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Parks have the potential to encourage physical activity among urban communities. However, existing research on the link between park use and physical activity has produced inconsistent results. Mixed findings in the past may be due in part to differences in park quality across studies. The aim of this study was to explore the association between park use and physical activity among New York City adults in low-income communities that recently received city-sponsored park renovation as part of the Community Parks Initiative (CPI). Using population-weighted survey data from eight neighborhoods with recent park renovation (n = 2,000), we measured associations between park use frequency (≥ once/week vs. < once/week) and self-reported physical activity (high vs. low-moderate based on the International Physical Activity Questionnaire). We adjusted models for age, sex, education, race/ethnicity, income, study site, and use of other (non-CPI) parks, and conducted stratified analysis for demographic variables with significant interactions with park use. After adjusting for covariates, we observed a positive association between park use and physical activity (prevalence ratio [PR] = 1.30, 95% CI = 1.16-1.46). Greater frequency of park use was more strongly associated with high physical activity among adults ≤ 50 y (PR = 1.39, 95% CI = 1.14-1.69), individuals with annual household income < $25,000 (PR = 1.54, 95% CI = 1.13-2.08), and Latinos (PR = 1.77, 95% CI = 1.44-2.18). Our findings suggest that high-quality parks might be particularly beneficial for promoting physical activity among those with a lower socioeconomic background and in younger and Latino adults, emphasizing the importance of continued investment in park revitalization among urban communities of color.
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Introduction The kinetic of C-reactive protein (CRP) in the early phase of therapy with checkpoint inhibitors (CPI) and its prognostic value has already been investigated in several tumor entities. In particular, flare dynamics have been described as a positive prognostic parameter. The aim of this retrospective study is to examine the extent to which such an application can also be transferred to patients with recurrent or metastatic squamous cell carcinoma of the head and neck region (R/M-HNSCC). Material and Methods All patients treated with CPI for R/M-HNSCC at our clinic between 2018 and 2023 were included (n = 44). Demographic, clinical, histopathologic and laboratory data were extracted from the digital patient records and statistically analyzed. We then examined the CRP kinetic using two previously published classifications and proposed a new classification ourselves. Subsequently, correlation analyses were performed with the overall survival (OS) of the patients. Results Of the two CRP kinetic classifications previously published, only one showed a correlation with the result of the first re-staging, and neither showed a correlation with the OS of R/M-HNSCC patients. Our new CRP kinetic classification showed a significant association with OS in R/M-HNSCC patients (p = 0.05). In a multivariate analysis, our CRP kinetic classification (p = 0.007) and the outcome of the first re-staging (p = 0.002) were significant independent factors for OS. Discussion Our novel CRP kinetic classification significantly correlates with OS in R/M-HNSCC patients, indicating a potential prognostic marker. Existing classifications from other cancer entities showed limited prognostic significance, emphasizing the need for tailored markers. For validation, however, testing on larger R/M-HNSCC patient collectives is necessary.
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The standard of care for non-metastatic renal cancer is surgical resection followed by adjuvant therapy for those at high risk for recurrences. However, for older patients, surgery may not be an option due to the high risk of complications which may result in death. In the past renal cancer was considered to be radio-resistant, and required a higher dose of radiation leading to excessive complications secondary to damage of the normal organs surrounding the cancer. Advances in radiotherapy technique such as stereotactic body radiotherapy (SBRT) has led to the delivery of a tumoricidal dose of radiation with minimal damage to the normal tissue. Excellent local control and survival have been reported for selective patients with small tumors following SBRT. However, for patients with poor prognostic factors such as large tumor size and aggressive histology, there was a higher rate of loco-regional recurrences and distant metastases. Those tumors frequently carry program death ligand 1 (PD-L1) which makes them an ideal target for immunotherapy with check point inhibitors (CPI). Given the synergy between radiotherapy and immunotherapy, we propose an algorithm combining CPI and SBRT for older patients with non-metastatic renal cancer who are not candidates for surgical resection or decline nephrectomy.
