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The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.
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Aprendizado Profundo , Diagnóstico por Imagem , Pneumonia/diagnóstico , Criança , Humanos , Redes Neurais de Computação , Pneumonia/diagnóstico por imagem , Curva ROC , Reprodutibilidade dos Testes , Tomografia de Coerência ÓpticaRESUMO
This research focused on how upregulation of S100A9 contributed to the pathogenesis of the dry eye disease (DED) and whether S100A9 served as a promising therapeutic target in DED. Public single-cell RNA sequencing (scRNA-seq) data of a lacrimal gland excision (LGE) murine DED model was analyzed. LGE model was established and expression of protein was measured through immunofluorescence and Western blot. DED-related signs were evaluated through tear secretion and fluorescent staining. TUNEL was performed to detect the level of cell death. Briefly, S100A9 was recognized as a highly variable gene in the DED group. LGE model was successfully established, and S100A9 showed a time-dependent increase in the corneal epithelia. Autophagic blockage was predicted by the scRNA-seq data in DED, and further verified by decrease of LC3B-II/LC3B-I and increase of SQSTM1 and p-mTOR/mTOR, while S100A9 inhibitor paquinimod (PAQ) reversed the changes. PAQ also downregulated TLR4, and inhibition of TLR4 also alleviated autophagic blockage in DED. Finally, signs of DED, chronic corneal inflammation and cell death got a remission after either inhibition of S100A9 or TLR4. In general, we deduced a S100A9-TLR4-Autophagic blockage pathway in the pathogenesis of DED.
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Mycotoxins are a heterogeneous group of toxins produced by fungi that can grow in staple crops (e.g., maize, cereals), resulting in health risks due to widespread exposure from human consumption and inhalation. Dried blood spot (DBS), dried serum spot (DSS), and volumetric tip microsampling (VTS) assays were developed and validated for several important mycotoxins. This review summarizes studies that have developed these assays to monitor mycotoxin exposures in human biological samples and highlights future directions to facilitate minimally invasive sampling techniques as global public health tools. A systematic search of PubMed (MEDLINE), Embase (Elsevier), and CINAHL (EBSCO) was conducted. Key assay performance metrics were extracted to provide a critical review of the available methods. This search identified 11 published reports related to measuring mycotoxins (ochratoxins, aflatoxins, and fumonisins) using DBS/DSS and VTS assays. Multimycotoxin assays adapted for DBS/DSS and VTS have undergone sufficient laboratory validation for applications in large-scale population health and human biomonitoring studies. Future work should expand the number of mycotoxins that can be measured in multimycotoxin assays, continue to improve multimycotoxin assay sensitivities of several biomarkers with low detection rates, and validate multimycotoxin assays across diverse populations with varying exposure levels. Validated low-cost and ultrasensitive minimally invasive sampling methods should be deployed in human biomonitoring and public health surveillance studies to guide policy interventions to reduce inequities in global mycotoxin exposures.
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Micotoxinas , Humanos , Saúde Global , Monitoramento Ambiental/métodosRESUMO
BACKGROUND: Radiotherapy is a primary local treatment for tumors, yet it may lead to complications such as radiation-induced heart disease (RIHD). Currently, there is no standardized approach for preventing RIHD. Dexmedetomidine (Dex) is reported to have cardio-protection effects, while its role in radiation-induced myocardial injury is unknown. In the current study, we aimed to evaluate the radioprotective effect of dexmedetomidine in X-ray radiation-treated mice. METHODS: 18 male mice were randomized into 3 groups: control, 16 Gy, and 16 Gy + Dex. The 16 Gy group received a single dose of 16 Gy X-ray radiation. The 16 Gy + Dex group was pretreated with dexmedetomidine (30 µg/kg, intraperitoneal injection) 30 min before X-ray radiation. The control group was treated with saline and did not receive X-ray radiation. Myocardial tissues were collected 16 weeks after X-ray radiation. Hematoxylin-eosin staining was performed for histopathological examination. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was performed to assess the state of apoptotic cells. Immunohistochemistry staining was performed to examine the expression of CD34 molecule and von Willebrand factor. Besides, western blot assay was employed for the detection of apoptosis-related proteins (BCL2 apoptosis regulator and BCL2-associated X) as well as autophagy-related proteins (microtubule-associated protein 1 light chain 3, beclin 1, and sequestosome 1). RESULTS: The findings demonstrated that 16 Gy X-ray radiation resulted in significant changes in myocardial tissues, increased myocardial apoptosis, and activated autophagy. Pretreatment with dexmedetomidine significantly protects mice against 16 Gy X-ray radiation-induced myocardial injury by inhibiting apoptosis and autophagy. CONCLUSION: In summary, our study confirmed the radioprotective effect of dexmedetomidine in mitigating cardiomyocyte apoptosis and autophagy induced by 16 Gy X-ray radiation.
