RESUMEN
Fertility refers to the ability of animals to maintain reproductive function and give birth to offspring, which is an important indicator to measure the productivity of animals. Fertility is affected by many factors, among which environmental factors may also play key roles. During the past years, substantial research studies have been conducted to detect the factors related to fecundity, including genetic factors and environmental factors. However, the identified genes associated with fertility from countless previous studies are randomly dispersed in the literature, whereas some other novel fertility-related genes are needed to detect from omics-based datasets. Here, we constructed a fertility index factor database FifBase based on manually curated published literature and RNA-Seq datasets. During the construction of the literature group, we obtained 3301 articles related to fecundity for 13 species from PubMed, involving 2823 genes, which are related to 75 fecundity indicators or 47 environmental factors. Eventually, 1558 genes associated with fertility were filtered in 10 species, of which 1088 and 470 were from RNA-Seq datasets and text mining data, respectively, involving 2910 fertility-gene pairs and 58 fertility-environmental factors. All these data were cataloged into FifBase (http://www.nwsuaflmz.com/FifBase/), where the fertility-related factor information, including gene annotation and environmental factors, can be browsed, retrieved and downloaded with the user-friendly interface.
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Animales Domésticos/genética , Minería de Datos , Bases de Datos Genéticas , Fertilidad , Anotación de Secuencia Molecular , Programas Informáticos , AnimalesRESUMEN
MicroRNAs (miRNAs) play vital roles in the development of oocytes and ovarian follicles. We have previously shown differential expression of miR-342-3p during yak oocyte maturation. In this study, we investigated the role of miR-342-3p in meiotic maturation of yak oocytes and the underlying mechanism. The profile of ovarian DNA methyltransferase 1 (DNMT1) expression was investigated in yak by RT-qPCR and western blot analyses. The pattern of Dnmt1 expression in various meiotic stages (GV stage, MI stage and MII stage) of yak oocyte maturation was then measured by immunofluorescence staining. The interaction between Dnmt1 and miR-342-3p was verified by dual-luciferase reporter assay. Finally, miR-342-3p inhibitors were microinjected into yak cumulus-oocyte complex to evaluate the effects on oocyte maturation. MiR-342-3p expression was upregulated in oocytes during meiotic maturation, with significantly higher levels in the MII stage compared with the GV- and MI stages (p < .05), whereas the opposite pattern of Dnmt1 expression was detected. In the period to sexual maturity (3-year-old), DNMT1 showed an age-related pattern of ovarian expression at both the gene and protein levels. Immunohistochemistry analysis also indicated maturation-stage-related differences in DNMT1 expression in the ovarian follicles and corpus luteum, with expression predominantly detected in cumulus cells and oocytes. MiR-342-3p inhibitors effectively upregulated Dnmt1 expression and significantly inhibited oocyte meiotic maturation. Taken together, our results indicate that miR-342-3p plays a vital role in the meiotic maturation of yak oocytes by targeting the 3'-untranslated regions (UTR) of Dnmt1 and provide a new perspective on the mechanism of this process.
