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Background: The planting of mangroves is extensively used to control the invasive plant Spartina alterniflora in coastal wetlands. Different plant species release diverse sets of small organic compounds that affect rhizosphere conditions and support high levels of microbial activity. The root-associated microbial community is crucial for plant health and soil nutrient cycling, and for maintaining the stability of the wetland ecosystem. Methods: High-throughput sequencing was used to assess the structure and function of the soil bacterial communities in mudflat soil and in the rhizosphere soils of S. alterniflora, mangroves, and native plants in the Oujiang estuarine wetland, China. A distance-based redundancy analysis (based on Bray-Curtis metrics) was used to identify key soil factors driving bacterial community structure. Results: S. alterniflora invasion and subsequent mangrove afforestation led to the formation of distinct bacterial communities. The main soil factors driving the structure of bacterial communities were electrical conductivity (EC), available potassium (AK), available phosphorus (AP), and organic matter (OM). S. alterniflora obviously increased EC, OM, available nitrogen (AN), and NO3 --N contents, and consequently attracted copiotrophic Bacteroidates to conduct invasion in the coastal areas. Mangroves, especially Kandelia obovata, were suitable pioneer species for restoration and recruited beneficial Desulfobacterota and Bacilli to the rhizosphere. These conditions ultimately increased the contents of AP, available sulfur (AS), and AN in soil. The native plant species Carex scabrifolia and Suaeda glauca affected coastal saline soil primarily by decreasing the EC, rather than by increasing nutrient contents. The predicted functions of bacterial communities in rhizosphere soils were related to active catabolism, whereas those of the bacterial community in mudflat soil were related to synthesis and resistance to environmental factors. Conclusions: Ecological restoration using K. obovata has effectively improved a degraded coastal wetland mainly through increasing phosphorus availability and promoting the succession of the microbial community.
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Espécies Introduzidas , Rizosfera , Microbiologia do Solo , Áreas Alagadas , China , Poaceae/microbiologia , Poaceae/crescimento & desenvolvimento , Solo/química , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Microbiota/fisiologia , EstuáriosRESUMO
Walking with heavy loads is a common task in military affairs and daily life. Considering that the shoulder and leg muscles fatigue will be caused during walking, which will affect the walking endurance and physical health. However, the suspended backpack is found to improve the energy efficiency of walking with a load. In this study, A lightweight suspended backpack is designed and proposing a model for estimating the metabolic cost of a suspended backpack based on gait phase. In this study, four inertial measurement units (IMUs) are fixed on the thigh and shank, six flexible pressure sensors are mounted on the soles of the feet and shoulders, respectively. The gait is defined as four successive phases. For each phase, the muscle tension is solved based on the muscle moment balance theory. Based on the phase segmentation method, the ECCF index is calculated by adding the gait phase constraint and backpack data calculation into the energy prediction model, and the relatively accurate data is obtained. In addition, In order to study the effects of the suspended backpack with different parameters on the cost metabolism, gait phase and biomechanics, the subjects need to carry the same load of 16.5 kg to walk 400 m at the different speeds, respectively. A group of seven healthy subjects in the same walking condition need to conduct two experiments: suspended backpack work (SB) and ordinary backpack (OB). The experimental results show that the suspended backpack can reduce plantar pressure and shoulder pressure in the SB condition. And at the speed of 5.0 km/h, ground reaction force (GRF) and shoulder reaction force (SRF) were reduced by 11.59 % and 13.22 % in the SB condition compared to the OB condition, respectively.