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Rudrasagar Lake, a vital habitat for diverse flora and fauna, supports over 2000 households to sustain their daily livelihoods. The current study attempts to examine the impact of human activities on spatio-temporal variation in the water quality of the study area. The study integrates extensive field surveys, sample processing, and statistical analysis to assess the recent status of wetland health. Latin Square Matrix (LSM) was employed to select the sampling sites while the Inverse Distance Weighting (IDW) interpolation technique was used for spatial variation mapping. Modified Weighted Arithmetic Water Quality Index (MWAWQI) and Comprehensive Pollution Index (CPI) were utilized for assessing seasonal variation water quality and pollution loads, respectively. The results showed that dissolved oxygen (DO) was strongly influenced by the tributaries, and recreational activities have substantially influenced the highest concentrations of biochemical oxygen demand (BOD), and total suspended solids (TSS). The central portion of the lake is particularly susceptible to pollution from extensive fishing and recreational activities while peripheral sites are strongly influenced by agricultural run-offs, seepages from brick industries, and municipal wastes characterized by high concentrations of pH, total hardness (TH), oxidation-reduction potential (ORP). The findings reveal remarkable spatio-temporal fluctuations and highlight the areas within the lake susceptible to anthropogenic activities. The study proposed a sustainable management model to ameliorate anthropogenic threats. Moreover, the study contributes to the scientific understanding of the challenges and ensures the long-term viability of wetland health as a vital ecological and socio-economic resource.
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Monitoramento Ambiental , Lagos , Qualidade da Água , Lagos/química , Índia , Monitoramento Ambiental/métodos , Poluentes Químicos da Água/análise , Análise Espaço-Temporal , Análise da Demanda Biológica de Oxigênio , Áreas Alagadas , Efeitos Antropogênicos , Poluição Química da Água/estatística & dados numéricosRESUMO
PARP inhibitors are used to treat cancers with a deficient homologous recombination (HR) DNA repair pathway. Interestingly, recent studies revealed that HR repair could be pharmacologically impaired by the inhibition of histone lysine demethylases (KDM). Thus, we investigated whether KDM inhibitors could sensitize head and neck cancer cells, which are usually HR proficient, to PARP inhibition or cisplatin. Therefore, we explored the effects of double combinations of KDM4-6 inhibitors (ML324, CPI-455, GSK-J4, and JIB-04) with olaparib or cisplatin, or their triple combinations with both drugs, on the level of DNA damage and apoptosis. FaDu and SCC-040 cells were treated with individual compounds and their combinations, and cell viability, apoptosis, DNA damage, and gene expression were assessed using the resazurin assay, Annexin V staining, H2A.X activation, and qPCR, respectively. Combinations of KDM inhibitors with cisplatin enhanced cytotoxic effects, unlike combinations with olaparib. Triple combinations of KDM inhibitors with cisplatin and olaparib exhibited the best cytotoxic activity, which was associated with DNA damage accumulation and altered expression of genes associated with apoptosis induction and cell cycle arrest. In conclusion, triple combinations of KDM inhibitors (especially GSK-J4 and JIB-04) with cisplatin and olaparib represent a promising strategy for head and neck cancer treatment.
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OBJECTIVE: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs. METHODS: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 h, while TNF-α was administered to sensitize HASMCs in the presence of 0.1, 0.2, and 0.5 µM LY333531 for 48 h in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction was stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed. RESULTS: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17, and MLC while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. CONCLUSIONS: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.
