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2.
Angew Chem Int Ed Engl ; : e202408665, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38976418

ABSTRACT

Enzyme-enabled biobatteries are promising green options to power the next-generation of bioelectronics and implantable medical devices. However, existing power sources based on enzymatic biofuel chemistry exhibit limited scale-down feasibility due to the solid and bulky battery structures. Therefore, miniature and soft alternatives are needed for integration with implants and tissues. Here, a biobattery built from nanolitre droplets, fuelled by the enzyme-enabled oxidation of reduced nicotinamide adenine dinucleotide, generates electrical outputs and powers ion fluxes in droplet networks. Optimization of the droplet biobattery components ensures a stable output current of ~13,000 pA for over 24 h, representing a more than 600-fold increase in output over previous approaches, including light-driven processes. The enzyme-enabled droplet biobattery opens new avenues in bioelectronics and bioiontronics, exemplified by tasks such as the ability to drive electrochemical signal transmission in integrated synthetic tissues.

3.
Inflammation ; 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38951356

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a common chronic lung disorder characterized by impaired proximal airway and bronchoalveolar development in premature births. Secreted phosphoprotein 1 (SPP1) is involved in lung development and lung injury events, while its role was not explored in BPD. For establishing the in vivo models of BPD, a mouse model of hyperoxia-induced lung injury was generated by exposing neonatal mice to hyperoxia for 7 days after birth. Alveolar myofibroblasts (AMYFs) were treated with hyperoxia to establish the in vitro models of BPD. Based on the scRNA-seq analysis of lungs of mice housed under normoxia or hyperoxia conditions, mouse macrophages and fibroblasts were main different cell clusters between the two groups, and differentially expressed genes in fibroblasts were screened. Further GO and KEGG enrichment analysis revealed that these differentially expressed genes were mainly enriched in the pathways related to cell proliferation, apoptosis as well as the PI3K-AKT and ERK/MAPK pathways. SPP1 was found up-regulated in the lung tissues of hyperoxia mice. We also demonstrated the up-regulation of SPP1 in the BPD patients, the mouse model of hyperoxia-induced lung injury, and hyperoxia-induced cells. SPP1 deficiency was revealed to reduce the hyperoxia-induced apoptosis, oxidative stress and inflammation and increase the viability of AMYFs. In the mouse model of hyperoxia induced lung injury, SPP1 deficiency was demonstrated to reverse the hyperoxia-induced alveolar growth disruption, oxidative stress and inflammation. Overall, SPP1 exacerbates BPD progression in vitro and in vivo by regulating oxidative stress and inflammatory response via the PI3K-AKT and ERK/MAPK pathways, which might provide novel therapeutic target for BPD therapy.

4.
J Hazard Mater ; 476: 135092, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38964040

ABSTRACT

Methylisothiazolinone (MIT) is a widely used preservative and biocide to prevent product degradation, yet its potential impact on plant growth remains poorly understood. In this study, we investigated MIT's toxic effects on Arabidopsis thaliana root growth. Exposure to MIT significantly inhibited Arabidopsis root growth, associated with reduced root meristem size and root meristem cell numbers. We explored the polar auxin transport pathway and stem cell regulation as key factors in root meristem function. Our findings demonstrated that MIT suppressed the expression of the auxin efflux carrier PIN1 and major root stem cell regulators (PLT1, PLT2, SHR, and SCR). Additionally, MIT hindered root regeneration by downregulating the quiescent center (QC) marker WOX5. Transcriptome analysis revealed MIT-induced alterations in gene expression related to oxidative stress, with physiological experiments confirming elevated reactive oxygen species (ROS) levels and increased cell death in root tips at concentrations exceeding 50 µM. In summary, this study provides critical insights into MIT's toxicity on plant root development and regeneration, primarily linked to modifications in polar auxin transport and downregulation of genes associated with root stem cell regulation.

