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Myocardial fibrosis, a common pathophysiological consequence of various cardiovascular diseases, is characterized by fibroblast activation and excessive deposition of extracellular matrix (ECM) collagen. Accumulating evidence indicates that myocardial fibrosis contributes to ventricular stiffness, systolic and diastolic dysfunction, and ultimately leads to the development of heart failure (HF). Early detection and targeted treatment of myocardial fibrosis is critical to reverse ventricular remodeling and improve clinical outcomes in patients with cardiovascular diseases. However, despite considerable progresses made in understanding molecular mechanisms of myocardial fibrosis, non-invasive imaging to assess myocardial fibrosis and guide clinical treatment is still not widely available, limiting the development of innovative treatment strategies. This review summarizes recent progresses of imaging modalities for detecting myocardial fibrosis, with a focus on nuclear medicine, echocardiography and cardiac magnetic resonance (CMR).
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BACKGROUND: Uremia-associated immunodeficiency, mainly characterized by T cell dysfunction, exists in patients on maintenance hemodialysis (MHD) and promotes systemic inflammation. However, T cell senescence, one of the causes of T cell dysfunction, has not been clearly revealed yet. In this cross-sectional research, we aimed to study the manifestation of T cell premature senescence in MHD patients and further investigate the associated clinical factors. METHODS: 76 MHD patients including 33 patients with cardiovascular diseases (CVD) and 28 patients with arteriovenous fistula (AVF) event history were enrolled in this study. Complementarity determining region 3 (CDR3) of T cell receptor (TCR) was analyzed by immune repertoire sequencing (IR-Seq). CD28- T cell subsets and expression of senescence marker p16 and p21 genes were detected by multicolor flow cytometry and RT-qPCR, respectively. RESULTS: MHD patients had significantly decreased TCR diversity (P < 0.001), increased CDR3 clone proliferation (P = 0.001) and a left-skewed CDR3 length distribution. The proportion of CD4 + CD28- T cells increased in MHD patients (P = 0.014) and showed a negative correlation with TCR diversity (P = 0.001). p16 but not p21 expression in T cells was up-regulated in MHD patients (P = 0.039). Patients with CVD exhibited increased expression of p16 and p21 genes (P = 0.010 and 0.004, respectively), and patients with AVF events showed further TCR diversity and evenness reduction (P = 0.002 and 0.017, respectively) compared to patients without the comorbidities. Moreover, age, average convection volume, total cholesterol, high-density lipoprotein cholesterol and transferrin saturation were associated with TCR diversity or CD4 + CD28- T cell proportion (P < 0.05). CONCLUSIONS: MHD patients undergo T cell premature senescence characterized by significant TCR diversity reduction and repertoire skew, as well as accumulation of the CD4 + CD28- subset and up-regulation of p16 gene. Patients with CVD or AVF events show higher level of immunosenescence. Furthermore, T cell senescence in MHD patients is associated with blood cholesterol and uremic toxin retention, suggesting potential intervention strategies in the future.
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Senescencia Celular , Receptores de Antígenos de Linfocitos T , Diálisis Renal , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Estudios Transversales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Linfocitos T/inmunología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Antígenos CD28 , Uremia/inmunología , Regiones Determinantes de Complementariedad/genética , Adulto , Enfermedades Cardiovasculares/inmunología , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.
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Insuficiencia Renal , Uremia , Ratas , Animales , Ácido Fólico , Tiamina , Ratas Sprague-Dawley , Uremia/complicaciones , Cognición , HomocisteínaRESUMEN
AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.