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Patients with chronic pelvic inflammation (CPI) experience irregular menstrual, ectopic pregnancy, and infertility. Yiyi Baijiang Decoction attenuates CPI in patients with uncovered mechanisms. CPI therapeutic targets intersected with those of Yiyi Baijiang Decoction, followed by importing into STRING to obtain protein-target interaction. "Drug-component-disease-target" interaction was constructed by Cytoscape. mRNA and protein levels were detected by real-time quantitative PCR (RT-qPCR) and western blot. Yiyi Baijiang Decoction contained 199 active ingredients. There were 1071 drug targets for Yiyi Baijiang Decoction and 1622 therapeutic targets for CPI. The GO functional enrichment analysis revealed 3445 biological processes, and the KEGG pathway enrichment analysis screened 67 signal pathways. Decreased ALB, increased protein kinase B (AKT1), interleukin (IL)-6, vascular endothelial growth factor A (VEGFA), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K/AKT)-extracellular-regulated protein kinases (ERK)1/2 activation in CPI mice were abolished by Yiyi Baijiang Decoction. Yiyi Baijiang Decoction attenuates CPI by inactivating PI3K/AKT and ERK1/2 and regulating ALB, VEGFA, AKT1, and IL-6.
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Actin polymerization is often associated with membrane proteins containing capping-protein-interacting (CPI) motifs, such as CARMIL, CD2AP, and WASHCAP/Fam21. CPI motifs bind directly to actin capping protein (CP), and this interaction weakens the binding of CP to barbed ends of actin filaments, lessening the ability of CP to functionally cap those ends. The protein V-1 / myotrophin binds to the F-actin binding site on CP and sterically blocks CP from binding barbed ends. CPI-motif proteins also weaken the binding between V-1 and CP, which decreases the inhibitory effects of V-1, thereby freeing CP to cap barbed ends. Here, we address the question of whether CPI-motif proteins on a surface analogous to a membrane lead to net activation or inhibition of actin assembly nucleated by Arp2/3 complex. Using reconstitution with purified components, we discovered that CARMIL at the surface promotes and enhances actin assembly, countering the inhibitory effects of V-1 and thus activating CP. The reconstitution involves the presence of an Arp2/3 activator on the surface, along with Arp2/3 complex, V-1, CP, profilin and actin monomers in solution, recreating key features of cell physiology.
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AIMS: The initial bundle of cares strongly affects haemodynamics and outcomes in acute decompensated heart failure cardiogenic shock (ADHF-CS). We sought to characterize whether 24 h haemodynamic profiling provides superior prognostic information as compared with admission assessment and which haemodynamic parameters best predict in-hospital death. METHODS AND RESULTS: All patients with ADHF-CS and with available admission and 24 h invasive haemodynamic assessment from two academic institutions were considered for this study. The primary endpoint was in-hospital death. Regression analyses were run to identify relevant predictors of study outcome. We included 127 ADHF-CS patients [65 (inter-quartile range 52-72) years, 25.2% female]. Overall, in-hospital mortality occurred in 26.8%. Non-survivors were older, with greater CS severity. Among admission variables, age [odds ratio (OR) = 1.06; 95% confidence interval (CI): 1.02-1.11; Padj = 0.005] and CPIRAP (OR = 0.62 for 0.1 increment; 95% CI: 0.39-0.95; Padj = 0.034) were found significantly associated with in-hospital death. Among 24 h haemodynamic univariate predictors of in-hospital death, pulmonary elastance (PaE) was the strongest (area under the curve of 0.77; 95% CI: 0.68-0.86). PaE (OR = 5.98; 95% CI: 2.29-17.48; Padj < 0.001), pulmonary artery pulsatility index (PAPi, OR = 0.77; 95% CI: 0.62-0.92; Padj = 0.013) and age (OR = 1.06; 95% CI: 1.02-1.11; Padj = 0.010) were independently associated with in-hospital death. Best cut-off for PaE was 0.85 mmHg/mL and for PAPi was 2.95; cohort phenotyping based on these PaE and PAPi thresholds further increased in-hospital death risk stratification; patients with 24 h high PaE and low PAPi exhibited the highest in-hospital mortality (56.2%). CONCLUSIONS: Pulmonary artery elastance has been found to be the most powerful 24 h haemodynamic predictor of in-hospital death in patients with ADHF-CS. Age, 24 h PaE, and PAPi are independently associated with hospital mortality. PaE captures right ventriclar (RV) afterload mismatch and PAPi provides a metric of RV adaptation, thus their combination generates four distinct haemodynamic phenotypes, enhancing in-hospital death risk stratification.