5.
Article in English | MEDLINE | ID: mdl-38963643

ABSTRACT

BACKGROUND: The current understanding of the prognostic significance of B cells and their role in the tumor microenvironment (TME) in esophageal carcinoma (ESCA) is limited. METHODS: We conducted a screening for B-cell-related genes through the analysis of single-cell transcriptome data. Subsequently, we developed a B-cell-related gene signature (BRGrisk) using LASSO regression analysis. Patients from The Cancer Genome Atlas cohort were divided into a training cohort and a test cohort. Patients were categorized into high- and low-risk groups based on their median BRGrisk scores. The overall survival was assessed using the Kaplan-Meier method, and a nomogram based on BRGrisk was constructed. Immune infiltration profiles between the risk groups were also compared. RESULTS: The BRGrisk prognostic model indicated significantly worse outcomes for patients with high BRGrisk scores (p < 0.001). The BRGrisk-based nomogram exhibited good prognostic performance. Analysis of immune infiltration revealed that patients in the high-BRGrisk group had notably higher levels of immune cell infiltration and were more likely to be in an immunoresponsive state. Enrichment analysis showed a strong correlation between the prognostic gene signature and cancer-related pathways. IC50 results indicated that patients in the low-BRGrisk group were more responsive to common drugs compared to those in the high-BRGrisk group. CONCLUSIONS: This study presents a novel BRGrisk that can be used to stratify the prognosis of ESCA patients and may offer guidance for personalized treatment strategies aimed at improving prognosis.

6.
J Med Chem ; 67(12): 10168-10189, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38855903

ABSTRACT

The NLRP3 inflammasome is a critical component of the innate immune system. The persistent abnormal activation of the NLRP3 inflammasome is implicated in numerous human diseases. Herein, sulfonamide-substituted tetrahydroquinoline derivative S-9 was identified as the most promising NLRP3 inhibitor, without obvious cytotoxicity. In vitro, S-9 inhibited the priming and activation stages of the NLRP3 inflammasome. Incidentally, we also observed that S-9 had inhibitory effects on the NLRC4 and AIM2 inflammasomes. To elucidate the multiple anti-inflammatory activities of S-9, photoaffinity probe P-2, which contained a photoaffinity label and a functional handle, was developed for target identification by chemical proteomics. We identified PKR as a novel target of S-9 in addition to NLRP3 by target fishing. Furthermore, S-9 exhibited a significant anti-neuroinflammatory effect in vivo. In summary, our findings show that S-9 is a promising lead compound targeting both PKR and NLRP3 that could emerge as a molecular tool for treating inflammasome-related diseases.


Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Quinolines , Sulfonamides , eIF-2 Kinase , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Quinolines/pharmacology , Quinolines/chemistry , Quinolines/chemical synthesis , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Humans , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , eIF-2 Kinase/antagonists & inhibitors , eIF-2 Kinase/metabolism , Animals , Mice , Mice, Inbred C57BL , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Structure-Activity Relationship
7.
Heliyon ; 10(11): e32000, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38868016

ABSTRACT

The drive of resilient city explores a new path for urban governance in the context of risk society, and China's demonstration city of safe development (DCSD) policies are the indigenous practice of resilient city idea. This paper used text mining technology and PMC-index model to establish an evaluation system for DCSD policies. Then eight representative sample DCSD policies were assessed. The results show that the average PMC-index scores 5.38 and reaches a great consistency grade. Nine model indicators indicate that the Chinese government has a clear policy focus on the efforts of DCSD, prefers to use compulsory type policy tools, and fully mobilizes the public to participate in safe city development jointly. Meanwhile, structural imbalance in policy instruments is a prominent disadvantage. The research establishes an evaluation system for DCSD policies, and provides a new perspective for the explorations of resilient cities worldwide. The extensive applicability of the policy evaluation model needs to be studied in depth in the future.

8.
Comput Biol Chem ; 111: 108106, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38833912

ABSTRACT

Bioretrosynthesis problem is to predict synthetic routes using substrates for given natural products (NPs). However, the huge number of metabolic reactions leads to a combinatorial explosion of searching space, which is high time-consuming and costly. Here, we propose a framework called BioRetro to predict bioretrosynthesis pathways using a one-step bioretrosynthesis network, termed HybridMLP combined with AND-OR tree heuristic search. The HybridMLP predicts precursors that will produce the target NPs, while the AND-OR tree generates the iterative multi-step biosynthetic pathways. The one-step bioretrosynthesis prediction experiments are conducted on MetaNetX dataset by using HybridMLP, which achieves 46.5%, 74.6%, 81.6% in terms of the top-1, top-5, top-10 accuracies. The great performance demonstrates the effectiveness of HybridMLP in one-step bioretrosynthesis. Besides, the evaluation of two benchmark datasets reveals that BioRetro can significantly improve the speed and success rate in predicting biosynthesis pathways. In addition, the BioRetro is further shown to find the synthetic pathway of compounds, such as ginsenoside F1 with the same substrates as reported but different enzymes, which may be the novel potential enzyme to have better catalytic performance.


