Discovery Small-Molecule p300 Inhibitors Derived from a Newly Developed Indazolone-Focused DNA-Encoded Library.

The DNA-encoded library (DEL) is a robust tool for chemical biology and drug discovery. In this study, we developed a DNA-compatible light-promoted reaction that is highly efficient and plate-compatible for DEL construction based on the formation of the indazolone scaffold. Employing this high-efficiency approach, we constructed a DEL featuring an indazolone core, which enabled the identification of a novel series of ligands specifically targeting E1A-binding protein (p300) after DEL selection. Taken together, our findings underscore the feasibility of light-promoted reactions in DEL synthesis and unveil promising avenues for developing p300-targeting inhibitors.

Sulfhydryl-Functionalized Amino Group Polymer Microcomposites toward Efficient Adsorption of Aqueous Cr(VI), As(III), Cd(II), and Pb(II).

The development of efficient adsorbents for heavy metal pollution, especially five toxic heavy metals, has attracted great research interest. Polymer-based adsorbents have aroused research value for their abundant functional groups and high porosity to the ability to capture metal ions. We designed a sulfhydryl-functionalized polymer microcomposite to take up Cr(VI), As(III), Cd(II), and Pb(II). The adsorption capacity achieved was 64.2 mg g-1 for Cr(VI), 44.9 mg g-1 for As(III), 35.5 mg g-1 for Cd(II), and 18.2 mg g-1 for Pb(II). Langmuir and Sips isotherm model is dominant for As(III), Cd(II), and Pb(II) adsorption. Pseudo-second-order kinetic models can better describe the adsorption behavior of Cr(VI), implying that chemisorption is accompanied by Cr(VI) adsorption. Cr(VI) simultaneous reduction to Cr(III) through the benzenoid amine oxidate pathway was the dominant mechanism, precipitation for Cd(II) adsorption was convinced, and chelation between As(III)/Pb(II) and─SH group and complexation between Pb(II) and C═O or benzene hydroxyl were a plausible mechanism for As(III) and Pb(II) adsorption.

Effects of photodegradation on the composition characteristics and metal binding behavior of sediment-derived dissolved organic matter (SDOM) in nansi lake, China.

Sediment-derived dissolved organic matter (SDOM) is instrumental in the cycling of nutrients and heavy metals within lakes, influencing ecological balance and contaminant distribution. Given the influence of photodegradation on the alteration and breakdown of SDOM, further understanding of this process is essential. In this research, the properties of the SDOM photodegradation process and its metal-binding reactions in Nansi Lake were analyzed using the EEM-PARAFAC and 2D-SF/FTIR-COS techniques. Our study identified three sorts of humic-like components and one protein-like component in SDOM, with the humic-like material accounting for 71.3 ± 5.19% of the fluorescence intensity (Fmax). Photodegradation altered the abundance and structure of SDOM, with a 41.6 ± 5.82% decrease in a280 and a 29.1 ± 9.31% reduction in Fmax after 7 days, notably reducing the protein-like component C4 by 54.0 ± 5.17% and the humic-like component C2 by 48.5 ± 2.54%, which led to SDOM being formed with lower molecular weight and aromaticity. After photodegradation, the LogKCu values for humic-like and protein-like substances decreased (humic-like C2: LogKCu: 1.35 ± 0.10-1.11 ± 0.15, protein-like C4: 1.49 ± 0.14-1.29 ± 0.34), yet the preferential binding sequence of protein-like materials and specific functional groups with Cu2+ such as aliphatic C-OH, amide (I) C=O and polysaccharide C-O groups remained unaltered. Our results enhance the knowledge of light-induced SDOM alterations and offer insights into SDOM-metal interactions in aquatic ecosystems.

The Encounter of Two Worlds: Divided Narratives of Decision-Making on Cancer Treatment Between Physicians and Patients.