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Somatic cell nuclear transfer (SCNT) technology holds great promise for livestock industry, life science and human biomedicine. However, the development and application of this technology is limited by the low developmental potential of SCNT embryos. The developmental competence of cloned embryos is influenced by the energy metabolic status of donor cells. The purpose of this study was to investigate the effects of CPI, an oxidative phosphorylation inhibitor, on the energy metabolism pathways of pig fibroblasts and the development of subsequent SCNT embryos. The results showed that treatment of porcine fibroblasts with CPI changed the cellular energy metabolic pathways from oxidative phosphorylation to glycolysis and enhanced the developmental ability of subsequent SCNT embryos. The present study establishes a simple, new way to improve pig cloning efficiency, helping to promote the development and application of pig SCNT technology.
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Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Doxorrubicina , Doença de Hodgkin , Inibidores de Checkpoint Imunológico , Humanos , Doença de Hodgkin/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Feminino , Adulto , Doxorrubicina/efeitos adversos , Doxorrubicina/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Pessoa de Meia-Idade , Dacarbazina/efeitos adversos , Dacarbazina/administração & dosagem , Neutropenia/induzido quimicamenteRESUMO
This study aims to determine the association between UpH (<5.5), Community Periodontal Index (CPI), and the number of remaining teeth-cumulative indicators of oral health-using data from the 7th Korea National Health and Nutrition Examination Survey (KNHANES, 2016-2018), which represents the Korean population. Data from 12,689 adults aged 19 years and older who had periodontal examinations were analyzed. Logistic regression analysis was performed after adjusting for demographic, health, and health-related behavioral factors as covariates to determine the association between UpH, CPI, and the number of remaining teeth. This study found that UpH (<5.5) was associated with CPI and the number of remaining teeth. For UpH (<5.5), the odds ratio for CPI (≥4 mm) was 1.19 times (95% CI: 1.06-1.33). The risk of tooth loss was 1.25 times (95% CI: 1.06-1.48) for those with 0-19 remaining teeth and 1.20 times (95% CI: 1.07-1.34) for those with 20-27 teeth. The results revealed an association between UpH, CPI, and the number of remaining teeth. However, further longitudinal research on UpH and oral status is necessary.
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In this study, we investigated the efficacy of kaempferol (a flavonoid found in plants and plant-derived foods such as kale, beans, tea, spinach and broccoli) on vascular contractibility and aimed to clarify the detailed mechanism underlying the relaxation. Isometric contractions of divested muscles were stored and linked with western blot analysis which was carried out to estimate the phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and phosphorylation-dependent inhibitory protein for myosin phosphatase (CPI-17) and to estimate the effect of kaempferol on the RhoA/ROCK/CPI-17 pathway. Kaempferol conspicuously impeded phorbol ester-, fluoride- and a thromboxane mimetic-derived contractions regardless of endothelial nitric oxide synthesis, indicating its direct effect on smooth muscles. It also conspicuously impeded the fluoride-derived elevation in phospho-MYPT1 rather than phospho-CPI-17 levels and phorbol 12,13-dibutyrate-derived increase in phospho-CPI-17 and phospho-ERK1/2 levels, suggesting the depression of PKC and MEK activities and subsequent phosphorylation of CPI-17 and ERK1/2. Taken together, these outcomes suggest that kaempferol-derived relaxation incorporates myosin phosphatase retrieval and calcium desensitization, which appear to be modulated by CPI-17 dephosphorylation mainly through PKC inactivation.