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Mitocondrias Musculares/fisiología , Debilidad Muscular/etiología , Músculo Esquelético/enzimología , Proteínas Quinasas/fisiología , Insuficiencia Renal Crónica/complicaciones , Adulto , Anciano , Femenino , Fuerza de la Mano , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/fisiopatología , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the incidence and the prognosis of cognitive impairment (CI) and to find out the risk factors associated with the outcome in maintenance haemodialysis (MHD) patients. METHODS: Enrolled the patients who met the criteria as below: MHD (≥3 months) patients before July 2014, ≥18 years old and could carry on the cognitive function test (Montreal Cognitive Assessment [MoCA]). All enrolled patients were divided into 2 groups: CI group (MoCA < 26) and non-CI group (MoCA ≥26). All patients were followed up for 36 months. The incidence, demography data, medical history, haemodialysis data, laboratory examination and prognosis of CI in haemodialysis patients were prospectively compared and analyzed. Multivariate logistic regression analysis was used to investigate the risk factors of CI. Kaplan-Meier survival curve was used for survival analysis. RESULTS: In the present study, 219 patients were enrolled. The ratio of male to female was 1.46: 1. Age was 60.07 ± 12.44 and dialysis vintage was 100.79 ± 70.23 months. One hundred thirteen patients' MoCA scores were lower than 26 were divided into CI group. Education status (OR 3.428), post-dialysis diastolic pressure (OR 2.234) and spKt/V (OR 1.982) were independent risk factors for CI in MHD patients. During the follow-up period, 15 patients died (13.2%) in the CI group and 5 died (4.72%) in the non-CI group (p < 0.05). The Kaplan-Meier survival curve analysis showed that the survival rate of patients with CI was lower than that of non-CI group in MHD patients during 3 years follow-up (p = 0.046). CONCLUSION: CI is one of the most common complications in MHD patients. The mortality is high in patients who had CI. Education status, post-dialysis diastolic pressure and spKt/V are independent risk factors for CI in MHD patients.
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Disfunción Cognitiva/etiología , Disfunción Cognitiva/mortalidad , Diálisis Renal/efectos adversos , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Our previous in vitro studies suggested that cyclin AMP (cAMP) signaling protects against podocyte injury. However, the molecular mechanisms remain unknown. The aim of the present study was to explore the role of forskolin, an agonist for adenylate cyclase, on ezrin/radixin/moesin (ERM) phosphorylation and chloride intracellular channel 5 (CLIC5) expressions in injured podocytes. METHODS: ADR nephrosis model were induced by adriamycin (ADR) injection in BalB/C mice. Parts of ADR nephrosis mice were pretreated with forskolin. Albuminuria was estimated by urine Coomassie blue stain. Nephrin, synaptopodin, CLIC5, phosphorylated ERM and podocalyxin were measured by confocal microscopy. CLIC5 and phosphorylated ERM also were studied using western blotting. RhoA and Rac1 were estimated by G-Lisa kit. RESULTS: We found that forskolin partially alleviated albuminuria and width of foot processes. Nephrin, synaptopodin, phosphorylated-ERM (p-ERM) and CLIC5 expression were decreased in ADR mice, which were improved by forskolin pretreatment. In vitro studies, pretreatment of podocytes with pCPT-cAMP(PKA-selective cAMP analogue)prevented puromycin aminonucleoside (PAN)-induced CLIC5 downregulation. 8-pCPT-2'-O-Me-cAMP (2Me-cAMP, an Epac-selective cAMP analogue) blocked PAN-induced p-ERM downregulation. PAN inhibited RhoA activation in podocytes, which could be prevented by pCPT-cAMP pretreatment. Y-27632, a Rho inhibitor, decreased CLIC5 expression in podocytes. CONCLUSION: Activation cAMP signaling might attenuate albuminuria in ADR-induced nephrosis mice. Different downstream signaling pathway might mediate cAMP protection on CLIC5 and p-ERM expression, respectively.
