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BACKGROUND: Dietary factors have consistently been associated with breast cancer risk. However, there is limited evidence regarding their associations in women with different genetic susceptibility to breast cancer, and their interaction with alcohol consumption is also not well understood. METHODS: We analyzed data from 261,853 female participants in the UK Biobank. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between dietary factors and breast cancer risk. Additionally, we assessed the interaction of dietary factors with alcohol consumption and polygenic risk score (PRS) for breast cancer. RESULTS: A moderately higher risk of breast cancer was associated with the consumption of processed meat (HR = 1.10, 95% CI 1.03, 1.18, p-trend = 0.016). Higher intake of raw vegetables and fresh fruits, and adherence to a healthy dietary pattern were inversely associated with breast cancer risk [HR (95% CI):0.93 (0.88-0.99), 0.87 (0.81, 0.93) and 0.93 (0.86-1.00), p for trend: 0.025, < 0.001, and 0.041, respectively]. Furthermore, a borderline significant interaction was found between alcohol consumption and the intake of processed meat with regard to breast cancer risk (P for interaction = 0.065). No multiplicative interaction was observed between dietary factors and PRS. CONCLUSION: Processed meat was positively associated with breast cancer risk, and vegetables, fruits, and healthy dietary patterns were negatively associated with breast cancer risk. We found no strong interaction of dietary factors with alcohol consumption and genetic predisposition for risk of breast cancer.
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Neoplasias da Mama , Feminino , Humanos , Estudos de Coortes , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Biobanco do Reino Unido , Bancos de Espécimes Biológicos , Fatores de Risco , Estudos Prospectivos , Dieta , Predisposição Genética para Doença , Modelos de Riscos ProporcionaisRESUMO
Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.
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Neuralgia , Receptores Opioides delta , Analgésicos Opioides/efeitos adversos , Animais , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Camundongos , Neuralgia/metabolismo , RatosRESUMO
Pain is a multidimensional experience and negative affect, or how much the pain is "bothersome", significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence in situ hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Using in vivo microdialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxP mice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.SIGNIFICANCE STATEMENT We show that KORs are sufficient to drive the tonic-aversive component of chronic pain; the emotional component of pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response to treatment of many patients, debilitating affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with chronic pain) and substance abuse. Indeed, coexisting psychopathology increases pain intensity, pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).
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Dor Crônica/metabolismo , Dor Crônica/psicologia , Emoções/fisiologia , Percepção da Dor/fisiologia , Receptores Opioides kappa/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-EvansRESUMO
Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Using in vivo microdialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.
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Dor Crônica/patologia , Sistema Límbico/patologia , Microglia/patologia , Rede Nervosa/patologia , Recompensa , Animais , Área Sob a Curva , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Cocaína/uso terapêutico , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Morfina/uso terapêutico , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
The real-time and label free detection abilities of surface plasmon resonance (SPR) biosensors provide a way of evaluating the influence of some genes' expression on anti-tumor drug cytotoxicity. However, studies in this field are lacking. Connexin 43 is a tumor suppressor gene and the mechanism of its effect in cisplatin cytotoxicity is still unclear. A phase SPR biosensor was used to determine the influence of connexin 43 expression on cisplatin cytotoxicity in three cancer cell lines. The results showed that the SPR signal curves have two stages. In the first hour, the SPR signal shows dramatic changes which are related to connexin 43 expression. In the subsequent stage, the SPR signal slowly declines and is related to apoptosis. Comparison of SPR measurements from several conventional biological assays showed that connexin 43 expression can affect cellular response to cisplatin in the period of oxidative stress, and results in the cells being more sensitive to cisplatin. The conclusion is further confirmed by long-term SPR measurement results and cellular morphological changes.
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Técnicas Biossensoriais , Cisplatino/farmacologia , Conexina 43/metabolismo , Ressonância de Plasmônio de Superfície , Células A549 , Comunicação Celular , Linhagem Celular Tumoral , Junções Comunicantes , HumanosRESUMO
Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by chronic and progressive apoptotic destruction of pancreatic beta cells. During the initial phases of T1DM, cytokines and other inflammatory mediators released by immune cells progressively infiltrate islet cells, induce alterations in gene expression, provoke functional impairment, and ultimately lead to apoptosis. Long noncoding RNAs (lncRNAs) are a new important class of pervasive genes that have a variety of biological functions and play key roles in many diseases. However, whether they have a function in cytokine-induced beta cell apoptosis is still uncertain. In this study, lncRNA microarray technology was used to identify the differently expressed lncRNAs and mRNAs in MIN6 cells exposed to proinflammatory cytokines. Four hundred forty-four upregulated and 279 downregulated lncRNAs were detected with a set filter fold-change â§2.0. To elucidate the potential functions of these lncRNAs, Gene Ontology (GO) and pathway analyses were used to evaluate the potential functions of differentially expressed lncRNAs. Additionally, a lncRNA-mRNA coexpression network was constructed to predict the interactions between the most strikingly regulated lncRNAs and mRNAs. This study may be utilized as a background or reference resource for future functional studies on lncRNAs related to the diagnosis and development of new therapies for T1DM.