Subject(s)
Biological Products , Biological Products/metabolism , Biological Products/chemistry , Biosynthetic Pathways , Computational Biology
9.
Int J Biol Macromol ; 274(Pt 2): 133446, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945337

ABSTRACT

Panax ginseng C.A. Mey., known for its medicinal and dietary supplement properties, primarily contains pharmacologically active ginsenosides. However, the regulatory mechanisms linking ginseng root development with ginsenoside biosynthesis are still unclear. Root meristem growth factors (RGFs) are crucial for regulating plant root growth. In our study, we identified five ginseng RGF peptide sequences from the ginseng genome and transcriptome libraries. We treated Arabidopsis and ginseng adventitious roots with exogenous Panax ginseng RGFs (PgRGFs) to assess their activities. Our results demonstrate that PgRGF1 influences gravitropic responses and reduces lateral root formation in Arabidopsis. PgRGF1 has been found to restrict the number and length of ginseng adventitious root branches in ginseng. Given the medicinal properties of ginseng, We determined the ginsenoside content and performed transcriptomic analysis of PgRGF1-treated ginseng adventitious roots. Specifically, the total ginsenoside content in ginseng adventitious roots decreased by 19.98 % and 63.71 % following treatments with 1 µM and 10 µM PgRGF1, respectively, compared to the control. The results revealed that PgRGF1 affects the accumulation of ginsenosides by regulating the expression of genes associated with auxin transportation and ginsenoside biosynthesis. These findings suggest that PgRGF1, as a peptide hormone regulator in ginseng, can modulate adventitious root growth and ginsenoside accumulation.

10.
Sensors (Basel) ; 24(11)2024 May 22.
Article in English | MEDLINE | ID: mdl-38894088

ABSTRACT

In this paper, a wide-band, low-profile antenna is presented for a high-integration phased array system. The proposed antenna, implemented using a tightly coupled array, operates over roughly the X-K frequency band and is performant at 8 GHz-18.5 GHz. The antenna can scan to ±60 degrees in both the E- and H-planes. Compared to previous tightly coupled antennas with smaller element spacing, the antenna in this paper reaches 9.4 mm, which corresponds to 0.58 λ of high frequency, suitable for engineering application conditions in production. The antenna can be soldered to BGA T/R chips in this space. Additionally, to facilitate flexible assembly for large arrays, the antenna is manufactured modularly using four elements and its parasitic radiation is analyzed. Then, a method for repressing parasitic radiation is presented. Finally, the antenna is fabricated and measured in a microwave chamber, exhibiting an excellent pattern and scanning radiation. The measured performance agrees with the full-wave finite array simulations.

11.
Environ Pollut ; : 124385, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38897274

ABSTRACT

Endocrine disrupting chemicals (EDCs) can disrupt normal endocrine function by interfering with the synthesis and release of hormones, causing adverse reactions to development, immunity, nerves, and reproduction. 4-tert-Butylphenol (4-t-BP) is disruptive to early zebrafish development, but its effects on zebrafish liver are unknown. In this study, the adverse effects of 4-t-BP on the liver were investigated using zebrafish as a model organism. 4-t-BP inhibited liver development in zebrafish embryos and induced liver damage in adult zebrafish. Even if F1 was not directly exposed to 4-t-BP, its growth and development were inhibited. 4-t-BP can lead to an increase in lipid accumulation, total cholesterol and triglycerides contents, and the activities of alanine transaminase and aspartate aminotransferase in zebrafish embryos and adult zebrafish livers, and also cause an acceleration of glucose metabolism in zebrafish embryos. In addition, qRT-PCR showed that 4-t-BP induced the changes in the expressions of liver development-, steroid and unsaturated fatty acid biosynthesis-, and glycerolipid and arachidonic acid metabolism-related genes in zebrafish embryos and inflammatory factors-, antioxidant enzymes- and lipid metabolism-related genes in adult zebrafish livers. Transcriptome sequencing of embryos showed that 4-t-BP altered the expressions of lipid metabolism pathways such as steroid and unsaturated fatty acid biosynthesis, glycerolipid, and arachidonic acid metabolism pathways. Therefore, 4-t-BP may be external stimuli that cause oxidative stress, inflammation, and lipid accumulation in zebrafish liver, resulting in tissue damage and dysfunction in zebrafish liver.