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Canales de Cloruro/metabolismo , AMP Cíclico/farmacología , Proteínas del Citoesqueleto/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Fosforilación/efectos de los fármacos , Podocitos/metabolismo , Animales , Antibacterianos , Canales de Cloruro/efectos de los fármacos , Colforsina/farmacología , Proteínas del Citoesqueleto/efectos de los fármacos , Doxorrubicina , Masculino , Proteínas de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Proteínas de Microfilamentos/efectos de los fármacos , Nefrosis/inducido químicamente , Nefrosis/metabolismo , Nefrosis/patología , Podocitos/efectos de los fármacos , Vasodilatadores/farmacología , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoARESUMEN
Nephrotoxicity is a major constraint of cisplatin application in many solid tumors. Since the lack of preventive strategies, the necessity exists to identify critical molecular targets involved in cisplatin nephrotoxicity. The Purinergic ligand-gcotedion channel 7 receptor (P2X7R) is a ligand-gated ion channel that is predominantly implicated in inflammation and cell death. Our aim is to investigate the role P2X7R in cisplatin-induced acute and chronic kidney injury, as well as the underlying mechanism. In this study, we found that cisplatin can cause an increase in the expression of P2X7R in mouse kidney tissue, and P2X7R knockout can alleviate acute renal function damage caused by cisplatin, as well as the expression of kidney injury molecule 1 (KIM-1) and interleukin-18 (IL-18). Cisplatin can cause an increase in the expression of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in mouse kidney tissue. Compared with wild-type mice, P2X7R -/- mice showed decreased expression of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved Caspase-1, and cleaved IL-1ß in kidney tissue after cisplatin administration, and the apoptosis of renal tubular epithelial cells were also decreased. In addition, we also found that NLRP3 knockout can improve cisplatin induced degeneration, detachment, and necrosis of renal tubular epithelial cells. Furthermore, P2X7R -/- mice also showed reduced renal fibrosis and better long-term renal prognosis. In conclusion, our study identified that P2X7R knockout can improve cisplatin induced acute renal injury and chronic renal fibrosis by inhibiting the activation of NLRP3 inflammasome.
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Lesión Renal Aguda , Cisplatino , Inflamasomas , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores Purinérgicos P2X7 , Animales , Cisplatino/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/deficiencia , Ratones , Inflamasomas/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Masculino , Antineoplásicos/toxicidadRESUMEN
BACKGROUND: Renin-angiotensin system inhibitors (RASi) treatment is the basic therapy for IgA nephropathy (IgAN) patients. However, there is few of biomarker that can predict the efficacy of RASi. This study aimed to find urinary exosomal mRNAs related to the therapeutic effect of RASi in the treatment of proteinuria in IgAN patients. METHODS: We divided IgAN patients in screening cohort into A1 (proteinuria increase at 3 months), B1 (proteinuria decrease less than 50 % at 3 months), C1 (proteinuria decrease more than 50 % at 3 months) groups according to changes of proteinuria after treatment. The urinary exosomes were collected before biopsy, RNAs were extracted and analyzed with the microarray assay. The candidate genes were screened by differentially expressed genes (DEGs) analysis and then validated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort. A receiver operating characteristic (ROC) curve was used to evaluate gene performance in predicting therapeutic effect on RASi reducing proteinuria in IgAN patients. RESULTS: ECE1 and PDE1A mRNAs were significantly different among the three groups, and were gradually decreased among A1, B1 and C1 groups. In the validation cohort, the level of urinary exosomal ECE1 and PDE1A mRNAs were also significantly lower in A2 group compared with C2 group(ECE1, P < 0.001;PDE1A, P < 0.01). Besides, the level of ECE1 mRNA was also lower in B2 group compared with C2 group (P < 0.01). The ROC curve verified that urinary exosomal ECE1 and PDE1A gene level predicted RASi efficacy in IgAN patients with area under curve (AUC) 0.68 and 0.63 respectively. CONCLUSION: Urinary exosomal ECE1 and PDE1A mRNAs expression can serve as potential biomarkers for predicting the RASi efficacy to reduce proteinuria in IgAN patients.