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Inflamação/genética , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Camundongos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transcriptoma/genéticaRESUMO
OBJECTIVE: The long-term effects of prenatal cocaine exposure (PCE) on physical health are largely unknown. No human studies support or refute a relationship between PCE and the long-term risk for cardiovascular and/or metabolic disease. We investigated the association of PCE on primary cardiometabolic disease risk factors in African Americans (AA) aged 18 to 20 years. DESIGN: Cohort, longitudinal, prospective. SETTING: Miami-Dade County, Florida, and the University of Miami Miller School of Medicine/Jackson Memorial Medical Center. PARTICIPANTS: Healthy full-term inner-city AA adolescents (aged 18 to 20 years, n=350) previously enrolled at birth from 1990-1993. MAIN OUTCOME MEASURES: Fasting serum insulin, glucose, lipids, and high-sensitivity C-reactive protein; systolic and diastolic blood pressures; and the components and prevalence of the metabolic syndrome. RESULTS: There were no PCE-associated differences in cardiometabolic disease risk factors including the metabolic syndrome and its individual components in AAs aged 18 to 20 years. CONCLUSIONS: The results of our study do not support an association between PCE and increased cardiometabolic disease risk in AAs aged 18 to 20 years. Whether PCE is associated with cardiovascular or metabolic disease in adulthood would require further investigation.
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Negro ou Afro-Americano , Transtornos Relacionados ao Uso de Cocaína/etnologia , Síndrome Metabólica/etnologia , Efeitos Tardios da Exposição Pré-Natal/etnologia , Adolescente , Pressão Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Jejum , Feminino , Florida , Humanos , Lipídeos/sangue , Masculino , Gravidez , Prevalência , Fatores de Risco , Adulto JovemRESUMO
In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states.
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Analgésicos Opioides/uso terapêutico , Condicionamento Operante/efeitos dos fármacos , Morfina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/psicologia , Recompensa , Análise de Variância , Animais , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
BACKGROUND: ABCB1 is a major determinant of opioid bioavailability; however, no previous studies have provided positive evidence of an association between single-nucleotide polymorphisms (SNPs) of ABCB1 and opioid usage in acute pain management. The aim of this study was to test the association between the functional SNP C3435T in ABCB1 and opioid consumption in postoperative pain in patients undergoing a nephrectomy. Additionally, we explored the association between C3435T and opioid side effect. METHODS: C3435T was genotyped in 152 patients undergoing a nephrectomy. Opioid consumption and pain scores were evaluated as well. The effect of genotype on opioid consumption was modeled using a general linear mixed model. RESULT: Based on a mixed linear model, the ABCB1 three genotypes showed a statistically significant effect on opioid consumption (F = 4.20, P = 0.017). There was a statistically significant difference in opioid consumption among the ABCB1 three genotypes in the 0-6 hours (P = 0.031, 95% confidence interval [CI] CC 14.7-24.8 mg and TT 5.2-14.6 mg) and 6-12 hours (P = 0.009, 95% CI CC 5.6-13.8 mg and TT 1.2 mg-5.1 mg) postoperative period. There were no significant statistical differences in opioid consumption among the ABCB1 three genotypes in the 12-24 hours (P = 0.302) and 24-48 hours (P = 0.763) postoperative period. The TT genotype had significantly lower levels of cumulative opioid consumption compared with the CC genotype in first 24 hours after surgery (P = 0.029). No statistically significant differences among the three genotype groups were noted for postoperative pain scores or emesis medication use in the first 24 hours after surgery. CONCLUSION: Our results demonstrate an association between the ABCB1 polymorphism (C3435T) and interindividual variations in opioid consumption in the acute postoperative period after nephrectomy. The ABCB1 polymorphism may serve as an important factor to guide acute pain therapy in postoperative patients.