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Apoptose , Autofagia , Dexmedetomidina , Miócitos Cardíacos , Lesões Experimentais por Radiação , Animais , Autofagia/efeitos dos fármacos , Autofagia/efeitos da radiação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos da radiação , Miócitos Cardíacos/metabolismo , Apoptose/efeitos dos fármacos , Masculino , Dexmedetomidina/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Camundongos , Proteínas Relacionadas à Autofagia/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Reguladoras de Apoptose/metabolismoRESUMO
Manure replacing synthetic fertilizer is a viable practice to ensure crop yield and increase soil organic carbon (SOC), but its impact on greenhouse gas (GHG) emissions is inconsistent, thus remains its effect on CF unclear. In this study, a 7-year field experiment was conducted to assess the impact of replacing synthetic fertilizer with manure on crop productivity, SOC sequestration, GHG emissions and crop CF under winter wheat-summer maize cropping system. Five treatments were involved: synthetic nitrogen, phosphorus, and potassium fertilizer (NPK) and 25%, 50%, 75%, and 100% of manure replacing synthetic N (25%M, 50%M, 75%M, and 100%M). Compared with NPK treatment, 25%M and 50%M treatments maintained annual yield (winter wheat plus summer maize) and sustainable yield index (SYI), but 75%M and 100%M treatments significantly decreased annual yield, and 100%M treatment also significantly reduced annual SYI. The SOC content exhibited a significant increasing trend over years in all treatments. After 7 years, SOC storage in manure treatments increased by 3.06-11.82 Mg ha-1 relative to NPK treatment. Manure treatments reduced annual GHG emissions by 14%-60% over NPK treatment. The CF of the cropping system ranged from 0.16 to 0.39 kg CO2 eq kg-1 of grain without considering SOC sequestration, in which the CF of manure treatments lowered by 18%-58% relative to NPK treatment. When SOC sequestration was involved in, the CF varied from -0.39 to 0.37 kg CO2 eq kg-1 of grain, manure treatments significantly reduced the CF by 22%-208% over NPK treatment. It was concluded that replacing 50% of synthetic fertilizer with manure was a sound option for achieving high crop yield and SYI but low CF under the tested cropping system.
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Pegada de Carbono , Fertilizantes , Esterco , Solo , Triticum , Zea mays , Zea mays/crescimento & desenvolvimento , Triticum/crescimento & desenvolvimento , Solo/química , Carbono , Estações do Ano , Nitrogênio , Produtos Agrícolas/crescimento & desenvolvimento , Agricultura/métodos , Gases de Efeito EstufaRESUMO
Cadmium (Cd) exposure damages the reproductive system. Lipid droplets (LDs) play an important role in steroid-producing cells to provide raw material for steroid hormone. We have found that the LDs of Leydig cells exposed to Cd are bigger than those of normal cells, but the effects on steroidogenesis and its underlying mechanism remains unclear. Using Isobaric tag for relative and absolute quantitation (iTARQ) proteomics, phosphodiesterase beta-2 (PLCß2) was identified as the most significantly up-regulated protein in immature Leydig cells (ILCs) and adult Leydig cells (ALCs) derived from male rats exposed to maternal Cd. Consistent with high expression of PLCß2, the size of LDs was increased in Leydig cells exposed to Cd, accompanied by reduction in cholesterol and progesterone (P4) levels. However, the high PLCß2 did not result in high diacylglycerol (DAG) level, because Cd exposure up-regulated diacylglycerol kinases ε (DGKε) to promote the conversion from DAG to phosphatidic acid (PA). Exogenous PA, which was consistent with the intracellular PA concentration induced by Cd, facilitated the formation of large LDs in R2C cells, followed by reduced P4 level in the culture medium. When PLCß2 expression was knocked down, the increased DGKε caused by Cd was reversed, and then the PA level was decreased to normal. As results, large LDs returned to normal size, and the level of total cholesterol was improved to restore steroidogenesis. The accumulation of PA regulated by PLCß2-DAG-DGKε signal pathway is responsible for the formation of large LDs and insufficient steroid hormone synthesis in Leydig cells exposed to Cd. These data highlight that LD is an important target organelle for Cd-induced steroid hormone deficiency in males.