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BACKGROUND: Suicide is a critical global public health issue that demands a better understanding of its complex causes and effective interventions. This study examines data from the Hangzhou Mental Health Hotline (2014-2023) to explore the relationship between consultation themes and suicidal ideation, with an emphasis on gender differences and how these associations changed during different phases of the COVID-19 pandemic. METHODS: This retrospective analysis covers 128,245 calls to the hotline over a decade. Chi-square tests identified differences in suicidal ideation across consultation themes and demographics. Multivariate logistic regression models were used to examine the relationship between specific themes and suicidal ideation, adjusting for confounders. The analysis was stratified by gender and pandemic phases to assess the interaction between gender and pandemic-related changes. RESULTS: The incidence of suicidal ideation was highest during the mid-pandemic phase (11.95%), compared to the pre-pandemic (7.68%) and post-pandemic phases (10.66%). Additionally, the rate was slightly higher among female callers (9.8%) than male callers (9.4%). Physical illness (OR = 4.70, 95% CI: 3.71-5.91) had the strongest association with suicidal ideation, followed by mental health issues (OR = 3.35, 95% CI: 3.03-3.70). Compared to male callers, female callers were more significantly affected by physical illness (OR = 6.86 vs. OR = 3.71, p < 0.001) and mental health issues (OR = 6.81 vs. OR = 2.11, p < 0.001). In the context of romantic relationship problems, female callers had a higher likelihood of suicidal ideation (OR = 4.13 vs. OR = 1.88, p < 0.001). Similarly, marital and family issues were more strongly associated with suicidal ideation in female callers (OR = 4.58 vs. OR = 1.21, p < 0.001). During the global COVID-19 pandemic, the association between suicidal ideation and consultation themes among male callers showed a sharp upward trend, which eased after the pandemic. In contrast, the association among female callers gradually accumulated and continued to worsen in the later stages of the pandemic. CONCLUSION: This study highlights the necessity of implementing gender-sensitive mental health interventions tailored to different gender groups during and after global crises such as the COVID-19 pandemic, to safeguard public mental health effectively.
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COVID-19 , Linhas Diretas , Ideação Suicida , Humanos , Masculino , Feminino , COVID-19/psicologia , COVID-19/epidemiologia , China/epidemiologia , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Linhas Diretas/estatística & dados numéricos , Fatores Sexuais , Adulto Jovem , Adolescente , Fatores de RiscoRESUMO
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.
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Antineoplásicos , Proliferação de Células , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quimera de Direcionamento de ProteóliseAssuntos
Transtornos da Consciência , Humanos , Transtornos da Consciência/etiologia , Transtornos da Consciência/diagnóstico por imagem , Doenças Talâmicas/diagnóstico por imagem , Doenças Talâmicas/complicações , Masculino , Feminino , Síndrome , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância MagnéticaRESUMO
What is already known about this topic?: Fine particulate matter (PM2.5) and ozone (O3) are prevalent pollutants in the atmosphere, which threaten human health, especially the respiratory system. Typically, people are exposed to a mixture of various pollutants in the environment. Thus, the single and combined effects of both pollutants need to be investigated. What is added by this report?: PM2.5 and O3 increase the risk of death from lung cancer, chronic obstructive pulmonary disease (COPD), and respiratory diseases, with their lagged and cumulative effects analyzed, indicating an acute effect. In addition, combined exposure to both pollutants can significantly affect disease deaths. What are the implications for public health practice?: This study provides further evidence of the single and combined effects of PM2.5 and O3 on respiratory diseases, emphasizing the need for sustained efforts in air pollution control, with greater attention to the synergistic management of air pollutants.