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Analgésicos Opioides/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Analgésicos Opioides/metabolismo , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Dor Pós-Operatória/etiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Intermedin (IMD) is a member of the calcitonin/calcitonin gene-related peptide (CGRP) family and has similar or more potent cardiovascular actions than adrenomedullin (ADM) and any other CGRP. The aim of the present work is to study the effects of IMD1-53 on cardiac fibroblast fibrosis in vivo and in vitro. Myocardial infarction model was prepared by ligating rats' left anterior descending coronary artery. Mesenchymal collagen contents in the left ventricle were accessed by Sirius-red stain. Heart functions were explored by hemodynamic changes. Expression of I and III type collagens, IMD1-53, receptor activity-modifying proteins (RAMP)1/2/3, and calcitonin receptor-like receptor (CRLR) in left ventricle were detected by western blot analysis. Cardiac fibroblasts (CFbs) fibrosis was induced by treating the cells with aldosterone (ALD). CFbs proliferation and the hydroxyproline contents in supernatants were determined by 3-[4,5-dimehyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide assay and enzyme-linked immunosorbent assay. Heart function was decreased in myocardial infarction model rats. Expression of type I and type III collagens in infarcted zone in myocardial rats was higher than those in the sham-operated group. IMD1-53, RAMP, and CRLR in left ventricle were also up-regulated. In vitro experiment showed that ALD was a powerful stimulator of CFbs activation. IMD1-53 decreased ALD-induced CFbs proliferation in a dose-dependent manner. Moreover, CGRP8-37 and ADM22-52 remarkably blocked the effect of IMD1-53 on ALD-induced myocardial cell fibrosis. IMD could be involved in the onset of cardiac fibrosis. Like ADM, IMD1-53 exerts an antifibrotic effect on CFbs, which might be mediated by CRLR/RAMP complex and ADM receptor.
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Adrenomedulina/metabolismo , Fibrose Endomiocárdica/metabolismo , Fibroblastos/metabolismo , Miocárdio/metabolismo , Neuropeptídeos/metabolismo , Animais , Células Cultivadas , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Several studies have provided ample evidence that hypertension in adults has its onset in childhood; children and adolescents with elevated blood pressure (BP) are more likely to become hypertensive adults. Shandong province is one of the areas of China with higher prevalence of hypertension. However, no studies on the relationship between physique and BP have been reported in Shandong Province, China. AIM: The present study examined the difference in body shape and physical activity (PA) between adolescents with normotensive and elevated BP in Shandong, China. SUBJECTS AND METHODS: Data for this study were obtained from a large cross-sectional survey of schoolchildren carried out in 2010.A total of 28 039 students (14 084 boys and 13 955 girls) aged 10-17 years participated in this study. Height, weight, waist circumference (WC), BP, triceps and subscapular skinfolds of all subjects were measured and the sum of triceps and subscapular skinfold thickness was applied. Body mass index (BMI) of adolescents was calculated from their height and weight and the prevalence of overweight and obesity were obtained according to the International Obesity Task Force (IOTF) cut-offs. Elevated BP was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ 95th percentile for age and gender. PA attitudes and behaviours were assessed by a standardized questionnaire. RESULTS: The mean values of BMI, WC and SFT for both boys and girls were all significantly higher in the elevated BP group than in the normal BP group in all age categories (p < 0.01). More adolescents with elevated BP were overweight or obese compared with normal BP subjects. Significant differences in PA were observed between the elevated and normal BP group, adolescents with elevated BP had poor PA attitudes and behaviours compared with normal BP subjects. CONCLUSION: Adolescents with elevated BP had high levels of BMI, WC, SFT and poor PA attitudes and behaviours. These findings reinforce the importance of preventing overweight and obesity and improving their attitudes towards physical activity.
