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Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency, throughput, and resource minimization. This review systematically summarizes the development history, typology, and prospective applications of encoding and displayed technologies, including phage display, ribosomal display, mRNA display, yeast cell display, one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, and new peptide-encoded technologies, and examples of preclinical and clinical translation. We discuss the progress of novel targeted therapeutic agents, covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear, monocyclic, and bicyclic peptides, in addition to antibodies. We also address the pending challenges and future prospects of drug discovery, including the size of screening libraries, advantages and disadvantages of the technology, clinical translational potential, and market space. This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.
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The primary aim of the present study was to investigate the effect of dexmedetomidine (DEX) on postoperative pain and early cognitive impairment in old male patients, who underwent laparoscopic cholecystectomy (LC). A total of 97 old patients, subjected to LC at the 980 Hospital of the Joint Service Support Force of the People's Liberation Army of China, were randomly divided into two groups, namely the DEX and normal saline groups. Patients in the DEX group received an intravenous infusion of 0.8 µg/kg DEX within 10 min following general anesthesia, followed by a maintenance infusion of 0.5 µg/(kg/h). Furthermore, patients in the normal saline group were treated with an equivalent volume of normal saline. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) tests at 6 h, 1, 2 and 3 days, postoperatively. The incidence of postoperative cognitive dysfunction (POCD) and postoperative adverse events were recorded for both groups. In addition, the Visual Analogue Scale (VAS) pain score was utilized to assess the pain level of all patients, while the Quality of Recovery-15 (QoR-15) scale was employed to analyze the postoperative recovery results. Therefore, the MoCA score was higher in the DEX group compared with the normal saline group at 6 h and day 1 postoperatively. Additionally, the MMSE score was higher at 6 h postoperatively in the DEX group compared with the normal saline group. Correspondingly, the incidence of POCD was lower in the DEX group compared with the normal saline group at 6 h and day 1, after LC (P<0.05). VAS score in resting state for patients in the DEX group was significantly lower compared with the normal-saline group (P<0.05). Furthermore, the QoR-15 scale score in patients in the DEX group was notably increased compared with the normal saline group on the first and second days after the operation (P<0.05). Overall, the present study verified that the continuous infusion of DEX at a rate of 0.5 µg/(kg/h) during LC could effectively reduce the incidence of early POCD and alleviate postoperative pain in old male patients, thus facilitating postoperative recovery.
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Soil heavy metal distributions exhibit regional heterogeneity due to the complex characteristics of parent materials and soil formation processes, emphasizing the need for appropriate regional standards prior to assessing soil risks. This study focuses on Hainan Island and employs the Multi-purpose Regional Geochemical Survey dataset to establish heavy metal geochemical baseline and background values for soil using an iterative method. Geographical detector analysis reveals that parent materials are the primary factor influencing heavy metal distribution, followed by soil types and land use. Heavy metal geochemical baseline values are established for the island's three environments and administrative regions. Notably, a universal geochemical baseline value cannot adequately represent regional variations in heavy metal distribution, with parent materials playing a crucial role in various scenarios. Locally applicable values based on parent material are the most representative for Hainan Island. This study provides a reference framework for developing region-specific environmental baseline values for soil heavy metal assessments.
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BACKGROUND AND AIMS: Morphological awareness is an essential ability for successful reading. This study aimed to explore the contribution of morphological awareness to reading comprehension (RC) in Chinese. Particularly, this study sought to determine whether the relation between morphological awareness and RC differs across various facets of morphological awareness (homophone awareness, homonym awareness, and compounding awareness), grades, or ability levels. SAMPLES AND METHODS: A total of 148 Chinese students were evaluated on a battery of tests from third to sixth grade. Multiple regression analyses were used to examine the unique roles of homophone, homonym, and compounding awareness on RC in different grades. Quantile regression analyses were conducted to investigate the more or less influences of facets of morphological awareness on RC across the ability range. RESULTS: A series of multiple and quantile regressions revealed that (1) compounding awareness rather than homophone awareness and homonym awareness, directly and uniquely explained the development of RC, (2) the effect of compounding awareness on RC increased with grade level, and (3) the contribution of compounding awareness to RC decreased as children move from poor to better readers. CONCLUSIONS: The findings reveal a developmental shift in the relation between morphological awareness and RC, as well as clarify when and for whom to enhance which facet of morphological awareness is particularly important.