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OBJECTIVES: To study the diagnosis, treatment, and complications of hypophosphatemic rickets (HR) in children, explore effectiveness evaluation indicators for the disease, and understand the pattern in height growth among these patients. METHODS: A retrospective analysis of the initial clinical data and five-year follow-up data of 85 children with HR treated at Children's Hospital of Nanjing Medical University from January 2008 to December 2022. RESULTS: Among the 85 children with HR, there were 46 males (54%) and 39 females (46%). The age at initial diagnosis ranged from 6 months to 13 years and 9 months, with a median age of 2.75 years. The average height standard deviation score was -2.0±1.1. At initial diagnosis, children exhibited reduced blood phosphate levels and elevated alkaline phosphatase (ALP), with 99% (84/85) presenting with lower limb deformities. The positive rate for PHEX gene mutations was 93% (55/59). One year post-treatment, there was a significant reduction in ALP levels and the gap between the lower limbs (P<0.05). The fastest height growth occurred in the first year after treatment, at 8.23 cm/year, with a peak height velocity (PHV) phase lasting about two years during puberty. The height increased by 9-20 cm in male children during the PHV stage and 10-15 cm in female children. Major complications included nephrocalcinosis and hyperparathyroidism. The incidence rate of nephrocalcinosis in the first year after treatment was 55% (22/40), which increased with the duration of the disease (P<0.001); an increased urinary phosphate/creatinine ratio was positively associated with a higher risk of nephrocalcinosis (OR=1.740, P<0.001). The incidence of hyperparathyroidism in the first year after treatment was 64% (27/42). CONCLUSIONS: For children presenting with lower limb deformities, short stature, and slow growth, early testing for blood levels of phosphate, calcium, and ALP, along with imaging examinations of the lower limbs, can aid in the early diagnosis of HR. Genetic testing may be utilized for definitive confirmation when necessary. ALP combined with improvements in skeletal deformities and annual height growth can serve as indicators of therapeutic effectiveness for HR. Compared to normal children, children with HR demonstrate a lower height increase during the PHV phase, necessitating close follow-up and timely adjustment of treatment plans Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 677-682.
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Raquitismo Hipofosfatêmico , Humanos , Masculino , Feminino , Criança , Estudos Retrospectivos , Pré-Escolar , Lactente , Adolescente , Seguimentos , Raquitismo Hipofosfatêmico/genética , Raquitismo Hipofosfatêmico/etiologia , Fosfatase Alcalina/sangue , Estatura , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/sangue , MutaçãoRESUMO
Background and aim: Most patients with hepatocellular carcinoma (HCC) in China have been diagnosed with spleen deficiency syndrome (SDS), which accelerates the progression of HCC by disrupting the tumor microenvironment homeostasis. This study aimed to investigate the intercellular crosstalk in HCC with SDS. Experimental procedure: An HCC-SDS mouse model was established using orthotopic HCC transplantation based on reserpine-induced SDS. Single-cell data analysis and cancer cell prediction were conducted using Seurat and CopyKAT package, respectively. Intercellular interactions were explored using CellPhoneDB and CellChat and subsequently validated using co-culture assays, ELISA and histological staining. We performed pathway activity analysis using gene set variation analysis and the Seurat package. The extracellular matrix (ECM) remodeling was assessed using a gel contraction assay, atomic force microscopy, and Sirius red staining. The deconvolution of the spatial transcriptomics data using the "CARD" package based on single-cell data. Results and conclusion: We successfully established the HCC-SDS mouse model. Twenty-nine clusters were identified. The interactions between cancer cells and cancer-associated fibroblasts (CAFs) were significantly enhanced via platelet-derived growth factor (PDGF) signaling in HCC-SDS. CAFs recruited in HCC-SDS lead to ECM remodeling and the activation of TGF-ß signaling pathway. Deconvolution of the spatial transcriptome data revealed that CAFs physically surround cancer cells in HCC-SDS. This study reveals that the crosstalk of CAFs-cancer cells is crucial for the tumor-promoting effect of SDS. CAFs recruited by HCC via PDGFA may lead to ECM remodeling through activation of the TGF-ß pathway, thereby forming a physical barrier to block immune cell infiltration under SDS.
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This paper looks at how social expectations and gender roles affect the mental health of Chinese women. Traditional Chinese culture, influenced by Confucianism and patriarchy, still has a negative impact on women's mental well-being, despite efforts for gender equality. Women's mental health is vital for both individuals and society, and this study aims to understand these issues better to help shape policies and interventions.