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Atitude Frente a Saúde , Pressão Sanguínea , Comportamentos Relacionados com a Saúde , Hipertensão/fisiopatologia , Atividade Motora , Obesidade/epidemiologia , Adolescente , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Sobrepeso , Fatores de Risco , Dobras Cutâneas , Estudantes , Circunferência da CinturaRESUMO
Background: Plasma cell mastitis (PCM) is a complex breast disease in the clinic. Currently, there are no unified diagnostic criteria for the disease and no standard treatment methods. The effects of hormone, Conventional Chinese medicine and other treatments are uncertain, with long treatment duration and notable side effects. Surgery is the preferred treatment, but the recurrence rate after conventional surgery is very high, which may be related to depression of the nipple. This study aimed to evaluate the efficacy of a novel corrective procedure in patients with cellular mastitis and depressed nipples. Methods: Patients with PCM who received surgical treatment in the Third Medical Center of PLA General Hospital from January 1996 to January 2018 were retrospectively analyzed. According to the presence or absence of nipple depression before surgery, the patients were divided into the nipple depression group and the non-nipple depression group. In the nipple depression group, patients were subdivided into a novel corrective surgery group ("one" suture or half pocket suture) and a conventional corrective surgery group (oil yarn traction valgus correction of nipple depression). Demographic, clinical, therapeutic, and postoperative relapse data were collected and analyzed. Results: Compared with the patients in the non-nipple depression group, patients in the nipple depression group had a significantly higher recurrence risk after surgery (HR = 2.129 95% CI: 1.110-4.083, p = 0.023). Patients who underwent novel corrective surgery had a significantly lower recurrence risk than those who underwent conventional corrective surgery (HR = 0.363 95% CI: 0.150-0.880, p = 0.025). In addition, the novel corrective surgery significantly reduced the postoperative recurrence risk (HR = 0.088 95% CI: 0.009-0.886, p = 0.037). Conclusion: How to correct nipple depression is a critical factor for postoperative recurrence of PCM, and this novel corrective surgery for nipple depression can effectively reduce the postoperative recurrence rate in patients with nipple depression.
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Intercropping achieved through agroforestry is increasingly being recognized as a sustainable form of land use. In agroforestry, the roots of trees and crops are intermingled, and their interactions and the production of exudates alter the soil environment and soil microbial community. Although tree-crop interactions vary depending on the stand age of the trees, how stand age affects beneficial microorganisms, including arbuscular mycorrhizal fungi (AMF), and whether changes in soil microorganisms feed back on crop growth in agroforestry systems are unknown. We therefore conducted a long-term field study to compare changes in the soil microbial and AMF communities in a jujube/wheat agroforestry system containing trees of different stand ages: 3-year-old jujube, 8-year-old jujube, and 13-year-old jujube. Our results showed that by changing soil moisture and available phosphorus content, the stand age of the trees had a significant effect on the soil microbial and AMF communities. Soil moisture altered the composition of soil bacteria, in particular the proportions of Gram-positive and Gram-negative species, and available phosphorus had significant effects on the AMF community. A network analysis showed that older stands of trees reduced both AMF diversity and network complexity. An ordinary least squares regression analysis indicated that AMF diversity, network complexity, and stability contributed to wheat yield. Finally, structural equation modeling showed that changes in edaphic factors induced by tree age brought about significant variation in the soil microbial and AMF communities, in turn, affecting crop growth. Our study highlights the crucial roles of soil microorganisms, in particular AMF, in supporting plant growth in agroforestry systems as well as the need to consider stand age in the establishment of these systems.
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Background: Although type 2 diabetes mellitus (T2DM) plays a significant role in the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and chronic kidney disease (CKD), how T2DM development and glycemic deterioration affect CKD and its renal function indicators, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), remains unknown. We aimed to assess the association between MAFLD, along with T2DM, and risk of CKD, and then evaluate the effect of metabolic goal achievement in MAFLD on the risk of CKD. Methods: In this cross-sectional study, 5,594 participants were included. Multivariate logistic regression and linear regression were used to examine the association between MAFLD with its T2DM status and metabolic goal achievement and risk of CKD, as well as eGFR and UACR. Results: The MAFLD group had a higher prevalence of CKD (16.2 vs. 7.6%, P < 0.001) than the non-MAFLD group. MAFLD was independently associated with an increased risk of CKD (odds ratio [OR]: 1.35, 95% CI: 1.09-1.67) and increased eGFR and UACR. Among the three MAFLD subtypes, only the T2DM subtype exhibited significant associations with increased risk of CKD (OR: 2.85, 95% CI: 2.24-3.63), as well as increased eGFR and UACR. Glycemic deterioration in MAFLD was dose-dependently associated with an increased risk of CKD (P-trend < 0.001). Achieved metabolic goals in MAFLD decreased the risk of CKD, eGFR, and UACR; MAFLD with 2 or 3 achieved metabolic goals was not significantly associated with the risk of CKD (OR: 0.81, 95% CI: 0.59-1.12) and albuminuria. Conclusion: MAFLD was independently associated with an increased risk of CKD, as well as increased eGFR and UACR. This association is strongly driven by T2DM status. Glycemic deterioration in MAFLD was dose-dependently associated with an increased risk of CKD. Achieved metabolic goals in MAFLD decreased the risk of CKD by reducing the risk of albuminuria.