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Cádmio , Células Intersticiais do Testículo , Ratos , Masculino , Animais , Células Intersticiais do Testículo/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Gotículas Lipídicas/metabolismo , Fosfolipase C beta/metabolismo , Ácidos Fosfatídicos/metabolismo , Diglicerídeos/metabolismo , Transdução de Sinais , Esteroides/metabolismo , Progesterona/metabolismo , Colesterol/metabolismoRESUMO
BACKGROUND: Plastic film mulch is widely used to improve crop yield and water use efficiency (WUE, yield per unit evapotranspiration) in semi-arid regions. It is commonly applied as partial-film mulch (PM: at least 50% soil cover) or full-film mulch (FM: complete soil cover). The PM has lower economic and environmental cost; hence it would be a superior technology provided it delivers similar gains in yield and WUE in relation to FM. RESULTS: To solve contradictory results from individual studies, we compared FM and PM in a meta-analysis of 100 studies with 1881 comparisons (685 for wheat; 1196 for maize). Compared with bare ground, FM and PM both increased yield of wheat (20-26%) and maize (37-52%), and WUE of wheat (16-20%) and maize (38-48%), with statistically undistinguishable differences between PM and FM. The increases in crop yield and WUE were stronger at elevation > 1000 m, with annual precipitation<400 mm, and on loess soil, especially for maize. CONCLUSIONS: We concluded that partial-film mulch could replace full-film mulch to return similar yield and WUE improvement, with reduced cost and environmental pollution. © 2021 Society of Chemical Industry.
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Agricultura/métodos , Plásticos/economia , Triticum/crescimento & desenvolvimento , Água/metabolismo , Zea mays/crescimento & desenvolvimento , Agricultura/economia , Poluição Ambiental/prevenção & controle , Solo/química , Triticum/metabolismo , Água/análise , Zea mays/metabolismoRESUMO
Triple negative breast cancer (TNBC) displays higher heterogeneity, stronger invasiveness, higher risk of metastasis and poorer prognosis compared with major breast cancer subtypes. KIF3A, a member of the kinesin family of motor proteins, serves as a microtubule-directed motor subunit and has been found to regulate early development, ciliogenesis and tumorigenesis. To explore the expression, regulation and mechanism of KIF3A in TNBC, 3 TNBC cell lines, 98 cases of primary TNBC and paired adjacent tissues were examined. Immunohistochemistry, real-time PCR, western blot, flow cytometry, short hairpin RNA (shRNA) interference, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation techniques, transwell assays, scratch tests, and xenograft mice models were used. We found that KIF3A was overexpressed in TNBC and such high KIF3A expression was also associated with tumor recurrence and lymph node metastasis. Silencing of KIF3A suppressed TNBC cell proliferation by repressing the Rb-E2F signaling pathway and inhibited migration and invasion by repressing epithelial-mesenchymal transition. The tumor size was smaller and the number of lung metastatic nodules was lower in KIF3A depletion MDA-MB-231 cell xenograft mice than in the negative control group. In addition, KIF3A overexpression correlated with chemoresistance. These results suggested that high expression of KIF3A in TNBC was associated with the tumor progression and metastasis.