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Compreensão , Leitura , Humanos , Criança , População do Leste Asiático , Conscientização , EstudantesRESUMO
To understand the distribution characteristics and potential ecological risks of heavy metals in soils in the typical volcanic area, 2,592 soil samples were collected from the surface layer (0-20 cm) and 269 samples were collected from the middle (80-100 cm) and deep layers (180-200 cm) in northeast of Hainan province, China. Accordingly, eight heavy metals (Cu, Pb, Zn, Cr, Ni, Cd, As, and Hg) were analyzed and determined. The effects of different parent materials and land use types on the accumulation of heavy metals in soils were compared, and the primary heavy metal sources were analyzed. The pollution level and ecological risk of heavy metals in soils in the study area were evaluated using the geo-accumulation index (Igeo) and potential ecological risk indices (E i & RI). The results showed that, except that of Pb, the median concentrations of the analyzed heavy metals in the surface soils were higher than the background concentrations in the Hainan Island soils, indicating varying degrees of accumulation. The influence of land use type on the accumulation of heavy metals in surface soils varied from that of the parent materials. Anthropogenic activities highly influenced As, Cd, Hg, and Pb concentrations, whereas geological conditions primarily influenced Cr, Cu, Ni, and Zn concentrations. The Igeo results showed that the mean value of the eight metal elements were greater than zero, except for Pb. In the surface soils, the Igeo values of As, Cd, Hg, and Zn mostly fell into the light to moderate pollution class, and those of Cr, Cu, and Ni fell into the medium and heavy pollution class. The RI of the study area showed a high to significantly high ecological risk because of the Cd, Hg, and Ni concentrations. The results give a new insight in the parent material's geochemical control on the heavy metal elements in soils, and it can serve as a reference for the background value of local soil heavy metals and provide a scientific basis for controlling the potential ecological risk of heavy metals and reasonable land use plans.
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To understand the enrichment factors and pollution levels of heavy metals in agricultural soils in the semi-arid region of Hainan island, 1818 surface soil samples were collected in Gancheng Town and analyzed for their heavy metal contents and physicochemical composition. Correlation analysis was used to determine the heavy metal enrichment factors. The geo-accumulation index (Igeo), comprehensive ecological risk index (RI), and hazard index (HI), as well as carcinogenic risk (CR), were used to assess the degree of pollution and health risk. Positive matrix factorization (PMF) was used to determine the primary sources of pollution and priority sources. The average values of heavy metal contents in the topsoil were 22.7, 0.128, 33.4, 14.5, 0.032, 9.32, 32.5, and 43.3 mg·kg-1 for As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn, respectively. With the exception of Zn, the concentrations of other heavy metals in the topsoil were higher than the soil background values of Hainan, showing different degrees of heavy metal accumulation effect. The Igeo revealed that the major pollutant element in soils was As, followed by Cd and Cu. The RI showed that the proportion of soil samples that were high-risk level or worse was 29.4% of the total number of samples, among which As was the major source of risk. The health risk assessment results indicated that As, Cr, and Ni exposure presented carcinogenic risk for children with high CR values. Based on PMF, four major sources of heavy metals were identified in the study area. Hg was derived mainly from industrial sources, and As was closely associated with agricultural activities. Ni, Cu, Cr, and Zn were related to soil parent materials. Pb and Cd were associated with agricultural activities and traffic emissions. The PMF models combined with correlation analysis were useful for estimating the source apportionment of heavy metals in soils.