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The combination of the cancer mitochondrial metabolic inhibitor CPI-613 and hydroxychloroquine has tumor-suppressive effects on clear cell sarcoma, which shares pathobiological properties with melanoma. Therefore, we intended to examine the effects of a combination of CPI-613 and hydroxychloroquine on the growth of melanoma cells in the present study. However, cell death was not induced in melanoma cells. Therefore, a monoclonal antibody, ICT, that induced apoptosis in melanoma cells in combination with CPI-613 and hydroxychloroquine was developed. Immunoprecipitation, mass spectrometry, and small interfering RNA (siRNA)-mediated gene silencing demonstrated that ICT targeted Endoplasmic Reticulum Resident Protein 57/ Protein Disulfide Isomerase Family A Member 3 (ERp57/PDIA3), which was first identified as being upregulated by metabolic depletion stress and is localized on the cell surface during immunogenic cell death. The combination of CPI-613 and hydroxychloroquine enhanced the localization of ERp57/PDIA3 to the surface of melanoma cells. siRNA-mediated downregulation of ERp57/PDIA3 did not significantly induce ICT-mediated apoptosis in melanoma cells in the presence of CPI-613 and hydroxychloroquine. Therefore, the ICT antibody acts as a tumor suppressor in melanoma cells by targeting the cell membrane ERp57/PDIA3, expression of which was enhanced by the combination of CPI-613 and hydroxychloroquine.
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Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.
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Vasoespasmo Coronário , Animais , Humanos , Ratos , Biomarcadores/metabolismo , Morte Súbita Cardíaca , Fosfoproteínas/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteína Quinase C-alfa/metabolismoRESUMO
The standard of care for locally advanced rectal cancer is total neoadjuvant therapy followed by surgical resection. Current evidence suggests that selected patients may be able to delay or avoid surgery without affecting survival rates if they achieve a complete clinical response (CCR). However, for older cancer patients who are too frail for surgery or decline the surgical procedure, local recurrence may lead to a deterioration of patient quality of life. Thus, for clinicians, a treatment algorithm which is well tolerated and may improve CCR in older and frail patients with rectal cancer may improve the potential for prolonged remission and potential cure. Recently, immunotherapy with check point inhibitors (CPI) is a promising treatment in selected patients with high expression of program death ligands receptor 1 (PD- L1). Radiotherapy may enhance PD-L1 expression in rectal cancer and may improve response rate to immunotherapy. We propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced rectal cancer who are too frail for surgery or who decline surgery.
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Objective: Follicular lymphoma (FL) is an indolent B-cell lymphoproliferative disorder, characterized by a lymphoid follicular pattern of growth. PFI-1 or CPI-203 has been known to effectively promote the inhibition of primary effusion lymphoma progression. This study aimed at investigating the anti-tumor properties of PFI-1 and CPI-203 on FL cells and uncover the underlying mechanism of action. Methods: FL cells were treated with PFI-1 and CPI-203, and the treated cells were evaluated for their cell viability, cell cycle and apoptosis using CCK8, flow cytometry, and Western blot assays. A xenograft mouse model was used for assessing the in vivo effects of CPI-203 on tumorigenesis. Results: PFI-1 or CPI-203 showed potential inhibitory effects on the cell viability of DOHH2 and RL cells in a dose-response-dependent manner. Furthermore, PFI-1 and CPI-203 inhibited cell growth, induced apoptosis of FL cells in vitro, and facilitated the translocation of ß-catenin into cytoplasm both in vitro and in vivo. After engrafted with FL cells, CPI-203-treated mice got a longer duration of survival and a smaller tumor size than control mice. Mechanistically, PFI-1 and CPI-203 impede the activity of ß-catenin and its downstream molecules by regulating the DVL2/GSK3ß axis. Conclusion: In conclusion, PFI-1 and CPI-203 may serve as potential anti-tumor inhibitors for the therapy of FL.