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Fatores de Transcrição E2F/genética , Cinesinas/genética , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ubiquitina-Proteína Ligases/genética , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cinesinas/antagonistas & inibidores , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND This study aimed to use three modeling methods, logistic regression analysis, random forest analysis, and fully-connected neural network analysis, to develop a diagnostic gene signature for the diagnosis of ventilator-associated pneumonia (VAP). MATERIAL AND METHODS GSE30385 from the Gene Expression Omnibus (GEO) database identified differentially expressed genes (DEGs) associated with patients with VAP. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment identified the molecular functions of the DEGs. The least absolute shrinkage and selection operator (LASSO) regression analysis algorithm was used to select key genes. Three modeling methods, including logistic regression analysis, random forest analysis, and fully-connected neural network analysis, also known as also known as the feed-forward multi-layer perceptron (MLP), were used to identify the diagnostic gene signature for patients with VAP. RESULTS Sixty-six DEGs were identified for patients who had VAP (VAP+) and who did not have VAP (VAP-). Ten essential or feature genes were identified. Upregulated genes included matrix metallopeptidase 8 (MMP8), arginase 1 (ARG1), haptoglobin (HP), interleukin 18 receptor 1 (IL18R1), and NLR family apoptosis inhibitory protein (NAIP). Down-regulated genes included complement factor D (CFD), pleckstrin homology-like domain family A member 2 (PHLDA2), plasminogen activator, urokinase (PLAU), laminin subunit beta 3 (LAMB3), and dual-specificity phosphatase 2 (DUSP2). Logistic regression, random forest, and MLP analysis showed receiver operating characteristic (ROC) curve area under the curve (AUC) values of 0.85, 0.86, and 0.87, respectively. CONCLUSIONS Logistic regression analysis, random forest analysis, and MLP analysis identified a ten-gene signature for the diagnosis of VAP.
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Perfilação da Expressão Gênica , Aprendizado de Máquina , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/genética , Algoritmos , Área Sob a Curva , Bases de Dados Genéticas , Regulação da Expressão Gênica , Ontologia Genética , Genoma Humano , Humanos , Anotação de Sequência Molecular , Mapas de Interação de Proteínas/genéticaRESUMO
OBJECTIVE: Saikosaponin c (SSc), a compound purified from the traditional Chinese herb of Radix Bupleuri was previously identified to exhibit anti-HBV replication activity. However, the mechanism through which SSc acts against HBV remains unknown. In this study, we investigated the mechanism of SSc mediated anti-HBV activity. METHODS: HepG2.2.15 cells were cultured at 37 â in the presence of 1-40 µg/mL of SSc or DMSO as a control. The expression profile of HBV markers, cytokines, HNF1α and HNF4α were investigated by real-time quantitative PCR, Elisa, Western blot and Dot blotting. Knockdown of HNF1α or HNF4α in HepG2.2.15 cells was mediated by two small siRNAs specifically targeting HNF1α or HNF4α. RESULTS: We found that SSc stimulates IL-6 expression, leading to attenuated HNF1α and HNF4α expression, which further mediates suppression of HBV pgRNA synthesis. Knockdown of HNF1α or HNF4α in HepG2.2.15 cells by RNA interference abrogates SSc's anti-HBV role. Moreover, SSc is effective to both wild-type and drug-resistant HBV mutants. CONCLUSION: SSc inhibits pgRNA synthesis by targeting HNF1α and HNF4α. These results indicate that SSc acts as a promising compound for modulating pgRNA transcription in the therapeutic strategies against HBV infection.
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Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Ácido Oleanólico/análogos & derivados , RNA Viral/biossíntese , RNA/biossíntese , Saponinas/farmacologia , Células Hep G2 , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Ácido Oleanólico/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , DNA Tumoral Circulante , Metilação de DNA , Neoplasias Hepáticas , Modelos Biológicos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Masculino , PrognósticoRESUMO
BACKGROUND Whether regional anesthesia is associated with tumor-free and long-term survival is controversial. Here, we focused on whether epidural anesthesia affects the long-term survival of gastric cancer patients after surgery. MATERIAL AND METHODS We obtained the records of 273 patients undergoing gastric cancer surgery between August 2006 and December 2010. All patients received elective surgery, and the end-point was death. The general anesthesia group comprised 116 patients and the epidural-supplemented group comprised 157 patients. The results were analyzed using a multivariable model to determine the relationship between epidural use and long-term survival. RESULTS No obvious association was detected between epidural use and long-term survival according to the Cox model (P=0.522); the adjusted estimated hazard ratio was 0.919 (95% CI 0.71-1.19). However, according to Kaplan-Meier analysis, epidural anesthesia was associated with long-term survival among younger patients (age up to 64) (p=0.042, log-rank) (but not among older patients (p=0.203, log-rank). A lower American Society of Anesthesiologists (ASA) class and less chemoradiotherapy exposure were also associated with a longer survival. However, advanced tumor stage still has a significant negative impact on survival. CONCLUSIONS No obvious difference was detected between the 2 anesthesia groups, but younger patients may benefit from epidural anesthesia.