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Técnicas de Maduración In Vitro de los Oocitos , MicroARNs , Regiones no Traducidas 3' , Animales , Bovinos/genética , ADN , Femenino , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Meiosis , MicroARNs/metabolismo , Oocitos/fisiología , Oogénesis/genéticaRESUMEN
Porcine reproductive and respiratory syndrome (PRRS) is a disease with a major economic impact in the global pig industry, and this study aims to identify potential anti-PRRSV drugs. We examined the cytotoxicity of four medium-chain fatty acids (MCFAs) (caprylic, caprylic monoglyceride, decanoic monoglyceride, and monolaurin) and their inhibition rate against PRRSV. Then the MCFAs with the best anti-PRRSV effect in in vitro assays were selected for subsequent in vivo experiments. Potential anti-PRRSV drugs were evaluated by viral load assay, pathological assay, and cytokine level determination. The results showed that caprylic monoglyceride (CMG) was the least toxic to cells of the four MCFAs, while it had the highest PRRSV inhibition rate. Then the animals were divided into a low-CMG group, a medium-CMG group, and a high-CMG group to conduct the in vivo evaluation. The results indicated that piglets treated with higher concentrations of caprylic monoglyceride were associated with lower mortality and lower viral load after PRRSV infection (p < 0.05). The pulmonary pathology of the piglets also improved after CMG treatment. The levels of pro-inflammatory cytokines (IL-6, IL-8, IL-1ß, IFN-γ, TNF-α) were significantly downregulated, and the levels of anti-inflammatory cytokine (IL-10) were significantly upregulated in the CMG-treated piglets compared to the positive control group (p < 0.05). Taken together, the present study revealed for the first time that caprylic monoglyceride has strong antiviral activity against PRRSV in vitro and in vivo, suggesting that caprylic monoglyceride could potentially be used as a drug to treat PRRS infection.
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Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Porcinos , Antivirales/farmacología , Monoglicéridos/farmacología , Síndrome Respiratorio y de la Reproducción Porcina/tratamiento farmacológico , CitocinasRESUMEN
OBJECTIVE: Liver damage is a common manifestation and can be life-threatening in adult-onset Still's disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD. METHODS: Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed. RESULTS: LCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694. CONCLUSION: Our results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.
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Lipocalina 2/metabolismo , Hígado/metabolismo , Enfermedad de Still del Adulto/metabolismo , Adulto , Biomarcadores/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Lipocalina 2/sangre , Hígado/patología , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Índice de Severidad de la Enfermedad , Enfermedad de Still del Adulto/sangre , Enfermedad de Still del Adulto/diagnóstico , Enfermedad de Still del Adulto/patologíaRESUMEN
BACKGROUND: Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. METHOD: This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. RESULTS: Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. CONCLUSIONS: In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.
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COVID-19 , Infecciones por Virus de Epstein-Barr , Enfermedad Crítica , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4 , Humanos , Estudios Retrospectivos , SARS-CoV-2 , Activación ViralRESUMEN
BACKGROUND: The global numbers of confirmed cases and deceased critically ill patients with COVID-19 are increasing. However, the clinical course, and the 60-day mortality and its predictors in critically ill patients have not been fully elucidated. The aim of this study is to identify the clinical course, and 60-day mortality and its predictors in critically ill patients with COVID-19. METHODS: Critically ill adult patients admitted to intensive care units (ICUs) from 3 hospitals in Wuhan, China, were included. Data on demographic information, preexisting comorbidities, laboratory findings at ICU admission, treatments, clinical outcomes, and results of SARS-CoV-2 RNA tests and of serum SARS-CoV-2 IgM were collected including the duration between symptom onset and negative conversion of SARS-CoV-2 RNA. RESULTS: Of 1748 patients with COVID-19, 239 (13.7%) critically ill patients were included. Complications included acute respiratory distress syndrome (ARDS) in 164 (68.6%) patients, coagulopathy in 150 (62.7%) patients, acute cardiac injury in 103 (43.1%) patients, and acute kidney injury (AKI) in 119 (49.8%) patients, which occurred 15.5 days, 17 days, 18.5 days, and 19 days after the symptom onset, respectively. The median duration of the negative conversion of SARS-CoV-2 RNA was 30 (range 6-81) days in 49 critically ill survivors that were identified. A total of 147 (61.5%) patients deceased by 60 days after ICU admission. The median duration between ICU admission and decease was 12 (range 3-36). Cox proportional-hazards regression analysis revealed that age older than 65 years, thrombocytopenia at ICU admission, ARDS, and AKI independently predicted the 60-day mortality. CONCLUSIONS: Severe complications are common and the 60-day mortality of critically ill patients with COVID-19 is considerably high. The duration of the negative conversion of SARS-CoV-2 RNA and its association with the severity of critically ill patients with COVID-19 should be seriously considered and further studied.