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Mercúrio , Metais Pesados , Poluentes do Solo , Cádmio/análise , Carcinógenos/análise , Criança , China , Monitoramento Ambiental/métodos , Humanos , Chumbo/análise , Mercúrio/análise , Metais Pesados/análise , Medição de Risco , Solo/química , Poluentes do Solo/análiseRESUMO
Canine parvovirus 2 (CPV2) causes one of the most serious canine viral infections, with high mortality in young dogs. In 2014, 2019, and 2021, we determined genetic sequences of CPV2 strains obtained from 39 fecal samples collected from the Yanbian Korean Autonomous Prefecture in the Jilin Province of China. Sequence alignments were performed using the major capsid protein (VP2) gene; protein sequences of these samples had high nucleotide (>97.4%) and amino acid (>95.6%) identity. All of the amino acid sequences contained Ser297Ala and Tyr324Ile mutations. Our survey indicated a high prevalence of CPV2 variants in Yanbian Prefecture, with the new CPV2a variant (26 of 39; 67%) being the most frequent. CPV2c, identified in 9 of 39 (23%) samples, had not been detected in this region previously, indicating the potential risk of CPV2 mutation. The sequences of our 39 CPV2 samples were more highly homologous to the published Chinese strains than to the CPV2 variant strains found in other countries.
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Doenças do Cão , Infecções por Parvoviridae , Parvovirus Canino , Animais , China/epidemiologia , Doenças do Cão/epidemiologia , Cães , Epidemiologia Molecular , Infecções por Parvoviridae/epidemiologia , Infecções por Parvoviridae/veterinária , Parvovirus Canino/genética , FilogeniaRESUMO
Heavy metals are naturally occurring elements with high natural background levels in the volcanic area. Therefore, it is necessary to conduct a risk assessment and identify potential sources of heavy metals. In this study, 4488 soil samples (0-20 cm) were collected in Chengmai County, a typical volcanic area in Hainan Province, and analyzed for eight heavy metals and major oxides. Pollution level, ecological risks, and health risks were evaluated by geo-accumulation index (Igeo), pollution index (PI), potential ecological risk index (RI), hazard index (HI), and carcinogenic risks (CR). The positive matrix factorization (PMF) model was further used to determine the priority source of heavy metals. The average values of heavy metal concentrations in soil were 7.06, 0.07, 156.88, 33.43, 0.05, 72.47, 19.48, and 67.51 mg kg-1 for As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn, respectively. Except for Pb, the average concentrations of all heavy metals exceeded background concentration in Hainan soils, indicating different degrees of heavy metal enrichment. The Igeo and PI showed that the main pollutant element in volcanic soils was Ni, followed by Cr and Cu. The RI shows that the percentage of soil samples with considerable or worse potential ecological risk was 44.4% of the total samples, with Hg, As, Cd, and Ni causing high ecological risks. The estimated average daily doses of heavy metals were below the tolerable limits and the HI values were below one for both adults and children, indicating that the residents had an acceptable potential non-carcinogenic risk. However, the potential carcinogenic risk of exposure to Cr, Ni, and As was unacceptable for residents, with high CR values exceeding 10-4, especially for children. Based on the PMF, five major sources of heavy metals were found in the study area: Ni, Cu, and Zn mainly from parent materials, As and Pb from daily life and vehicle emissions, Cd from agricultural activities, Hg from industrial activities, and Cr from parent materials under different environmental conditions. Significant positive correlations between Al2O3, TFe2O3, Mn, soil organic carbon (SOC), and heavy metals reflect that aluminium-rich minerals, Fe-Mn oxides, and SOC are the most critical factors affecting heavy metal accumulation in volcanic agricultural soils.
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Mercúrio , Metais Pesados , Poluentes do Solo , Adulto , Cádmio , Carbono , Carcinógenos , Criança , China , Monitoramento Ambiental , Humanos , Chumbo , Metais Pesados/análise , Óxidos , Medição de Risco , Solo , Poluentes do Solo/análiseRESUMO
The accumulation of some harmful elements in plants from intensive production systems pose a serious threat to human health. In this study, seven heavy metals(Cu, Pb, Zn, Cr, Cd, As, and Hg) and their distribution characteristics in the crops, vegetables, and fruits were analyzed alongside single factor evaluation and Nemero index analysis. Combined with dietary recommended consumption data from the Chinese Nutrition Society, the dietary exposure of heavy metals were further analyzed, and a consequent safety risk assessment was conducted. A total of 673 crop, vegetable, and fruit samples were collected from typical intensive production systems in Hainan Province. The results showed that the content of Cu, As, and Hg in the 673 plant samples was below the value of the national food standard. The exceed rates of Pb, Zn, Cr, and Cd were 2.67%, 3.71%, 2.53%, and 3.71%, respectively. The heavy metal comprehensive pollution degree of six species of plants showed the trend of leafy vegetables > tuber crops > non-leafy vegetables > legume crops > fruits > cereals. In particular, Cr in leafy vegetables showed significantly higher hazard quotients(HQ) than that in other types, and exceeded 1, suggesting a high potential health risk via the ingestion of heavy metals through leafy vegetables. The relatively lower hazard index(HI) values of tuber crops, non-leafy vegetables, legume crops, fruits, and cereals suggest that these types of plants are more suitable for intensive production systems.