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Bispecific antibodies (bsAbs) are a class of antibodies that can mediate novel mechanisms of action compared to monospecific monoclonal antibodies (mAbs). Since the discovery of mAbs and their adoption as therapeutic agents in the 1980s and 1990s, the development of bsAbs has held substantial appeal. Nevertheless, only three bsAbs (catumaxomab, blinatumomab, emicizumab) were approved through the end of 2020. However, since then, 11 bsAbs received regulatory agency approvals, of which nine (amivantamab, tebentafusp, mosunetuzumab, cadonilimab, teclistamab, glofitamab, epcoritamab, talquetamab, elranatamab) were approved for the treatment of cancer and two (faricimab, ozoralizumab) in non-oncology indications. Notably, of the 13 currently approved bsAbs, two, emicizumab and faricimab, have achieved blockbuster status, showing the promise of this novel class of therapeutics. In the 2020s, the approval of additional bsAbs can be expected in hematological malignancies, solid tumors and non-oncology indications, establishing bsAbs as essential part of the therapeutic armamentarium.
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Anticorpos Biespecíficos , Antineoplásicos , Neoplasias Hematológicas , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológicoRESUMO
Accurately predicting compound-protein interactions (CPI) is a critical task in computer-aided drug design. In recent years, the exponential growth of compound activity and biomedical data has highlighted the need for efficient and interpretable prediction approaches. In this study, we propose GraphsformerCPI, an end-to-end deep learning framework that improves prediction performance and interpretability. GraphsformerCPI treats compounds and proteins as sequences of nodes with spatial structures, and leverages novel structure-enhanced self-attention mechanisms to integrate semantic and graph structural features within molecules for deep molecule representations. To capture the vital association between compound atoms and protein residues, we devise a dual-attention mechanism to effectively extract relational features through .cross-mapping. By extending the powerful learning capabilities of Transformers to spatial structures and extensively utilizing attention mechanisms, our model offers strong interpretability, a significant advantage over most black-box deep learning methods. To evaluate GraphsformerCPI, extensive experiments were conducted on benchmark datasets including human, C. elegans, Davis and KIBA datasets. We explored the impact of model depth and dropout rate on performance and compared our model against state-of-the-art baseline models. Our results demonstrate that GraphsformerCPI outperforms baseline models in classification datasets and achieves competitive performance in regression datasets. Specifically, on the human dataset, GraphsformerCPI achieves an average improvement of 1.6% in AUC, 0.5% in precision, and 5.3% in recall. On the KIBA dataset, the average improvement in Concordance index (CI) and mean squared error (MSE) is 3.3% and 7.2%, respectively. Molecular docking shows that our model provides novel insights into the intrinsic interactions and binding mechanisms. Our research holds practical significance in effectively predicting CPIs and binding affinities, identifying key atoms and residues, enhancing model interpretability.
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Aprendizado Profundo , Proteínas , Humanos , Proteínas/química , Proteínas/metabolismo , Animais , Algoritmos , Caenorhabditis elegans/metabolismo , Desenho de Fármacos , Ligação ProteicaRESUMO
Lysine-specific histone demethylase 5A (KDM5A) is known to facilitate proliferation in cancer cells and maintain stemness to repress the astrocytic differentiation of neural stem cells (NSCs). In the study presented here, we investigated the effect of a KDM5 inhibitor, CPI-455, on NSC fate control. CPI-455 induced astrocytogenesis in NSCs during differentiation. Kdm5a, but not Kdm5c, knockdown induced glial fibrillary acidic protein (Gfap) transcription. CPI-455 induced signal transducer and activator of transcription 3, increased bone morphogenetic protein 2 expression, and enhanced mothers against decapentaplegic homolog 1/5/9 phosphorylation. The treatment of CPI-455 enhanced the methylation of histone H3 lysine 4 in the Gfap promoter when compared to that of the dimethyl sulfoxide control. In addition, CPI-455 treatment significantly reduced the recruitment of KDM5A to the Gfap promoter. Our data suggest that the KDM5 inhibitor CPI-455 effectively controls NSC cell fate via KDM5A inhibition and induces astrocytogenesis.