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Papel de Gênero , Linhas Diretas , Transtornos Mentais , Adulto , Feminino , Humanos , China , População do Leste Asiático , Transtornos Mentais/terapia , Transtornos Mentais/etnologia , Saúde Mental , Saúde da MulherRESUMO
Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of end-stage kidney disease in children, mostly associated with focal segmental glomerulosclerosis (FSGS). Advances in genomic science have enabled the identification of causative variants in 20-30% of SRNS patients. Methods: We used whole exome sequencing to explore the genetic causes of SRNS in children. Totally, 101 patients with SRNS and 13 patients with nephrotic proteinuria and FSGS were retrospectively enrolled in our hospital between 2018 and 2022. For the known monogenic causes analysis, we generated a known SRNS gene list of 71 genes through reviewing the OMIM database and literature. Results: Causative variants were identified in 23.68% of our cohort, and the most frequently mutated genes in our cohort were WT1 (7/27), NPHS1 (3/27), ADCK4 (3/27), and ANLN (2/27). Five patients carried variants in phenocopy genes, including MYH9, MAFB, TTC21B, AGRN, and FAT4. The variant detection rate was the highest in the two subtype groups with congenital nephrotic syndrome and syndromic SRNS. In total, 68.75% of variants we identified were novel and have not been previously reported in the literature. Conclusion: Comprehensive genetic analysis is key to realizing the clinical benefits of a genetic diagnosis. We suggest that all children with SRNS undergo genetic testing, especially those with early-onset and extrarenal phenotypes.
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Mangrove forests are colloquially referred to as "Earth's kidneys" and serve many important ecological and commercial functions. Salinity and waterlogging stress are the most important abiotic stressors restricting the growth and development of mangroves. Kandelia obovata (K. obovata) is the greatest latitudinally-distributed salt mangrove species in China.Here, morphology and transcriptomics were used to study the response of K. obovata to salt and waterlogging stress. In addition, weighted gene co-expression network analysis of the combined gene expression and phenotypic datasets was used to identify core salinity- and waterlogging-responsive modules. In this study, we observed that both high salinity and waterlogging significantly inhibited growth and development in K. obovata. Notably, growth was negatively correlated with salt concentration and positively correlated with waterlogging duration, and high salinity was significantly more inhibitive than waterlogging. A total of 7, 591 salt-responsive and 228 waterlogging-responsive differentially expressed genes were identified by RNA sequencing. Long-term salt stress was highly correlated with the measured physiological parameters while long-term waterlogging was poorly correlated with these traits. At the same time, 45 salinity-responsive and 16 waterlogging-responsive core genes were identified. All 61 core genes were mainly involved in metabolic and biosynthesis of secondary metabolites pathways. This study provides valuable insight into the molecular mechanisms of salinity and waterlogging tolerance in K. obovata, as well as a useful genetic resource for the improvement of mangrove stress tolerance using molecular breeding techniques.
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Objective: To investigate the preference of elderly patients for "Internet + Nursing Service", so as to provide reference for accurately matching their service needs. Methods: Based on discrete choice experiments, the elderly patients' "Internet + Nursing Service" choice preference questionnaire was prepared, and 410 elderly patients were interviewed face-to-face. The Conditional Logit Model was used for quantitative analysis of the experimental data. Results: The six attributes included in the study had a significant impact on the elderly patients' preference for "Internet + Nursing Service" (P < .05). Among non-economic attributes, "medical insurance reimbursement ratio -70%" has the highest utility (.263, P < .001), with "hospital size - larger (.205, P < .05)" and "medical insurance reimbursement ratio -50%" (.188, P < .05) ranking second and third, respectively. The relative importance of the attribute of medical insurance reimbursement proportion is the highest (26.44%), and the relative importance of service content is the lowest (9.78%). If the proportion of medical insurance reimbursement increases from 30% to 70%, patients are willing to pay 202.9 yuan, and the probability of choosing "Internet + Nursing Service" increases by 6.1%. Conclusion: Patients prefer to choose a higher proportion of medical insurance reimbursement, a larger medical institution, a higher level of nurses, low single service costs, a basic package, and "Internet + Nursing Service" led by the government and hospitals. Improvement of the price and medical insurance payment policy is recommended, along with the enhancement of the ability of primary nursing services, strengthening of the management of Internet enterprise platforms, and scientific assessment of the needs of patients for personalized nursing services.