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Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/mortalidad , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Anciano , COVID-19 , China/epidemiología , Infecciones por Coronavirus/terapia , Enfermedad Crítica , Femenino , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/terapia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: A COVID-19 outbreak started in Wuhan, China, last December and now has become a global pandemic. The clinical information in caring of critically ill patients with COVID-19 needs to be shared timely, especially under the situations that there is still a largely ongoing spread of COVID-19 in many countries. METHODS: A multicenter prospective observational study investigated all the COVID-19 patients received in 19 ICUs of 16 hospitals in Wuhan, China, over 24 h between 8 AM February 2h and 8 AM February 27, 2020. The demographic information, clinical characteristics, vital signs, complications, laboratory values, and clinical managements of the patients were studied. RESULTS: A total of 226 patients were included. Their median (interquartile range, IQR) age was 64 (57-70) years, and 139 (61.5%) patients were male. The duration from the date of ICU admission to the study date was 11 (5-17) days, and the duration from onset of symptoms to the study date was 31 (24-36) days. Among all the patients, 155 (68.6%) had at least one coexisting disease, and their sequential organ failure assessment score was 4 (2-8). Organ function damages were found in most of the patients: ARDS in 161 (71.2%) patients, septic shock in 34 (15.0%) patients, acute kidney injury occurred in 57 (25.2%) patients, cardiac injury in 61 (27.0%) patients, and lymphocytopenia in 160 (70.8%) patients. Of all the studied patients, 85 (37.6%) received invasive mechanical ventilation, including 14 (6.2%) treated with extracorporeal membrane oxygenation (ECMO) at the same time, 20 (8.8%) received noninvasive mechanical ventilation, and 24 (10.6%) received continuous renal replacement therapy. By April 9, 2020, 87 (38.5%) patients were deceased and 15 (6.7%) were still in the hospital. CONCLUSIONS: Critically ill patients with COVID-19 are associated with a higher risk of severe complications and need to receive an intensive level of treatments. COVID-19 poses a great strain on critical care resources in hospitals. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000030164. Registered on February 24, 2020, http://www.chictr.org.cn/edit.aspx?pid=49983&htm=4.
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Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Cuidados Críticos , Brotes de Enfermedades , Unidades de Cuidados Intensivos , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Anciano , COVID-19 , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The genetic polymorphisms of 23 autosomal short tandem repeat (STR) loci included in the HuaxiaTM Platinum kit were evaluated in 1533 unrelated healthy Guangdong Han individuals living in the Guangdong Province in southern China. All of the loci reached the Hardy-Weinberg equilibrium. These loci were examined to determine the allele frequencies and forensic statistical parameters. The genetic relationship between the Guangdong Han and other Chinese populations was also estimated. The combined discrimination power and the probability of excluding the paternity of 23 STR loci were 0.999 999 999 999 999 999 999 999 999 74 and 0.999 999 999 72, respectively. These results suggested that the 23 STR loci are highly polymorphic and suitable for personal forensic identification and paternity testing.