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Diabetes Mellitus Tipo 2 , Hepatopatias , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Albuminúria , Estudos Transversais , Objetivos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologiaRESUMO
Transcription factors (TFs) play key roles in biological processes, and previous studies revealed that they can control oncogenic processes. However, the functional impact of TFs on the prognosis of patients with cancer has not been extensively elucidated. In the context of The Cancer Genome Atlas, few studies have focused on the roles of TFs in tumorigenesis. In the present study, a TF-based robust MYC-estrogen related receptor α-regulatory factor X5 (MYC-ESRRA-RFX5) signature was developed for predicting the survival of patients with renal cell carcinoma. Functional enrichment analysis of this signature revealed that it was associated with the immune system of these patients. Further analysis demonstrated that this panel could characterize the immune microenvironment and potentially predicts the effectiveness of immune checkpoint inhibitors. Therefore, the present study recommends future exploration on TF-based biomarkers for their potential as prognostic predictors. Overall, the highlights of this study are: i) This novel study pinpoints a TF panel for the robust prediction of renal cell carcinoma prognosis, and ii) the MYC-ESRRA-RFX5 panel is proposed as a signature for characterizing the immune microenvironment, and to potentially predict the effectiveness of immune checkpoint inhibitors.
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Agroforestry is a common traditional practice in China-especially in the southern Xinjiang of Northwest China. However, the productivity of many agroforestry systems has been lower than expected in recent years, highlighting the need for an actionably deep mechanistic understanding of the competition between crops and trees. Here, three different fruit tree/wheat (jujube/wheat, apricot /wheat, and walnut /wheat) intercropping agroforestry systems were chosen to investigate influence of different fruit tree shade intensity on the growth, yield and quality of intercropping wheat. Compared to the monoculture wheat system, the mean daily shade intensity of the jujube-, apricot-, and walnut-based intercropping systems were, respectively, 23.2%, 57.5%, and 80.7% shade. The photosynthetic rate of wheat in the jujube-, apricot-, and walnut-based intercropping systems decreased by, respectively, 11.3%, 31.9%, and 36.2% compared to monoculture wheat, and the mean number of fertile florets per spike decreased by 26.4%, 37.4%, and 49.5%. Moreover, the apricot- and walnut-based intercropping systems deleteriously affected grain yield (constituent components spike number, grains per spike, and thousand grain weight) and decreased the total N, P, and K content of intercropping wheat. Tree shading intensity strongly enhanced the grain protein content, wet gluten content, dough development time, and dough stability time of wheat, but significantly decreased the softening degree. Strong negative linear correlations were observed between tree shade intensity and the number of fertile florets, grain yield related traits (including spike number, grains per spike, and thousand grain weight), nutrient content (N, P and K), and softening degree of wheat. In contrast, Daily shade intensity was positively linearly correlated with grain protein content, wet gluten content, dough development time, and dough stability time. We conclude that jujube-based intercropping systems can be practical in the region, as they do not decrease the yield and quality of intercropping wheat.
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Produção Agrícola , Frutas , Árvores , Triticum/crescimento & desenvolvimentoRESUMO
BACKGROUND: Demyelination is the end product of numerous pathological processes, and also is one of the main causes of neurological disability in Multiple sclerosis (MS). Research into the pathogenesis of MS is hampered by the conventional rodent models' inability to produce stable demyelination. NEW METHOD: Focal demyelinating lesions were stereotactically targeted to the corpus callosum with a two-point injection of lysophosphatidylcholine (LPC-2) in mice. Three groups were analyzed (nâ¯=â¯8, each) and water maze, sensorimotor test, and compound action potential were included in functional tests. Electron microscopy was used for morphological analyses while western blot and immunohistochemistry were included for molecular detection. RESULTS: Ten days after the LPC-2 injection, the expression of myelin basic protein (MBP) was reduced, while non-phosphorylated neurofilament (SMI-32) was increased. The amplitude of the N1 segment decreased and less well-defined myelin sheaths was found. Behavioral tests showed increased latency to escape and reduced time spent in target quadrant. Four weeks later, MBP expression still reduced, SMI-32 expression was increased, both spatial learning (D24-D27) and spatial memory (D28) were still significantly impaired in LPC-2 injection mice. COMPARISON WITH EXISTING METHOD(S): Compared with the classic single-point LPC-injection model, our studies showed that the two-point LPC-injection not only could induce demyelination in a short-term manner, but also could cause demyelination in a long-term manner with little remyelination in the mouse corpus callosum. CONCLUSIONS: We established a simple, reliable, and inexpensive model of demyelination in the corpus callosum in mice, with functional and morphological reproducibility, and good validity.
Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Leucoencefalopatias/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/fisiopatologia , Corpo Caloso/ultraestrutura , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/induzido quimicamente , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Comportamento Exploratório/efeitos dos fármacos , Cápsula Externa/efeitos dos fármacos , Cápsula Externa/fisiopatologia , Cápsula Externa/ultraestrutura , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Leucoencefalopatias/induzido quimicamente , Leucoencefalopatias/patologia , Lisofosfatidilcolinas/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Proteína Básica da Mielina/metabolismo , Proteínas de Neurofilamentos/metabolismo , Teste de Desempenho do Rota-Rod , Transdução GenéticaRESUMO
OBJECTIVE: This study examined the influence of prenatal cocaine exposure on attention and response inhibition measured by continuous performance tests (CPTs) at ages 5 and 7 years. METHODS: The baseline sample consisted of 253 cocaine-exposed and 223 non-cocaine-exposed children enrolled prospectively at birth and assessed comprehensively through age 7 years in the longitudinal Miami Prenatal Cocaine Study. This report includes a subsample of 415 children (219 cocaine-exposed, 196 non-cocaine-exposed) who completed at least one CPT assessment at ages 5 and/or 7 years. Prenatal cocaine exposure was measured by maternal self-report and maternal and infant bioassays. Deficits in attention and response inhibition are estimated in relation to prenatal cocaine exposure using generalized estimating equations within the general linear model. RESULTS: Results indicate cocaine-associated increases in omission errors at ages 5 and 7 as well as increases in response times for target tasks (i.e., slower reaction times) and decreased consistency in performance at age 7. There were no demonstrable cocaine-associated deficits in commission errors. Estimates did not change markedly with statistical adjustment for selected prenatal and postnatal covariates. CONCLUSION: Evidence supports cocaine-associated deficits in attention processing through age 7 years.
Assuntos
Atenção/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Inibição Psicológica , Efeitos Tardios da Exposição Pré-Natal , Tempo de Reação/efeitos dos fármacos , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Transtornos Relacionados ao Uso de Cocaína/complicações , Transtornos Relacionados ao Uso de Cocaína/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Gravidez , Estudos Prospectivos , Psicometria , Índice de Gravidade de Doença , Análise e Desempenho de TarefasRESUMO
Risk for developing a learning disability (LD) or impaired intellectual functioning by age 7 was assessed in full-term children with prenatal cocaine exposure drawn from a cohort of 476 children born full term and enrolled prospectively at birth. Intellectual functioning was assessed using the Wechsler Intelligence Scale for Children-Third Edition (Wechsler, 1991) short form, and academic functioning was assessed using the Wechsler Individual Achievement Test (WIAT; Wechsler, 1993) Screener by examiners blind to exposure status. LDs were categorized based on ability-achievement discrepancy scores, using the regression-based predicted achievement method described in the WIAT manual. The sample in this report included 409 children (212 cocaine-exposed, 197 non-cocaine-exposed) from the birth cohort with available data. Cumulative incidence proportions and relative risk values were estimated using STATA software (Statacorp, 2003). No differences were found in the estimate of relative risk for impaired intellectual functioning (IQ below 70) between children with and without prenatal cocaine exposure (estimated relative risk = .95; 95% confidence interval [CI] = 0.65, 1.39; p = .79). The cocaine-exposed children had 2.8 times greater risk of developing a LD by age 7 than non-cocaine-exposed children (95% CI = 1.05, 7.67; p = .038; IQ >/= 70 cutoff). Results remained stable with adjustment for multiple child and caregiver covariates, suggesting that children with prenatal cocaine exposure are at increased risk for developing a learning disability by age 7 when compared to their non-cocaine-exposed peers.
Assuntos
Cocaína/toxicidade , Inteligência/efeitos dos fármacos , Deficiências da Aprendizagem/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Consumo de Bebidas Alcoólicas/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Cocaína Crack/toxicidade , Escolaridade , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Fumar Maconha/efeitos adversos , Gravidez , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fatores Socioeconômicos , Escalas de WechslerRESUMO
Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.