12.
Radiother Oncol ; : 110390, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38897316

ABSTRACT

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

13.
Immunity ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38908373

ABSTRACT

Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.

14.
Front Pharmacol ; 15: 1339153, 2024.
Article in English | MEDLINE | ID: mdl-38841368

ABSTRACT

Treatment of glomerulonephritis presents several challenges, including limited therapeutic options, high costs, and potential adverse reactions. As a recognized Chinese patent medicine, Tripterygium wilfordii poly-glycosides (TWP) have shown promising benefits in managing autoimmune diseases. To evaluate clinical effectiveness and safety of TWP in treating glomerulonephritis, we systematically searched PubMed, Cochrane Library, Web of Science, and Embase databases for controlled studies published up to 12 July 2023. We employed weighted mean difference and relative risk to analyze continuous and dichotomous outcomes. This meta-analysis included 16 studies that included primary membranous nephropathy (PMN), type 2 diabetic kidney disease (DKD), and Henoch-Schönlein purpura nephritis (HSPN). Analysis revealed that additional TWP administration improved patients' outcomes and total remission rates, reduced 24-h urine protein (24hUP) and decreased relapse events. The pooled results demonstrated the non-inferiority of TWP to glucocorticoids in achieving total remission, reducing 24hUP, and converting the phospholipase A2 receptor (PLA2R) status to negative. For DKD patients, TWP effectively reduced 24hUP levels, although it did not significantly improve the estimated glomerular filtration rate (eGFR). Compared to valsartan, TWP showed comparable improvements in 24hUP and eGFR levels. In severe cases of HSPN in children, significant clinical remission and a reduction in 24hUP levels were observed with the addition of TWP treatment. TWP did not significantly increase the incidence of adverse reactions. Therefore, TWP could offer therapeutic benefits to patients with PMN, DKD, and severe HSPN, with a minimal increase in the risk of side effects.

15.
J Oral Rehabil ; 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38924570

ABSTRACT

OBJECTIVES: Noncarious cervical lesions (NCCLs) are multifactorial and can be caused by the anatomical structure of the teeth, erosion, abrasion and abnormal occlusion. The aim of this case-control study was to explore the risk factors for NCCLs. METHODS: Cone-beam computed tomography was used to determine whether a wedge-shaped defect existed at the cementoenamel junction. We compared 63 participants with NCCLs with 63 controls without NCCLs, matched for sex, age (±1 year) and toothbrushing-related factors (e.g., type of bristle and brushing patterns, frequency and strength). All participants were asked to complete a questionnaire about self-administered daily diet habits and health condition. Univariate and multivariate logistic regression analyses were conducted to determine the risk factors for NCCLs. RESULTS: Significant variables in the univariate analysis (i.e., p < .2) included frequency of carbonated beverage consumption, sella-nasion-point B angle (SNB) and Frankfort-mandibular plane angle (FMA). Multivariate logistic regression demonstrated that the consumption frequency of carbonated beverages (odds ratio [OR] = 3.147; 95% confidence interval [CI], 1.039-9.532), FMA (OR = 1.100; 95% CI, 1.004-1.204) and SNB (OR = 0.896; 95% CI, 0.813-0.988) was independent influencing factors. The area under the receiver operating characteristic curve (AUC) value of regression Model 1 (established with the frequency of carbonated beverage consumption, FMA, SNB and sleep bruxism) was 0.700 (95% CI, 0.607-0.792; p < .001), and that of regression Model 2 (established using the frequency of carbonated beverage consumption, FMA and SNB) was 0.704 (95% CI, 0.612-0.796; p < .001). CONCLUSIONS: The consumption frequency of carbonated beverages and FMA was risk factors for NCCLs; the higher the frequency of carbonated beverage consumption and FMA, the higher was the probability of NCCLs. SNB was a protective factor for NCCL occurrence; the larger the SNB, the lower was the probability of NCCL occurrence. These findings have further clarified the aetiology of NCCLs and provided clinicians with valuable insights into strategies for preventing the loss of dental tissue.