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Metais Pesados , Poluentes do Solo , China , Grão Comestível/química , Monitoramento Ambiental , Frutas/química , Humanos , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise , VerdurasRESUMO
INTRODUCTION: Transplantation of bone marrow mesenchymal stem cells (BMSCs) can repair injured hearts. However, whether BMSC populations contain cells with cardiac stem cell characteristics is ill-defined. We report here that Notch signalling can promote differentiation of c-Kit(POS)/NKX2.5(POS) BMSCs into cardiomyocyte-like cells. METHODS: Total BMSCs were isolated from Sprague-Dawley rat femurs and c-Kit(POS) cells were purified. c-Kit(POS)/NKX2.5(POS) cells were isolated by single-cell cloning, and the presence of cardiomyocyte, smooth muscle cell (SMC), and endothelial cell differentiation markers assessed by immunofluorescence staining and semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Levels of c-Kit and Notch1-4 in total BMSCs and c-Kit(POS)/NKX2.5(POS) BMSCs were quantitated by flow cytometry. Following infection with an adenovirus over-expressing Notch1 intracellular domain (NICD), total BMSCs and c-Kit(POS)/NKX2.5(POS) cells were assessed for differentiation to cardiomyocyte, SMC, and endothelial cell lineages by immunofluorescence staining and real-time quantitative RT-PCR. Total BMSCs and c-Kit(POS)/NKX2.5(POS) cells were treated with the Notch1 ligand Jagged1 and markers of cardiomyocyte, SMC, and endothelial cell differentiation were examined by immunofluorescence staining and real-time quantitative RT-PCR analysis. RESULTS: c-Kit(POS)/NKX2.5(POS) cells were present among total BMSC populations, and these cells did not express markers of adult cardiomyocyte, SMC, or endothelial cell lineages. c-Kit(POS)/NKX2.5(POS) BMSCs exhibited a multi-lineage differentiation potential similar to total BMSCs. Following sorting, the c-Kit level in c-Kit(POS)/NKX2.5(POS) BMSCs was 84.4%. Flow cytometry revealed that Notch1 was the predominant Notch receptor present in total BMSCs and c-Kit(POS)/NKX2.5(POS) BMSCs. Total BMSCs and c-Kit(POS)/NKX2.5(POS) BMSCs overexpressing NICD had active Notch1 signalling accompanied by differentiation into cardiomyocyte, SMC, and endothelial cell lineages. Treatment of total BMSCs and c-Kit(POS)/NKX2.5(POS) BMSCs with exogenous Jagged1 activated Notch1 signalling and drove multi-lineage differentiation, with a tendency towards cardiac lineage differentiation in c-Kit(POS)/NKX2.5(POS) BMSCs. CONCLUSIONS: c-Kit(POS)/NKX2.5(POS) cells exist in total BMSC pools. Activation of Notch1 signalling contributed to multi-lineage differentiation of c-Kit(POS)/NKX2.5(POS) BMSCs, favouring differentiation into cardiomyocytes. These findings suggest that modulation of Notch1 signalling may have potential utility in stem cell translational medicine.
