental Verification Define Different Angiogenesis Subtypes in Endometrial Carcinoma and Identify a Prognostic Signature.

Increasing evidence indicates that peripheral blood vessels play a pivotal role in regulating tumor growth with the presence of new blood vessels facilitating tumor growth and metastasis. Nevertheless, the impact of specific molecule-mediated angiogenesis on the tumor immune microenvironment (TIME) and individual prognosis of uterine corpus endometrial carcinoma (UCEC) remains uncertain. The transcriptome information on 217 prognostic angiogenesis-related genes was integrated, and the angiogenesis patterns of 506 UCEC patients in The Cancer Genome Atlas (TCGA) cohort were comprehensively evaluated. We identified five angiogenic subtypes, namely, EC1, EC2, EC3, EC4, and EC5, which differed significantly in terms of prognosis, clinicopathological features, cancer hallmarks, genomic mutations, TIME patterns, and immunotherapy responses. Additionally, an angiogenesis-related prognostic risk score (APRS) was constructed to enable an individualized comprehensive evaluation. In multiple cohorts, APRS demonstrated a powerful predictive ability for the prognosis of UCEC patients. Likewise, APRS was confirmed to be associated with clinicopathological features, genomic mutations, cancer hallmarks, and TIME patterns in UCEC patients. The predictability of APRS for immune checkpoint inhibitor (ICI) therapy was also salient. Subsequently, the expression levels of four angiogenesis-related hub genes were verified by qRT-PCR, immunohistochemistry, and single-cell sequencing data analysis. The effects of four representative genes on angiogenesis were validated by Wound-Healing and Transwell assays, tube formation assay in vitro, and tumor xenograft model in vivo. This study proffered a new classification of UCEC patients based on angiogenesis. The established APRS may contribute to individualized prognosis prediction and immunotherapy selections that are better suited for UCEC patients.

Diagnostic value of combined ultrasound contrast and elastography for differentiating benign and malignant thyroid nodules: a meta-analysis.

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.

Balancing Act: Exploring the Gut Microbiota-Brown Adipose Tissue Axis in PCOS Pathogenesis and Therapeutic Frontiers.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive, endocrine, and metabolic disease that affects 5-18% of women worldwide, with a rising incidence. Hyperandrogenemia and insulin resistance are two key pathophysiological factors that contribute to PCOS, both of which contribute to a variety of health issues such as menstrual irregularities, obesity, dysfunctional glucose and lipid homeostasis, infertility, mental disorders, and cardiovascular and cerebrovascular diseases. Despite ongoing studies, the origin and pathogenesis of PCOS remain elusive; there is also a clinical need for simpler, more effective, longer lasting, and more comprehensive treatments for women with PCOS. The gut-fat axis, a critical regulatory route for metabolism, endocrine function, and immune response, has received considerable interest in recent years in the research of the etiology and treatment of metabolic illnesses such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. The latest research in PCOS has revealed significant alterations in the homogeneity and phylogenetic diversity of the gut microbiota. Animal research using fecal microbiota transplantation has confirmed the importance of gut microbiota in regulating insulin sensitivity and sex hormone balance in PCOS. Furthermore, studies have shown a decrease in the volume and/or activity of brown adipose tissue (BAT) in PCOS patients, a change that alters adipokine release, leading to insulin resistance and hyperandrogenemia, aggravating PCOS progression. Given the function of BAT in increasing energy expenditure and alleviating metabolic parameters, efforts to activate BAT or induce browning of white adipose tissue have emerged as possible treatments for PCOS. Recent research has suggested that the gut microbiota can influence BAT creation and activity via metabolites such as short-chain fatty acids and bile acids, as well as the gut-brain axis. Cold exposure, healthy dieting, metformin, bariatric surgery, glucagon-like peptide 1 receptor agonists and melatonin have all been shown in basic and clinical studies to modulate BAT activity by influencing the gut microbiota, demonstrating significant clinical potential. However, more studies into the regulation mechanisms of the gut-BAT axis are required to produce more effective, comfortable, and safe tailored therapeutics for PCOS.

Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein.

BACKGROUND: The adaptor protein apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD) can be activated through pyrin domain (PYD) interactions between sensors and ASC, and through CARD interactions between caspase-1 and ASC. Although the majority of ternary inflammasome complexes depend on ASC, drugs targeting ASC protein remain scarce. After screening natural compounds from Isatidis Radixin, we found that tryptanthrin (TPR) could inhibit NLRP3-induced IL-1ß and caspase-1 production, but the underlying anti-inflammatory mechanisms remain to be elucidated. PURPOSE: The purpose of this study was to determine the impact of TPR on the NLRP3, NLRC4, and AIM2 inflammasomes and the underlying mechanisms. Additionally, the efficacy of TPR was analysed in the further course of methionine- and choline-deficient (MCD)-induced NASH and lipopolysaccharide (LPS)-induced sepsis models of mice. METHODS: In vitro studies used bone marrow-derived macrophages to assess the anti-inflammatory activity of TPR, and the techniques included western blot, testing of intracellular K+ and Ca2+, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation, ASC oligomerization assay, surface plasmon resonance (SPR), and molecular docking. We used LPS-induced sepsis models and MCD-induced NASH models in vivo to evaluate the effectiveness of TPR in inhibiting inflammatory diseases. RESULTS: Our observations suggested that TPR could inhibit NLRP3, NLRC4, and AIM2 inflammasome activation. As shown in a mouse model of inflammatory diseases caused by MCD-induced NASH and LPS-induced sepsis, TPR significantly alleviated the progression of diseases. TPR interrupted the interactions between ASC and NLRP3/NLRC4/AIM2 in the co-immunoprecipitation experiment, and stable binding of TPR to ASC was also evident in SPR experiments. The underlying mechanisms of anti-inflammatory activities of TPR might be associated with targeting ASC, in particular, PYD domain of ASC. CONCLUSION: In general, the requirement for ASC in multiple inflammasome complexes makes TPR, as a novel broad-spectrum inflammasome inhibitor, potentially useful for treating a wide range of multifactorial inflammasome-related diseases.

Associated factors leading to misdiagnosis of a combined diagnostic model of different types of strain imaging and conventional ultrasound in evaluation of breast lesions: Selection strategy for using different types of strain imaging in evaluation of breast lesions.

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.

Autonomous ultrasound scanning robotic system based on human posture recognition and image servo control: an application for cardiac imaging.

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.

IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway.

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.

Superconductivity above 105 K in Nonclathrate Ternary Lanthanum Borohydride below Megabar Pressure.

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.

Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions.

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.

Potential mitigation of titanium dioxide nanoparticles against 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis through inhibiting the canonical NF-κB pathway.

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.

A Practical Method for Synthesizing Iptacopan.

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.

Novel pyxinol amide derivatives bearing an aliphatic heterocycle as P-glycoprotein modulators for overcoming multidrug resistance.

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.

Pre-programmable pneumatic actuator: leveraging mechanical anisotropy of nonwoven fabrics with an integrated tensile sensor.

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.

Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol.

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.

Hardness Perceived When Sliding Over Roughened Surfaces.

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.