INTRODUCTION: Divided narratives pose long-standing difficulties in physician and patient communication. In decision-making on cancer treatment, divided narratives between physicians and patients hinder mutual understanding and agreement over the illness and its treatment. For effective decision-making on treatments, it is necessary to investigate the similarities and differences in these divided narratives. METHODS: This study adopted a qualitative research design of narrative inquiry to examine the data, which included interviews with 32 cancer patients and 16 paired physicians in two hospitals in China. Data analysis was conducted using grounded theory to generate findings. RESULTS: Both physicians and patients were concerned about goals and obstacles to their decision-making on cancer treatment. Four common aspects of goal setting were identified from the divided narratives: decision pools, treatment goals, identity practice and preferred identity. Four common obstacles were identified: pains and trust, communication gap, financial issues and complex family. However, the meanings attached to these eight aspects differed between physicians and patients. CONCLUSION: Cancer treatment decision-making is an encounter of the scientific world and lifeworld. A divided narrative approach can identify the similarities and differences in the decision-making on cancer treatment between physicians and patients. Physicians generally adopt a rational decision-making approach, whereas patients generally adopt a relational decision-making approach. Despite the common concerns in their goals and obstacles, physicians and patients differed in their contextualized interpretations, which demonstrates the physicians' and the patients' pursuit of preferred identities in decision-making. The results of this study provide a new perspective to treatment decision-making, emphasizing the importance of narrative integration in reaching mutual agreement. PATIENT AND PUBLIC CONTRIBUTION: The findings were shared with 15 cancer patients and caregivers for feedback and advice in June 2024. This study was also presented at the international conferences of COMET (International and Interdisciplinary Conference on Communication, Medicine, and Ethics) and ICCH (International Conference on Communication in Healthcare) 2023 for continuous feedback and comments.

Mechanisms of anaerobic treatment of sulfate-containing organic wastewater mediated by Fe0 under different initial pH values.

The anaerobic treatment of sulfide-containing organic wastewater (SCOW) is significantly affected by pH, causing dramatic decrease of treatment efficiency when pH deviates from its appropriate range. Fe0 has proved as an effective strategy on mitigating the impact of pH. However, systematic analysis of the influence mechanism is still lacking. To fill this gap, the impact of different initial pH values on anaerobic treatment efficiency of SCOW with Fe0 addition, the change of fermentation type and methanogens, and intra-extracellular electron transfer were explored in this study. The results showed that Fe0 addition enhanced the efficacy of anaerobic treatment of SCOW at adjusted initial pH values, especially at pH 6. Mechanism analysis showed that respiratory chain-related enzymes and electron shuttle secretion and resistance reduction were stimulated by soluble iron ions generated by Fe0 at pH 6, which accelerated intra-extracellular electron transfer of microorganisms, and ultimately alleviated the impact of acidic pH on the system. While at pH 8, Fe0 addition increased the acetogenic bacteria abundance, as well as optimized the fermentation type and improved the F420 coenzyme activity, resulting in the enhancement of treatment efficiency in the anaerobic system and remission of the effect of alkaline pH on the system. At the neutral pH, Fe0 addition had both advantages as stimulating the secretion of respiratory chain and electron transfer-related enzymes at pH 6 and optimizing the fermentation type pH 8, and thus enhanced the treatment efficacy. This study provides important insights and scientific basis for the application of new SCOW treatment technologies.

[Research on Electromagnetic Compatibility Immunity Testing Methods for Proton Therapy System].

The proton therapy system has significant clinical advantages over traditional tumor radiation treatment equipment and is also far more complex in terms of system architecture. However, due to the large size and complexity of these devices, electromagnetic compatibility testing faces considerable challenges. To address these challenges, this paper studies the electromagnetic characteristics and working principles of various components in the proton therapy system, combines them with corresponding standard requirements, and delves into the difficulties and testing methods of electromagnetic compatibility immunity detection through actual repeated tests. Furthermore, the paper proposes testing key points for beam quality tests and provides references for the selection of emission sources and distance settings in radio frequency electromagnetic field radiation immunity testing. The paper also supplements and improves the descriptions of alternative methods in the standards and offers solutions and testing suggestions for issues such as the excessive thickness of cables in the proton therapy system and the lack of suitable fixtures in conducted anti-interference tests. The provision of these solutions offers more effective references for related staff during testing, helps address difficulties encountered in practical operations, and thus more effectively ensures the safety and effectiveness of proton therapy systems.

ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries.

DNA-encoded chemical library (DEL) has been extensively used for lead compound discovery for decades in academia and industry. Incorporating an electrophile warhead into DNA-encoded compounds recently permitted the discovery of covalent ligands that selectively react with a particular cysteine residue. However, noncysteine residues remain underexplored as modification sites of covalent DELs. Herein, we report the design and utility of tyrosine-targeting DELs of 67 million compounds. Proteome-wide reactivity analysis of tyrosine-reactive sulfonyl fluoride (SF) covalent probes suggested three enzymes (phosphoglycerate mutase 1, glutathione s-transferase 1, and dipeptidyl peptidase 3) as models of tyrosine-targetable proteins. Enrichment with SF-functionalized DELs led to the identification of a series of tyrosine-targeting covalent inhibitors of the model enzymes. In-depth mechanistic investigation revealed their novel modes of action and reactive ligand-accessible hotspots of the enzymes. Our strategy of combining activity-based proteome profiling and covalent DEL enrichment (ABPP-CoDEL), which generated selective covalent binders against a variety of target proteins, illustrates the potential use of this methodology in further covalent drug discovery.