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Células da Medula Óssea/citologia , Proteínas de Homeodomínio/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Células Endoteliais/citologia , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1 , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/citologia , Proteínas dos Microfilamentos/metabolismo , Microscopia de Fluorescência , Proteínas Musculares/metabolismo , Miócitos Cardíacos/citologia , Miócitos de Músculo Liso/citologia , Proteínas Proto-Oncogênicas c-kit/genética , Ratos , Ratos Sprague-Dawley , Receptor Notch1/química , Receptor Notch1/genética , Proteínas Serrate-Jagged , Transdução de Sinais , Fatores de Transcrição/genética , Troponina T/genética , Troponina T/metabolismo , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
In the present study, we evaluated the role of phosphatidylinositol-3 OH kinase/protein kinase B (PI3K/Akt) signaling on changes to epithelial-to-mesenchymal reverting transition (EMrT) in nasopharyngeal carcinoma (NPC). Protein expression levels of p-Akt (Ser473), and the epithelialto-mesenchymal transition (EMT) markers E-cadherin, vimentin, α smooth muscle actin (α-SMA), were examined in clinical samples from 130 cases of undifferentiated non-keratinizing NPC, and 20 cases of benign nasopharyngitis. The relationship between protein expression levels and the statue of NPC lymph node metastasis was analyzed. The poorlydifferentiated NPC cell line CNE2Z was treated with various concentrations of the PI3K inhibitor, LY294002, and western blotting and quantitative polymerase chain reaction assays were used to analyze the activation of PI3K/Akt signaling and expression of E-cadherin, vimentin and α-SMA. The ability of cellular migration and invasion was assessed using Transwell assays. The in vivo effects of LY294002 on metastasis and expression of EMT markers in CNE2Z cells was evaluated using tumor xenograft experiments. The expression levels of p-Akt (Ser473) in NPC samples were higher than those in nasopharyngitis. There were reduced levels of membrane E-cadherin protein expression, and increased cytosol vimentin and α-SMA expression levels in NPC samples compared with those in nasopharyngitis samples. High expression levels of p-Akt (Ser473), vimentin, and α-SMA, and low expression levels of E-cadherin were positively associated with lymph node metastasis of NPC cells. Treating CNE2Z cells with LY294002 inhibited p-Akt (Ser473), vimentin and α-SMA expression but upregulated E-cadherin expression, leading to significantly attenuated cell invasion and migration. Administration of mice with LY294002 resulted in upregulation of membrane E-cadherin, and downregulation of vimentin and α-SMA in CNE2Z xenografts, with reduced pulmonary metastasis. Our findings suggest that inhibiting the PI3K/Akt pathway using LY294002 attenuated NPC metastasis via induction of EMrT.
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Cromonas/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Metástase Linfática/patologia , Morfolinas/administração & dosagem , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais/efeitos dos fármacos , Actinas/metabolismo , Animais , Caderinas/metabolismo , Carcinoma , Linhagem Celular Tumoral , Cromonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vimentina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To identify differentially expressed proteins between pancreatic tumor tissues and the adjacent noncancerous tissues by comparative proteomics analysis. METHODS: Six pairs pancreatic tumor tissues and the adjacent noncancerous tissues were obtained and selected for two-dimensional polyacrylamide gel electrophoresis (2-DE) analysis. The differentially expressed proteins were identified using the PDQuest 2-D analysis software. After cutting and enzymolysis, the differentially expressed proteins were analysised by ESI-Q-TOF mass spectrometer. The MS/MS data were acquired and searched in the Swiss-Prot database using MASCOT software. Altered expression of representative proteins was validated by immunohistochemical staining. RESULTS: A total of 97 points were identified as differentially expressed by two-dimensional gel electrophoresis, of which 31 were successfully identified by ESI-Q-TOF mass spectrometer. Among the proteins identified by mass spectrometer, 23 were upregulated and the other 8 were downregulated. These proteins were involved in different functional processes and protein families: glucolysis, hyaluronidase, I, II-phase metabolic enzymes, metalloproteinase, cytoskeleton, Ca2+ metabolism and so on. Immunohistochemical staining revealed an overexpression of HYAL1 and low expression of CYP2C8 and GSTM2 in pancreatic tumor. CONCLUSION: The differentially expressed proteins between pancreatic tumor tissues and the adjacent noncancerous tissues can be identified by comparative proteomics approach. The selected proteins will provide a valuable clue and help for further research.