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Anestesia Epidural/métodos , Anestesia Geral/métodos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Idoso , Anestesia Epidural/estatística & dados numéricos , Anestesia Geral/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sobreviventes , Resultado do TratamentoRESUMO
Metal additive manufacturing technology has developed by leaps and bounds in recent years; selective laser melting technology is a major form in metal additive manufacturing, and its application scenarios are numerous. For example, it is involved in many fields including aerospace field, automotive, mechanical processing, and the nuclear industry. At the same time, it also indirectly provides more raw materials for all walks of life in our country. However, during the selective laser melting process, due to the action of high-energy-density lasers, the temperature of most metal powders can reach above the vaporization temperature. Light metals with relatively low vaporization temperatures such as magnesium and zinc have more significant vaporization and other behaviors. At the same time, during the metal vaporization process, a variety of by-products are generated, which seriously affect the forming quality and mechanical properties of the workpiece, resulting in the workpiece quality possibly not reaching the expected target. This paper mainly interprets the metal vaporization behavior in the LPBF process and summarizes the international research progress and suppression methods for vaporization.
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INTRODUCTION: The morbidity and mortality of spinal cord injury (SCI) are increasing year by year. It is of vital importance to ascertain the mechanism of SCI. Phosphoglycerate mutase family member 5 (PGAM5) is viewed as a molecular marker of SCI, but its specific role in SCI is elusive. MATERIAL AND METHODS: Following establishment of the SCI mouse model, the pathological examination of the spinal cord was initially assessed using H&E staining. PGAM5 expression in spinal cord tissues was appraised utilizing immunohistochemistry and RT-qPCR. Subsequently, after the expression of PGAM5 in SCI mice was inhibited by adenovirus transfection, the degree of SCI was determined, and the motor ability of hind limbs was estimated with the BBB score. In addition, the apoptosis of neurons, microglia activation and the generation of inflammatory cytokines in the spinal cord of mice were detected. Next, at the cellular level, PGAM5 expression was inhibited in the BV2 microglial cells induced by lipopolysaccharide (LPS), so as to explore the effects of down-regulation of PGAM5 on the activation, inflammation and apoptosis of neurons. Finally, western blot was applied for the appraisement of apoptosis signal-regulating kinase-1 (ASK-1)/p38/nuclear factor-kappa B (NF-kB) signaling-associated proteins. RESULTS: PGAM5 expression in SCI mice was found to be raised. Inhibition of PGAM5 expression in SCI mice can significantly reduce spinal cord pathological injury, SCI-induced neuronal apoptosis, microglial cell activation and inflammation. The above regulatory process might be realized through the ASK-1/p38/NF-kB signaling pathway mediated by PGAM5. CONCLUSIONS: Down-regulation of PGAM5 attenuated SCI-induced neuronal injury by inhibiting ASK-1/p38/NF-kB signaling.