Prefrontal cortex activity of active motion, cyclic electrical muscle stimulation, assisted motion, and imagery of wrist extension in stroke using fNIRS.

OBJECTIVES: This study aimed to determine whether the prefrontal cortex (PFC) was activated during four training approaches for wrist extension in patients with stroke, including active motion, cyclic electrical muscle stimulation (EMS), assisted motion, and motor imagery (MI). MATERIALS AND METHODS: We conducted a cross-sectional study involving 16 patients with stroke, and adopted functional near-infrared spectroscopy (fNIRS) to observe PFC activity during four treatment paradigms. The beta value of 53 channels in fNIRS under each paradigm, compared to the baseline, was evaluated using single sample t-test. The one-way analysis of variance with post hoc analysis was employed to compare the difference of significantly activated channels among four treatment paradigms. RESULTS: This study revealed that the active motion (t values ranging from 2.399 to 4.368, p values <0.05), as well as MI of wrist extension (t values ranging from 2.161 to 4.378, p values <0.05), significantly increased HBO concentration across the entire PFC. The cyclic EMS enhanced the activation of Broca's area and frontal pole (FP) (t values ranging from -2.540 to 2.303, p values <0.05). The assisted motion induced significant activation in Broca's area, dorsolateral prefrontal cortex, and FP (t values ranging from -2.226 to 3.056, p values <0.05). The difference in ΔHBO among the four tasks was seen in Broca's area, FP, and frontal eye field. CONCLUSIONS: Active wrist extension and MI activate most PFC areas, whereas assisted motion and single-use of cyclic EMS have limited effectiveness for PFC activation in stroke patients.

The effects of climate warming on microbe-mediated mechanisms of sediment carbon emission.

Due to significant differences in biotic and abiotic properties of soils compared to those of sediments, the predicted underlying microbe-mediated mechanisms of soil carbon emissions in response to warming may not be applicable for estimating similar emissions from inland water sediments. We addressed this issue by incubating different types of sediments, (including lake, small river, and pond sediments) collected from 36 sites across the Yangtze River basin, under short-term experimental warming to explore the effects of climate warming on sediment carbon emission and the underlying microbe-mediated mechanisms. Our results indicated that under climate warming CO2 emissions were affected more than CH4 emissions, and that pond sediments may yield a greater relative contribution of CO2 to total carbon emissions than lake and river sediments. Warming-induced CO2 and CH4 increases involve different microbe-mediated mechanisms; Warming-induced sediment CO2 emissions were predicted to be directly positively driven by microbial community network modularity, which was significantly negatively affected by the quality and quantity of organic carbon and warming-induced variations in dissolved oxygen, Conversely, warming-induced sediment CH4 emissions were predicted to be directly positively driven by microbial community network complexity, which was significantly negatively affected by warming-induced variations in pH. Our findings suggest that biotic and abiotic drivers for sediment CO2 and CH4 emissions in response to climate warming should be considered separately when predicting sediment organic carbon decomposition dynamics resulting from climate change.

Quantitative Validation and Application of the Photo-Cross-Linking Selection for Double-Stranded DNA-Encoded Libraries.

The DNA-encoded compound library (DEL) technology has accelerated the target hits discovery in new drug development. While affinity-based DEL selection can distinguish high-affinity ligands, moderate-affinity ligands are also potential drug candidates with further modifications. Herein, we designed a photo-cross-linking selection method for DELs with double-stranded DNA (dsDELs) to screen moderate-affinity ligands. We constructed two photo-cross-linking libraries with linkers of different lengths that connect a diazirine group to the DNA encoded compound. The diazirine group can be activated by UV irradiation and thus bond with the target protein in a reachable distance. In the model selection, the feasibility of the photo-cross-linking screening system was verified by qPCR and NGS technology. Both high-affinity and moderate-affinity ligands were successfully selected from the libraries.

Divergent On-DNA Transformations from DNA-Linked Piperidones.

A group of highly efficient and divergent transformations for constructing multiple DNA-linked chemotypes based on a piperidone core were successfully developed. We reported the first procedure for the synthesis of a DNA-conjugated piperidine intermediate under basic conditions. Subsequently, this substructure was subjected to additional reactions to generate several privileged scaffolds, including 4-aminopiperidine, fused [1,2,4]triazolo[1,5-a]pyrimidine, and a quinoline derivative. These transformations paved the way for constructing focused scaffold-based DNA-encoded libraries with druglike properties.