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Etnicidad/genética , Genética de Población , Repeticiones de Microsatélite , Pueblo Asiatico/genética , China , Dermatoglifia del ADN , Frecuencia de los Genes , Humanos , Polimorfismo GenéticoRESUMEN
BACKGROUND: Mechanical ventilation (MV) sustains life in critically ill patients by providing adequate alveolar ventilation. However, prolonged MV could induce inspiratory muscle atrophy known as ventilator-induced diaphragmatic dysfunction (VIDD). Insulin-like growth factor (IGF)-1 has been proven to play crucial roles in regulating skeletal muscle size and function. Meanwhile, the forkhead box protein O1 (FOXO1) has been linked to muscle atrophy. This study aimed to explore the effect of IGF-1 on muscle degradation and remodeling in VIDD and delved into the association of the underlying mechanism involving FOXO1. METHODS: VIDD models were established by treating rats with MV. Adeno-associated virus (AAV) was used for transfection to construct IGF-1 and/or FOXO1 overexpressed rats. There were four groups in this study: normal rats (NC), normal rats with MV treatment (MV), IGF-1-overexpressed rats with MV treatment (MV+IGF-1), and rats overexpressing both IGF-1 and FOXO1 with MV treatment (MV+IGF-1+FOXO1). Protein levels were measured by western blot or enzyme-linked immunosorbent assay (ELISA), and mRNA levels were detected by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). IGF-1 and FOXO1 expression were validated by detecting mRNA and protein levels. Diaphragmatic muscle contractility and morphometry were tested using stimulating electrodes in conjunction with hematoxylin and eosin (H&E) staining. Interleukin (IL)-6 and carbonylated protein were used for evaluating muscle atrophy and oxidation, respectively. Protein degradation was determined by troponin-I level and tyrosine release. Apoptosis was assessed using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay, alongside markers like Bax, B-cell lymphoma 2 (BCL-2), and Cleaved Caspase-3. Atrogin-1, muscle RING finger 1 (MURF1), neuronally expressed developmentally downregulated 4 (NEDD4), muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1), and ubiquitinated protein was used to determine proteolysis. Additionally, protein synthesis was measured by assessing the rates of mixed muscle protein (MMP) and myosin heavy chain (MHC). RESULTS: MV treatment caused IGF-1 downregulation (p < 0.01) and FOXO1 upregulation (p < 0.01). The IGF-1 upregulation downregulated FOXO1 in the MV+IGF-1 group (p < 0.001) while IGF-1 and FOXO1 were both upregulated in the MV+IGF-1+FOXO1 group (p < 0.001). The treatment of MV decreased muscle contractility and cross-sectional areas of diaphragm muscle fibers (p < 0.01). Additionally, IL-6, troponin-1, tyrosine release, carbonylated protein, TUNEL positive nuclei, Bax, Cleaved Caspase-3, Atrogin-1, MURF1, neuronally expressed developmentally downregulated 4 (NEDD4), MUSA1, and ubiquitinated protein levels increased significantly in MV group (p < 0.001) while levels of BCL-2, fractional synthetic rate of MMP and MHC, and type I and type II MHC protein mRNA expression decreased in MV group (p < 0.001). All of these alterations were reversed in the MV+IGF-1 group (p < 0.01), while the IGF-1-induced reversion was disrupted in the MV+IGF-1+FOXO1 group (p < 0.01). CONCLUSIONS: IGF-1 may protect diaphragmatic muscles from VIDD-induced structural damage and function loss by downregulating FOXO1. This action suppresses muscle breakdown and facilitates muscle remodeling in diaphragmatic muscles affected by VIDD.