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Intestine damage is an acute abdominal disease that usually requires emergency sealing. However, traditional surgical suture not only causes secondary damage to the injured tissue, but also results in adhesion with other tissues in the abdominal cavity. To this end, a thermally reversible injectable gelatin-based hydrogel adhesive (GTPC) is constructed by introducing transglutaminase (TGase) and proanthocyanidins (PCs) into a gelatin system. By reducing the catalytic activity of TGase, the density of covalent and hydrogen bond crosslinking in the hydrogel can be regulated to tune the sol-gel transition temperature of gelatin-based hydrogels above the physiological temperature (42 °C) without introducing any synthetic small molecules. The GTPC hydrogel exhibits good tissue adhesion, antioxidant, and antibacterial properties, which can effectively seal damaged intestinal tissues and regulate the microenvironment of the damaged site, promoting tissue repair and regeneration. Intriguingly, temperature-induced hydrogen bond disruption and reformation confer the hydrogel with asymmetric adhesion properties, preventing tissue adhesion when applied in vivo. Animal experiment outcomes reveal that the GTPC hydrogel can seal the damaged intestinal tissue firmly, accelerate tissue healing, and efficiently prevent postoperative adhesion.
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Gelatina , Hidrogéis , Intestinos , Temperatura , Animais , Hidrogéis/química , Hidrogéis/administração & dosagem , Hidrogéis/farmacologia , Aderências Teciduais/prevenção & controle , Intestinos/efeitos dos fármacos , Gelatina/química , Gelatina/administração & dosagem , Transglutaminases/metabolismo , Adesivos Teciduais/farmacologia , Adesivos Teciduais/química , Adesivos Teciduais/administração & dosagem , Proantocianidinas/farmacologia , Proantocianidinas/química , Proantocianidinas/administração & dosagem , Cicatrização/efeitos dos fármacos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Injeções , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/administração & dosagemRESUMO
Fetal and neonatal exposures to perinatal oxidative stress (OS) are key mediators of bronchopulmonary dysplasia (BPD). To characterize these exposures, adductomics is an exposure science approach that captures electrophilic addition products (adducts) in blood protein. Adducts are bound to the nucleophilic cysteine loci of human serum albumin (HSA), which has a prolonged half-life. We conducted targeted and untargeted adductomics to test the hypothesis that adducts of OS vary with BPD. We studied 205 preterm infants (≤28 weeks) and 51 full-term infants from an ongoing birth cohort. Infant plasma was collected at birth (cord blood), 1-week, 1-month, and 36-weeks postmenstrual age. HSA was isolated from plasma, trypsin digested, and analyzed using high-performance liquid chromatography-mass spectrometry to quantify previously annotated (known) and unknown adducts. We identified 105 adducts in cord and postnatal blood. A total of 51 known adducts (small thiols, direct oxidation products, and reactive aldehydes) were increased with BPD. Postnatally, serial concentrations of several known OS adducts correlated directly with supplemental oxygen exposure. The application of large-scale adductomics elucidated OS-mediated pathways of BPD. This is the first study to investigate the "neonatal-perinatal exposome" and to identify oxidative stress-related exposure biomarkers that may inform antioxidant strategies to protect the health of future generations of infants.
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To compare the impact of nanoselenium and sodium selenite on the performance, blood indices, and milk metabolites of dairy cows during the peak lactation period, two groups of dairy cows under the same conditions were selected as the control group (CON group) and treatment group (NSe group) for a 38-day (10 days for adaptation and 28 days for sampling) experiment. The control group (CON) was provided a basal diet +3.3 g/d of sodium selenite (purity1%), whereas the nanoselenium group (NSe) was offered the same diet +10 mL/d of nanoselenium (selenium concentration 1,500 mg/L). The results showed that NSe significantly increased the milk yield, milk selenium content, and feed efficiency (p < 0.05), but had no significant effect on other milk components (p > 0.05). NSe significantly increased blood urea nitrogen (BUN) and alkaline phosphatase (ALP) (p < 0.05), but had no significant effects on malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), blood total antioxidant capacity (T-AOC), or blood selenium (p > 0.05). In addition, the nontargeted metabolomics of the milk was determined by LC-MS technology, and the differentially abundant metabolites and their enrichment pathways were screened. According to these findings, NSe considerably increased the contents of cetylmannoside, undecylenoic acid, 3-hydroxypentadecanoic acid, 16-hydroxypentadecanoic acid, threonic acid, etc., but decreased the contents of galactaric acid, mesaconic acid, CDP-glucose etc. Furthermore, the enriched metabolic pathways that were screened with an impact value greater than 0.1 included metabolism of niacin and niacinamide, pyruvate, citrate cycle, riboflavin, glycerophospholipid, butanoate and tyrosine. Pearson correlation analysis also revealed a relationship between different milk metabolites and blood selenium, as well as between milk selenium and blood biochemical indices. In conclusion, compared with sodium selenite, nanoselenium improves the milk yield, feed efficiency, and milk selenium content of dairy cows and regulates milk metabolites and related metabolic pathways in Holstein dairy cows during the peak lactation period, which has certain application prospects in dairy production.