Anionic Porous Zn-Metalated Porphyrin Metal-Organic Framework with PtS Topology for Gas-Phase Photocatalytic CO2 Reduction.

Presented here are the synthesis and gas-phase photocatalytic CO2 reduction of an anionic porous Zn-metalated porphyrin metal-organic framework (MOF) induced by an ionic liquid. The desired CO2 affinity and deep conduction band position of the MOF catalyst provide strong kinetic and thermodynamic advantages for photocatalytic CO2 to CH4 conversion with high selectivity (∼70%) in H2O vapor.

The role of TRPV channels in osteoporosis.

As the world's population ages, the treatment of osteoporosis is a major problem to be addressed. The cause of osteoporosis remains unclear. Ca2+ is not only an important component of bones but also plays a key role in osteoporosis treatment. Transient receptor potential vanilloid (TRPV) channels are one of the TRP channel families that is widely distributed in various organs, playing an important role in the physiological regulation of the human body. Bone formation and bone absorption may require Ca2+ transport via TRPV channels. It has been proven that the TRPV subtypes 1, 2, 4, 5, 6 (TRPV1, TRPV2, TRPV4, TRPV5, TRPV6) may affect bone metabolism balance through selective regulation of Ca2+. They significantly regulate osteoblast/osteoclast proliferation, differentiation and function. The purpose of this review is to explore the mechanisms of TRPV channels involved in regulation of the differentiation of osteoblasts and osteoclasts, as well as to discuss the latest developments in current researches, which may provide new clues and directions for an in-depth study of osteoporosis and other related bone metabolic diseases.

HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in Low-Density Lipoprotein Receptor-Deficient Mice.

PURPOSE: HIV infection is consistently associated with an increased risk of atherosclerotic cardiovascular disease, but the underlying mechanisms remain elusive. HIV protein Tat, a transcriptional activator of HIV, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV Tat have not been investigated in vivo. Macrophages are one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously revealed the important role of IκB kinase ß (IKKß), a central inflammatory coordinator through activating NF-κB, in the regulation of macrophage functions and atherogenesis. This study investigated the impact of HIV Tat exposure on macrophage functions and atherogenesis. METHODS: To investigate the effects of Tat on macrophage IKKß activation and atherosclerosis development in vivo, myeloid-specific IKKß-deficient LDLR-deficient (IKKßΔMyeLDLR-/-) mice and their control littermates (IKKßF/FLDLR-/-) were exposed to recombinant HIV protein Tat. RESULTS: Exposure to Tat significantly increased atherosclerotic lesion size and plaque vulnerability in IKKßF/FLDLR-/- but not IKKßΔMyeLDLR-/- mice. Deficiency of myeloid IKKß attenuated Tat-elicited macrophage inflammatory responses and atherosclerotic lesional inflammation in IKKßΔMyeLDLR-/- mice. Further, RNAseq analysis demonstrated that HIV protein Tat affects the expression of many atherosclerosis-related genes in vitro in an IKKß-dependent manner. CONCLUSIONS: Our findings reveal atherogenic effects of HIV protein Tat in vivo and demonstrate a pivotal role of myeloid IKKß in Tat-driven atherogenesis.

LLLI promotes BMSC proliferation through circRNA_0001052/miR-124-3p.

Osteoporosis (OP) is a multifactorial bone disease that occurs worldwide. The treatment of OP is still unsatisfactory. Bone mesenchymal stem cell (BMSC) differentiation is a key process in OP pathogenesis. Low-level laser irradiation (LLLI) has been reported to regulate BMSC proliferation, but the role of circRNAs in the LLLI-based promotion of BMSC proliferation remains unclear. CircRNAs are essential molecular regulators that participate in numerous biological processes and have therapeutic potential. miR-124-3p is an essential microRNA (miRNA), and its expression changes are related to BMSC proliferation ability. In the present study, gain-loss function of experiments demonstrated that circRNA_0001052 could regulate the proliferation of BMSCs by acting as a miR-124-3p sponge through the Wnt4/ß-catenin pathway. The results of this study strongly suggest that circRNA_0001052 plays an essential role in BMSC proliferation in response to LLLI treatment, which is a potential therapeutic manipulation with clinical applications.

A Sign Language Recognition System Applied to Deaf-Mute Medical Consultation.