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Comportamento de Escolha , Internet , Preferência do Paciente , Humanos , Idoso , Masculino , Feminino , Inquéritos e Questionários , Preferência do Paciente/estatística & dados numéricos , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Serviços de Enfermagem/estatística & dados numéricosRESUMO
OBJECTIVES: To investigate the clinical characteristics, pathological features, treatment regimen, and prognosis of children with lupus nephritis (LN) and thrombotic microangiopathy (TMA), as well as the treatment outcome of these children and the clinical and pathological differences between LN children with TMA and those without TMA. METHODS: A retrospective analysis was conducted on 12 children with LN and TMA (TMA group) who were admitted to the Department of Nephrology, Children's Hospital of Nanjing Medical University, from December 2010 to December 2021. Twenty-four LN children without TMA who underwent renal biopsy during the same period were included as the non-TMA group. The two groups were compared in terms of clinical manifestations, laboratory examination results, and pathological results. RESULTS: Among the 12 children with TMA, 8 (67%) had hypertension and 3 (25%) progressed to stage 5 chronic kidney disease. Compared with the non-TMA group, the TMA group had more severe tubulointerstitial damage, a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score at onset, and higher cholesterol levels (P<0.05). There were no significant differences between the two groups in the percentage of crescent bodies and the levels of hemoglobin and platelets (P>0.05). CONCLUSIONS: There is a higher proportion of individuals with hypertension among the children with LN and TMA, as well as more severe tubulointerstitial damage. These children have a higher SLEDAI score and a higher cholesterol level.
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Hipertensão , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Microangiopatias Trombóticas , Criança , Humanos , Nefrite Lúpica/complicações , Rim/patologia , Estudos Retrospectivos , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/terapia , Prognóstico , Hipertensão/complicações , ColesterolRESUMO
Flooding stress on mangroves is growing continually with rising sea level. In this study, the physiology and transcriptome of the mangrove species Kandelia obovata under flooding stress were analyzed. With increasing inundation time, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), soluble sugar (SS), soluble protein (SP), and proline (Pro) content declined, while peroxidase (POD) and ascorbate peroxidase (APX) activity rose significantly. According to the KEGG pathway enrichment analysis, upregulated differentially expressed genes (DEGs) were enriched in the plant hormone signaling pathway. Furthermore, MYB44 and MYB108 genes from the MYB transcription factor family and RAP2.12, DREB2B, and ERF4 genes from the AP2/ERF family were up-regulated under flooding conditions. A strong correlation was established between the expression levels of 12 DEGs under flooding stress and RNA sequencing data and was verified by qRT-PCR. These results provide new insights into the molecular mechanism of K. obovata in response to flooding stress.
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Rhizophoraceae , Rhizophoraceae/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Antioxidantes/metabolismo , Superóxido Dismutase/metabolismo , Glutationa/metabolismo , Estresse FisiológicoRESUMO
This paper focuses on predicting the length of stay for patients on the first day of admission and propose a predictive model named DGLoS. In order to capture the influence of various complex factors on the length of stay as well as the dependencies among various factors, DGLoS uses a deep neural network to model both the patient information and diagnostic information. Targeting at different attribution types, we utilize different coding methods to convert raw data to the input features. Besides, we find that similar patients have closer lengths of stay. Therefore, we further design a module based on graph representation learning to generate patients' similarity-aware representations, capturing the similarity between patients and therefore enhancing predictions. These similarity-aware representations are incorporated into the output of the deep neural network to jointly perform the prediction. We have conducted comprehensive experiments on a real-world hospitalization dataset. The performance comparison shows that our proposed DGLoS model improves predictive performance and the significance test demonstrates the improvement is significant. The ablation study verifies the effectiveness of each of the proposed components and the hyper-parameter investigation shows the robustness of the proposed model.