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Diafragma , Factor I del Crecimiento Similar a la Insulina , Humanos , Ratas , Animales , Diafragma/metabolismo , Diafragma/patología , Caspasa 3/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Ventiladores Mecánicos/efectos adversos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , ARN Mensajero , Tirosina/metabolismoRESUMEN
BACKGROUND: The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity. Aminophylline (AP) has the potential to enhance the contractility of animal skeletal muscle fibers and improve the activity of human respiratory muscles, and the insulin-like growth factor-1 (IGF-1)- forkhead box protein O1 (FOXO1)-muscle RING finger-1 (MURF1) pathway plays a crucial role in skeletal muscle dysfunction. This study aimed to investigate the impact of AP on VIDD and to elucidate the role of the IGF-1-FOXO1-MURF1 pathway as an underlying mechanism. METHODS: Rat models of VIDD were established through MV treatment. IGF-1 lentiviral (LV) interference (LV-IGF-1-shRNA; controlled by lentiviral negative control LV-NC) was employed to inhibit IGF-1 expression and thereby block the IGF-1-FOXO1-MURF1 pathway. Protein and mRNA levels of IGF-1, FOXO1, and MURF1 were assessed using western blot and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), respectively. Diaphragm contractility and morphometry were examined through measurement of compound muscle action potentials (CMAPs) and hematoxylin and eosin (H&E) staining. Oxidative stress was evaluated by levels of hydrogen peroxide (H2O2), superoxide dismutase (SOD), antioxidant glutathione (GSH), and carbonylated protein. Mitochondrial stability was assessed by measuring the mitochondrial membrane potential (MMP), and mitochondrial fission and mitophagy were examined through protein levels of dynamin-related protein 1 (DRP1), mitofusin 2 protein (MFN2), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), and Parkin (western blot). Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay and levels of Bax, B-cell lymphoma 2 (BCL-2), and Caspase-3. Levels of Atrogin-1, neuronally expressed developmentally downregulated 4 (NEDD4), and muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1) mRNA, as well as ubiquitinated protein, were utilized to determine protein degradation. Furthermore, the SUnSET (surface sensing of translation) method was employed to determine rates of protein synthesis. RESULTS: MV treatment upregulated IGF-1 while downregulated FOXO1 and MURF1 (p < 0.05). AP administration reversed IGF-1, FOXO1 and MURF1 (p < 0.05), which was suppressed again by IGF-1 inhibition (p < 0.05), demonstrating the blockage of the IGF-1-FOXO1-MURF1 pathway. MV treatment caused decreased CMAP and cross-sectional areas of diaphragm muscle fibers, and increased time course of CMAP (p < 0.05). Additionally, oxidative stress, cell apoptosis, and protein degradation were increased and mitochondrial stability was decreased by MV treatment (p < 0.05). Conversely, AP administration reversed all these changes induced by MV, but this reversal was disrupted by the blockage of the IGF-1-FOXO1-MURF1 pathway. CONCLUSIONS: In this study, MV treatment induced symptoms of VIDD in rats, which were all effectively reversed by AP regulating the IGF-1-FOXO1-MURF1 pathway, demonstrating the potential of AP in ameliorating VIDD.
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Aminofilina , Diafragma , Animales , Masculino , Ratas , Aminofilina/farmacología , Diafragma/efectos de los fármacos , Diafragma/patología , Diafragma/fisiopatología , Diafragma/metabolismo , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Respiración Artificial/efectos adversos , Transducción de Señal/efectos de los fármacos , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Linc00265, a long intergenic non-coding RNA, has garnered significant research attention due to its involvement in various human diseases, particularly cancer. It exhibits tissue-specific and dysregulated expression across multiple cancer types, including blood malignancies, colorectal, gastric, bladder, osteosarcoma, and hepatocellular carcinoma. This dysregulation is often associated with tumor aggressiveness, metastasis, and poor prognosis. Moreover, aberrant expression of Linc00265 has been reported in inflammation-related diseases such as osteoarthritis and sepsis. Mechanistically, Linc00265 acts as a competing endogenous RNA (CeRNA), sequestering specific microRNAs and thereby modulating their downstream targets. Additionally, it influences critical signaling pathways by mediating the key effectors within these pathways. Importantly, the dysregulation of Linc00265 shows promising potential as a diagnostic and prognostic biomarker in several human diseases. This review aims to comprehensively analyze the expression patterns, regulatory mechanisms, and potential biomarker roles of Linc00265 in human diseases, with a particular focus on cancer. By elucidating the functional implications of Linc00265, we can deepen our understanding of its roles in human diseases, potentially paving the way for novel therapeutic interventions in disease management.