It is an objective reality that deaf-mute people have difficulty seeking medical treatment. Due to the lack of sign language interpreters, most hospitals in China currently do not have the ability to interpret sign language. Normal medical treatment is a luxury for deaf people. In this paper, we propose a sign language recognition system: Heart-Speaker. Heart-Speaker is applied to a deaf-mute consultation scenario. The system provides a low-cost solution for the difficult problem of treating deaf-mute patients. The doctor only needs to point the Heart-Speaker at the deaf patient and the system automatically captures the sign language movements and translates the sign language semantics. When a doctor issues a diagnosis or asks a patient a question, the system displays the corresponding sign language video and subtitles to meet the needs of two-way communication between doctors and patients. The system uses the MobileNet-YOLOv3 model to recognize sign language. It meets the needs of running on embedded terminals and provides favorable recognition accuracy. We performed experiments to verify the accuracy of the measurements. The experimental results show that the accuracy rate of Heart-Speaker in recognizing sign language can reach 90.77%.

[Study on Test Method of Radiation Emission of Proton Therapy Equipment].

Electromagnetic compatibility testing of proton therapy system is different from that of traditional products in an anechoic chamber. It has high requirements on the division of sample composition, the understanding of applicable standards, the formulation of operation mode, the selection of test location, and the test of ambient noise. According to the requirements of GB 4824-2019 standard, the test method of radiation emission of proton therapy equipment was developed to provide reference advice for the industry, and the problems encountered in the actual test were studied.

Silencing long non-coding RNA MEG8 inhibits the proliferation and induces the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Even though long non-coding RNA (lncRNA) MEG8 plays vital roles in carcinogenesis of malignances, its roles and mechanisms in hemangioma remain unknown. Therefore, we evaluate the oncogenic roles of MEG8 in hemangioma. Small interfering RNA (siRNA)-mediated depletion of MEG8 inhibited the proliferation and increased MDA level in human hemangioma endothelial cells (HemECs). The inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) abolished the MEG8 silence induced cell viability loss. Knockdown of MEG8 increased the miR-497-5p expression and reduced the mRNA and protein levels of NOTCH2. Using a dual-luciferase assay, we confirmed the binding between MEG8 and miR-497-5p, and between the miR-497-5p and 3'UTR of NOTCH2. We further found that silencing MEG8 significantly decreased the expressions of SLC7A11 and GPX4 both in mRNA and protein level and had no effect on the level of AIFM2. Importantly, blocking miR-497-5p abrogated the effects of MEG8 loss on cell viability, MDA level and expression levels of NOTCH2, SLC7A11 and GPX4 in HemECs. Taken together, our results suggested that knockdown of long non-coding RNA MEG8 inhibited the proliferation and induced the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Thrombin Aggravates Hypoxia/Reoxygenation Injury of Cardiomyocytes by Activating an Autophagy Pathway-Mediated by SIRT1.

BACKGROUND Acute myocardial infarction is the leading cause of mortality among adults worldwide. The present study aimed to investigate the role and mechanism of thrombin and SIRT1 in hypoxia/reoxygenation (H/R) injury. MATERIAL AND METHODS H9c2 cardiomyocytes were used to create an H/R model to simulate in vivo ischemia/reperfusion injury. The MTT assay was used to measure cell viability, qRT-PCR was used to detect the level of SIRT1, thrombin, and PAR-1, and western blot analysis was conducted for evaluation of thrombin, PAR-1, SIRT1, LC3I, LC3II, and Beclin1. ELISA was applied for determination of IL-1ß, IL-6, TNF-alpha, MMP-9, and ICAM-1. After the establishment of the H/R model, superoxide dismutase (SOD) activity was evaluated by the xanthine oxidase method, malondialdehyde content was detected by thiobarbituric acid assay, and reactive oxygen species generation was measured by CM-H2DCFDA. RESULTS The findings showed that thrombin enhanced inflammatory factor secretion and oxidative stress but inhibited cell viability in H/R-injured cardiomyocytes. We also observed that thrombin promoted autophagy in H/R-injured cardiomyocytes. In addition, thrombin enhanced the upregulation of SIRT1 expression by H/R. However, it was found that inhibition of SIRT1 could suppress the effect of thrombin on inflammatory factor secretion, oxidative stress, and cell viability. Moreover, downregulation of SIRT1 suppressed the inhibitory effect of thrombin on autophagy in H/R injury. CONCLUSIONS Thrombin aggravates H/R injury of cardiomyocytes by activating an autophagy pathway mediated by SIRT1. These findings might provide a potential target therapy for the treatment of ischemia/reperfusion injury in future clinical work.

Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice.

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR-/-) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR-/- mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR-/- mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.