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The fetus and infants are particularly vulnerable to Cadmium (Cd) due to the immaturity of the blood-brain barrier. In utero and early life exposure to Cd is associated with cognitive deficits. Although such exposure has attracted widespread attention, its gender-specificity remains controversial, and there are no reports disclosing the underlying mechanism of genderspecific neurotoxicity. We extensively evaluated the learning and cognitive functions and synaptic plasticity of male and female rats exposed to maternal Cd. Maternal Cd exposure induced learning and memory deficits in male offspring rats, but not in female offspring rats. PLCß4 was identified as a critical protein, which might be related to the genderspecific cognitive deficits in male rats. The up-regulated PLCß4 competed with PLCγ1 to bind to PIP2, which counteracted the hydrolysis of PIP2 by PLCγ1. The decreased activation of PLCγ1 inhibited the phosphorylation of CREB to reduce BDNF transcription, which consequently resulted in the damage of hippocampal neurons and cognitive deficiency. Moreover, the low level of BDNF promoted AEP activation to induce Aß deposition in the hippocampus. These findings highlight that PLCß4 might be a potential target for the therapy of learning and cognitive deficits caused by Cd exposure in early life.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Cádmio , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Hipocampo , Lactação , Fosfolipase C gama , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Animais , Feminino , Masculino , Gravidez , Cádmio/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fosfolipase C gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Fosfolipase C beta/metabolismo , Ratos Sprague-Dawley , Fosfatidilinositol 4,5-Difosfato/metabolismo , Exposição Materna , RatosRESUMO
The present study assessed the effects of oligosaccharide-chelated organic trace minerals (OTM) on the growth performance, digestive enzyme activity, blood parameters, slaughter performance, and meat quality indexes of mutton sheep. A total of 60 East Ujumuqin × small-tailed Han crossbred mutton sheep were assigned to two groups (10 duplicates per group) by body weight (26.12 ± 3.22 kg) according to a completely randomized design. Compared to the CON group, the results of the OTM group showed: (1) no significant changes in the initial body weight, final body weight, dry matter intake, average daily gain, and feed conversion ratio (p > 0.05); (2) the activities of trypsin, lipase, and amylase in the jejunum were significantly increased (p < 0.05); (3) serum total protein, albumin, and globulin of the blood were significantly increased (p < 0.05), and the growth factor interleukin IL-10 was significantly higher (p < 0.05), while IL-2, IL-6, and γ-interferon were significantly lower (p < 0.05). Immunoglobulins A, M, and G were significantly higher (p < 0.05); (4) the live weight before slaughter, carcass weights, dressing percentage, eye muscle areas, and GR values did not differ significantly (p > 0.05); (5) shear force of mutton was significantly lower (p < 0.05), while the pH45min, pH24h, drip loss, and cooking loss did not show a significant difference (p > 0.05). The content of crude protein was significantly higher (p < 0.05), while the ether extract content was significantly reduced (p < 0.05), but no significant difference was detected between moisture and ash content; (6) the total amino acids, essential amino acids, semi-essential amino acids, and umami amino acids were significantly increased (p < 0.05). Although umami amino acids were not significant, the total volume increased (p > 0.05). Among these, the essential amino acids, threonine, valine, leucine, lysine in essential amino acids and arginine were significantly increased (p < 0.05). Also, non-essential amino acids, glycine, serine, proline, tyrosine, cysteine, and aspartic acid, were significantly higher (p < 0.05). The content of alanine, aspartate, glutamic acid, phenylalanine, and tyrosine in umami amino acids was significantly higher (p < 0.05).
RESUMO
Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of ß-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the ß-lactam SPOP inhibitor.