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Biomarcadores de Tumor , Neoplasias , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/genéticaRESUMEN
Although complexation between dissolved organic matter (DOM) and ubiquitous Fe is known to have a major influence on electron transferring ability in redoximorphic soil, it was unclear whether and how this complexation affected nitrate reduction and N2O productivity. The nitrate reduction of paddy soil in the presence of crop residues returning under flooding conditions was explored in this study. The rate of nitrate reduction in control soil was 0.0677 d-1, while it improved 1.99 times in treatment soil with Chinese milk vetch (CMV) straw returning. During a 28-day incubation period, N2O productivity decreased 0.08-0.91 ppb in CMV soil and 0.43-0.50 ppb in rice straw soil compared with control. The presence of crop residue increased DOC content and Fe (III) reduction rate, which aided in the formation of Fe (II)-DOC complexation. Meanwhile, the addition of CMV increased the content of DOC by 5.14-78.77 mg/kg and HCl extractable Fe (II) by 35.12-1221.03 mg/kg. Crop residues returning to soil increased the relative abundance of iron reductive and electroactive genera, as well as denitrifying genera with more copies of denitrification genes (Archangiaceae, Gemmatimonadaceae, and Burkholderiaceae). The synergistic effect of Fe-DOC complexation, electroactive genera, and denitrifying genera contributed to up-regulated expression of napA and narG (5.84 × 106 and 3.39 × 107 copies increased in the CMV soil compared to the control) numbers and equally accelerated reduction of nitrate to nitrite, while further nitrite reduction was primarily attributed to the abiotic reaction by Fe (II). From a bio-electrochemical point of view, this work provided new insight into the nitrate reduction of paddy soil impacted by Fe-DOC complexation.
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Nitratos , Suelo , Suelo/química , Oryza , Hierro/química , Agricultura/métodos , Oxidación-Reducción , Productos Agrícolas , Microbiología del Suelo , Desnitrificación , Contaminantes del SueloRESUMEN
Background: collagen type I is a fundamental composition of extracellular matrix. Typically it exists in the form of a heterotrimer, consisting of two α1 chains encoded by COL1A1 and one α2 chain encoded by COL1A2. However, in cancer a homotrimeric form of collagen type I comprises three α1 chains encoded by COL1A1 was founded. There is still a lack of transcriptional and histologic methods for detecting homotrimeric collagen type I. Furthermore, a comprehensive analysis of the pan-cancer distribution pattern and clinical relevance of homotrimeric collagen type I is conspicuously absent. Method: Using transcriptional and immunoflourance method, we established homocol signature, which is able to transcriptionally and histologically detect homotrimeric collagen type I. We investigated the diagnostic and prognostic potential of homocol as a novel cancer biomarker in a pan-cancer cohort. Furthermore, we assessed its association with clinical manifestations in a liver cancer cohort undergoing treatment at our institute. Result: Homotrimer Collagen Type I is predominantly expressed by cancer cells and is linked to several critical cancer hallmarks, particularly inflammatory response and proliferation. Survival analyses have indicated that a high Homocol expression is correlated with poor outcomes in most types of cancer studied. In terms of cancer detection, Homocol demonstrated strong performance in Receiver Operating Characteristic (ROC) analysis, with an Area Under Curve (AUC) of 0.83 for pan-cancer detection and between 0.72 and 0.99 for individual cancers.In cohorts undergoing PD1 treatment, we noted a higher presence of Homocol in the response group. In a Hepatocellular Carcinoma (HCC) clinical set, high Homocol expression was associated with an increased formation of intra-tumor tertiary lymphoid structures (TLS), larger tumor sizes, more advanced Barcelona Clinic Liver Cancer (BCLC) stages, higher microvascular invasion (MVI) grades, absence of a capsule, and an enriched para-tumor collagen presence. Conclusion: our research has led to the development of a novel gene signature that facilitates the detection of Homotrimer Collagen Type I. This may greatly assist efforts in cancer detection, prognosis, treatment response prediction, and further research into Homotrimer Collagen Type I.