16.
Ecotoxicol Environ Saf ; 280: 116564, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38865939

ABSTRACT

Natural estrogens, including estrone (E1), 17ß-estradiol (E2), and estriol (E3), are potentially carcinogenic pollutants commonly found in water and soil environments. Bacterial metabolic pathway of E2 has been studied; however, the catabolic products of E3 have not been discovered thus far. In this study, Novosphingobium sp. ES2-1 was used as the target strain to investigate its catabolic pathway of E3. The metabolites of E3 were identified by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) combined with stable 13C3-labeling. Strain ES2-1 could almost completely degrade 20 mg∙L-1 of E3 within 72 h under the optimal conditions of 30°C and pH 7.0. When inoculated with strain ES2-1, E3 was initially converted to E1 and then to 4-hydroxyestrone (4-OH-E1), which was then cleaved to HIP (metabolite A6) via the 4, 5-seco pathway or cleaved to the B loop via the 9,10-seco pathway to produce metabolite with a long-chain ketone structure (metabolite B4). Although the ring-opening sequence of the above two metabolic pathways was different, the metabolism of E3 was achieved especially through continuous oxidation reactions. This study reveals that, E3 could be firstly converted to E1 and then to 4-OH-E1, and finally degraded into small molecule metabolites through two alternative pathways, thereby reducing E3 pollution in water and soil environments.


Subject(s)
Biodegradation, Environmental , Estriol , Estrone , Sphingomonadaceae , Estriol/metabolism , Estrone/metabolism , Sphingomonadaceae/metabolism , Chromatography, High Pressure Liquid , Hydroxyestrones/metabolism , Metabolic Networks and Pathways
17.
J Invest Dermatol ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38909841

ABSTRACT

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

18.
J Invest Dermatol ; 2024 May 30.
Article in English | MEDLINE | ID: mdl-38823435

ABSTRACT

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.

19.
Bioinformatics ; 40(7)2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38905501

ABSTRACT

MOTIVATION: In the field of drug discovery, accurately and effectively predicting the binding affinity between proteins and ligands is crucial for drug screening and optimization. However, current research primarily utilizes representations based on sequence or structure to predict protein-ligand binding affinity, with relatively less study on protein surface information, which is crucial for protein-ligand interactions. Moreover, when dealing with multimodal information of proteins, traditional approaches typically concatenate features from different modalities in a straightforward manner without considering the heterogeneity among them, which results in an inability to effectively exploit the complementary between modalities. RESULTS: We introduce a novel multimodal feature extraction (MFE) framework that, for the first time, incorporates information from protein surfaces, 3D structures, and sequences, and uses cross-attention mechanism for feature alignment between different modalities. Experimental results show that our method achieves state-of-the-art performance in predicting protein-ligand binding affinity. Furthermore, we conduct ablation studies that demonstrate the effectiveness and necessity of protein surface information and multimodal feature alignment within the framework. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/Sultans0fSwing/MFE.


Subject(s)
Protein Binding , Proteins , Ligands , Proteins/metabolism , Proteins/chemistry , Computational Biology/methods , Drug Discovery/methods , Algorithms , Binding Sites , Databases, Protein , Protein Conformation
20.
Sci Total Environ ; 945: 173878, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-38866153

ABSTRACT

Thallium (Tl), a highly toxic heavy metal, which may pose significant environmental threats due to extensive discharge from anthropogenic activities. It is crucial to understand geochemical behavior of Tl in soils for initiating proper measures for Tl pollution control. For this purpose, transport behavior of Tl and its dominant factors in soils collected from a typically Tl-enriched depth profile, surrounding a historical tailing dump near an independent HgTl mine area in China, were investigated by using Tl isotope compositions. Results showed that an overall enrichment of Tl (48.68-375.21 mg/kg) was accompanied with As elevation (135.00-619.00 mg/kg) in the whole depth profile, and Tl and As exhibited co-migration behavior with Fe, S, K, and Rb. Geochemical fractionation of Tl unveiled by sequential extraction further indicated that Mn-/Fe-bearing minerals and clay minerals act as main hosts of Tl in the studied soils. Thallium isotopic composition and its fractionation pattern further revealed that the major contributors to high Tl levels in the depth profile were tailing and lorandite minerals, with mean contribution rate of 51.99% and 42.47%, respectively. These findings facilitate the understanding of Tl transport behavior in highly contaminated environment, providing valuable insights for developing new technologies in mining waste treatment and historical mine reclamation.

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