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Aprendizagem , Pacientes , Humanos , Tempo de Internação , Hospitalização , Redes Neurais de ComputaçãoRESUMO
[This corrects the article DOI: 10.1016/j.apsb.2022.08.024.].
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In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe3O4@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe3O4@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe3O4@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.
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Ultra-sensitive detection of cancer-related biomarkers in serum is of great significance for early diagnosis, treatment, prognosis, and staging of cancer. In this work, we proposed a surface-enhanced Raman scattering and fluorescence (SERS/FL) dual-mode biosensor for hepatocellular carcinoma (HCC)-related miRNA (miR-224) detection using the composition of well-arranged Au nanoarrays (Au NAs) substrate coupled with the target-catalyzed hairpin assembly (CHA) strategy. The hot spots densely and uniformly distributed on the Au array offers considerably enhanced and reproducible SERS signals, along with their wide and open surface to facilitate miR-224 adsorption. By this sensing strategy, the target miR-224 can be detected in a wide linear range (1 fM to 1 nM) with a limit of detection of 0.34 fM in the SERS mode and 0.39 fM in the FL mode. Meanwhile, this biosensor with exceptional specificity and anti-interference ability can discriminate target miR-224 from other interference miRNAs. Practical analysis of human blood samples also demonstrated considerable reliability and repeatability of our developed strategy. Furthermore, this biosensor can distinguish HCC cancer subjects from normal ones and monitor HCC patients before and after hepatectomy as well as guide the distinct Barcelona clinic liver cancer (BCLC) stages. Overall, benefiting from a well-arranged Au nanoarray, CHA amplification strategy, and SERS/metal enhanced fluorescence effect, this established biosensor opens new avenues for the early prediction, warning, monitoring, and staging of HCC.
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Técnicas Biossensoriais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas Metálicas , MicroRNAs , Humanos , Carcinoma Hepatocelular/diagnóstico , Ouro/química , Limite de Detecção , Neoplasias Hepáticas/diagnóstico , Nanopartículas Metálicas/química , Nanoestruturas , Reprodutibilidade dos Testes , Análise Espectral Raman , Corantes Fluorescentes/químicaRESUMO
The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.
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Proteínas Nucleares , Fatores de Transcrição , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , ProteóliseRESUMO
BACKGROUND: The effect of recombinant human GH (rhGH) in Chinese children with chronic kidney disease (CKD) is unclear. METHODS: This was a 52-week, multicenter, randomized, open-label, negative-controlled phase 3 study. Prepubertal subjects were randomized 1:1 to either daily subcutaneous injections of rhGH 0.05 mg/kg/day or no treatment for 52 weeks. RESULTS: A total of 68 subjects with a mean age of 7.8 ± 3.27 years were enrolled. At week 52, the height standard deviation score (HT-SDS) in the treated group increased by 0.75 ± 0.58, which was significantly higher compared with 0.17 ± 0.47 in the untreated group (least squares mean 0.58, 95% confidence interval, 0.32-0.84; P < 0.001). At week 52, significant improvements were observed in other growth parameters (height velocity [P < 0.001]), insulin-like growth factor 1 (IGF-1) SDS [P < 0.001], IFG-1/insulin-like growth factor binding protein-3 molar ratio [P < 0.001], and height [P < 0.001]) compared with the untreated control. Seven patients reported treatment-related adverse events (TRAEs) and most TRAEs were mild in severity. Most subjects recovered without further intervention. CONCLUSIONS: Daily rhGH for 52 weeks in children with CKD-induced growth retardation significantly improved HT-SDS and other growth parameters without compromising safety. IMPACT: The efficacy and safety of growth hormone (GH) therapy in Chinese children with chronic kidney disease (CKD) are unclear. This study found that giving short stature Chinese children with CKD daily recombinant human growth hormone (rhGH) for 52 weeks improved growth parameters without compromising safety. This study's information can give physicians the confidence to treat these patients in their clinical practice.