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Electrical stimulation therapy is effective in promoting wound healing by rescuing the decreased endogenous electrical field, where self-powered and miniaturized devices such as nanogenerators become the emerging trends. While high-voltage and unidirectional electric field may pose thermal effect and damage to the skin, nanogenerators with lower voltages, pulsed or bidirectional currents, and less invasive electrodes are preferred. Herein, we construct a polydopamine (PDA)-modified poly-L-lactic acid (PLLA) /MXene (PDMP/MXene) nanofibrous composite membrane that generates piezoelectric voltages matching the transepithelial potential (TEP) to accelerate wound healing. PDA coating not only enhances the piezoelectricity of PLLA by dipole attraction and alignment, but also increases its hydrophilicity and facilitates subsequent MXene adhesion for electrical conductivity and stability in physiological environment. When applied as wound dressings in mice, the PDMP/MXene membranes act as a nanogenerators with reduced internal resistances and satisfactory piezoelectric performances that resemble bioelectric potentials (~10 mV) responding to physical activities. The membrane significantly accelerates wound closure by facilitating fibroblast migration, collagen deposition and angiogenesis, and suppressing the expression of inflammatory responses. This piezoelectric fibrous membrane therefore provides a convenient solution for speeding up wound healing by sustained low voltage mimicking bioelectricity, better cell affinity.
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BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.
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Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Evasión Inmune , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Ratones Endogámicos C57BL , Escape del Tumor/efectos de los fármacosRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.
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Background: The worldwide pandemic of coronavirus disease 2019 (COVID-19) has still been an overwhelming public health challenge, and it is vital to identify determinants early to forecast the risk of severity using indicators easily available at admission. The current multicenter retrospective study aimed to derive and validate a user-friendly and effective nomogram to address this issue. Methods: A training cohort consisting of 437 confirmed COVID-19 cases from three hospitals in Hubei province (Tongji Hospital affiliated with Huazhong University of Science and Technology, Wuhan Third Hospital of Wuhan University and Wuhan Jinyintan Hospital in Hubei province) was retrospectively analyzed to construct a predicting model, and another cohort of 161 hospitalized patients from Public Health Clinical Center of Shanghai was selected as an external validation cohort from January 1, 2020 to March 8, 2020. Determinants of developing into severe COVID-19 were probed using univariate regression together with a multivariate stepwise regression model. The risk of progression to severe COVID-19 was forecasted using the derived nomogram. The performances of the nomogram regarding the discrimination and calibration were assessed in the cohort of training as well as the cohort of external validation, respectively. Results: A total of 144 (32.95%) and 54 (33.54%) patients, respectively, in cohorts of training and validation progressed to severe COVID-19 during hospitalization. Multivariable analyses showed determinants of severity consisted of hypertension, shortness of breath, platelet count, alanine aminotransferase (ALT), potassium, cardiac troponin I (cTnI), myohemoglobin, procalcitonin (PCT) and intervals from onset to diagnosis. The nomogram had good discrimination with concordance indices being 0.887 (95% CI: 0.854-0.919) and 0.850 (95% CI: 0.815-0.885) in internal and external validation, respectively. Calibration curves exhibited excellent concordance between the predictions by nomogram and actual observations in two cohorts. Conclusions: We have established and validated an early predicting nomogram model, which can contribute to determine COVID-19 cases at risk of progression to severe illness.
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Since the past decades, more lung cancer patients have been experiencing lasting benefits from immunotherapy. It is imperative to accurately and intelligently select appropriate patients for immunotherapy or predict the immunotherapy efficacy. In recent years, machine learning (ML)-based artificial intelligence (AI) was developed in the area of medical-industrial convergence. AI can help model and predict medical information. A growing number of studies have combined radiology, pathology, genomics, proteomics data in order to predict the expression levels of programmed death-ligand 1 (PD-L1), tumor mutation burden (TMB) and tumor microenvironment (TME) in cancer patients or predict the likelihood of immunotherapy benefits and side effects. Finally, with the advancement of AI and ML, it is believed that "digital biopsy" can replace the traditional single assessment method to benefit more cancer patients and help clinical decision-making in the future. In this review, the applications of AI in PD-L1/TMB prediction, TME prediction and lung cancer immunotherapy are discussed.
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Inteligencia Artificial , Neoplasias Pulmonares , Humanos , Antígeno B7-H1 , Neoplasias Pulmonares/terapia , Aprendizaje Automático , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: Dialysis or non-dialysis end-stage renal disease (ESRD) patients are accompanied by cardiovascular disease (CVD) or hypertension. We aimed to study the effect of a common treatment for CVD, ß-blockers, on the survival of ESRD patients, improving their prognosis from the perspective of drug therapy. METHODS: It was a retrospective cohort study using the Medical Information Mart for Intensive Care dataset. ESRD patients in the intensive care unit from June 2001 to October 2012 were included. We examined the effect of using versus not using ß-blockers in the overall population and subgroups with the risk of 28-day and 3-year mortality through Cox proportional hazards models and Kaplan-Meier curves. RESULTS: A total of 1639 participants were included with 371 (22.64%) ß-blockers users. There were 315 (19.22%) 28-day and 970 (59.18%) 3-year mortality events during follow-up. Using ß-blockers in overall ESRD patients could reduce all-cause 28-day mortality [adjusted hazard ratio (HR) 0.450, 95% confidence interval (CI) 0.325-0.624] and 3-year mortality (adjusted HR 0.695, 95% CI 0.589-0.821). This result was consistent among subgroups (ESRD without hypertension: adjusted HR 0.412, 95% CI 0.289-0.588; with CVD: adjusted HR 0.478, 95% CI 0.321-0.711; without CVD: adjusted HR 0.448, 95% CI 0.248-0.810; with dialysis: adjusted HR 0.471, 95% CI 0.320-0.694) in 28-day mortality, and the 3-year mortality was consistent. In ESRD patients with hypertension and without dialysis subgroups, ß-blockers had no effect on survival. CONCLUSION: Using ß-blockers could reduce the risk of 28-day and 3-year mortality in ESRD patients, including those with CVD. This study provided a reference for the treatment of ß-blockers in patients with ESRD.
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Enfermedades Cardiovasculares , Hipertensión , Fallo Renal Crónico , Humanos , Estudios Retrospectivos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Enfermedades Cardiovasculares/complicaciones , Modelos de Riesgos Proporcionales , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológicoRESUMEN
The ongoing development of assisted reproductive technologies has provided hope to individuals struggling with infertility, promising the potential for a healthy pregnancy. One significant innovation in field of pre-implantation genetic screening (PGS) requires the biopsy of embryos or oocytes, which has potential implications for the health and development of the resultant offspring. Therefore, a non-invasive approach to preimplantation genetic screening is highly sought after. The clinical application of non-invasive preimplantation genetic testing (ni-PGT) is currently limited, with its sensitivity and specificity requiring further investigation. In this study, we used 218 human embryos for single-cell whole genome amplification (WGA), along with ni-PGT of blastocoele fluid (BF) and spent culture medium (SCM). Whole blastocyst (WB), trophectoderm biopsy (TB), and inner cell mass (ICM) from embryo biopsies were used as controls to track genomic signal alterations. Our results showed that the overall genome similarity between SCM and ICM was higher than that of BF. Apart from the Y chromosome, both SCM and ICM demonstrated numerous variant sites across other chromosomes.Further categorization of gene variants in these two sample types revealed that missense variants were the most prevalent, single nucleotide polymorphisms were more common than insertions or deletions, and C > T was the dominant single nucleotide variants in both ICM and SCM. Lastly, we found that the mutant genes in SCM and ICM had different biological functions and pathways. This study indicates that SCM provides a more effective source of embryonic DNA for preimplantation genetic screening, offering a novel reference point for genetic screening research.