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Biomarcadores , Exosomas , Glomerulonefritis por IGA , ARN Mensajero , Sistema Renina-Angiotensina , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/orina , Glomerulonefritis por IGA/genética , Masculino , ARN Mensajero/genética , ARN Mensajero/orina , Adulto , Femenino , Exosomas/genética , Exosomas/metabolismo , Biomarcadores/orina , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genética , Persona de Mediana Edad , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéuticoRESUMEN
BACKGROUND: The relationship between Bowman's capsule thickening and progression of diabetic kidney disease (DKD) remains uncertain. METHODS: Renal biopsy specimens from 145 DKD patients and 20 control subjects were evaluated for Bowman's capsule thickness. Immunohistochemical staining assessed col4α2, laminin ß1, and albumin expression. In a discovery cohort of 111 DKD patients with eGFR ≥ 30 ml/min/1.73 m2, thickening was classified as fibrotic or exudative. The composite endpoint included CKD stage 5, dialysis initiation, and renal disease-related death. Prognosis was analyzed using Kaplan-Meier and Cox regression analyses. Two validation cohorts were included. RESULTS: Three types of thickening were observed: fibrotic, exudative, and periglomerular fibrosis. Parietal epithelial cell matrix protein accumulation contributed to fibrotic thickening, while albumin was present in exudative thickening. Bowman's capsule was significantly thicker in DKD patients (5.74 ± 2.09 µm) compared to controls (3.38 ± 0.43 µm, P < 0.01). In discovery cohort, the group of exudative thickning had a poorer prognosis(median time 20 months vs 57 months, P = 0.000). Cox multivariate analysis revealed that exudative thickening of Bowman's capsule were associated with a poor prognosis. The validation cohorts confirmed the result. CONCLUSIONS: Various mechanisms contribute to Bowman's capsule thickening in DKD. The proportion of exudative thickening may serve as a valuable prognostic indicator for DKD patients.
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Diabetes Mellitus , Nefropatías Diabéticas , Fallo Renal Crónico , Humanos , Cápsula Glomerular/metabolismo , Cápsula Glomerular/patología , Nefropatías Diabéticas/patología , Fallo Renal Crónico/patología , Diálisis Renal , Albúminas , Diabetes Mellitus/patologíaRESUMEN
Thermal stability determines a material's ability to maintain its performance at desired service temperatures. This is especially important for aluminum (Al) alloys, which are widely used in the commercial sector. Herein, an ultra-strong and heat-resistant Al-Cu composite is fabricated with a structure of nano-AlN and submicron-Al2 O3 particles uniformly distributed in the matrix. At 350 °C, the (8.2AlN+1Al2 O3 )p /Al-0.9Cu composite achieves a high strength of 187 MPa along with a 4.6% ductility under tension. The high strength and good ductility benefit from strong pinning effect on dislocation motion and grain boundary sliding by uniform dispersion of nano-AlN particles, in conjunction with the precipitation of Guinier-Preston (GP) zones, enhancing strain hardening capacity during plastic deformation. This work can expand the selection of Al-Cu composites for potential applications at service temperatures as high as ≈350 °C.
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Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. In our study we found that Adenosine triphosphate (ATP) content was significantly increased in the urine of diabetic mice. We examined the expression of all purinergic receptors in the renal cortex and found that only purinergic P2X7 receptor (P2X7R) expression was significantly increased in the renal cortex of wild-type diabetic mice and that the P2X7R protein partially co-localized with podocytes. Compared with P2X7R(-/-) non-diabetic mice, P2X7R(-/-) diabetic mice showed stable expression of the podocyte marker protein podocin in the renal cortex. The renal expression of microtubule associated protein light chain 3 (LC-3II) in wild-type diabetic mice was significantly lower than in wild-type controls, whereas the expression of LC-3II in the kidneys of P2X7R(-/-) diabetic mice was not significantly different from that of P2X7R(-/-) non-diabetic mice. In vitro, high glucose induced an increase in p-Akt/Akt, p-mTOR/mTOR and p62 protein expression along with a decrease in LC-3II levels in podocytes, whereas after transfection with P2X7R siRNA, Phosphorylated protein kinase B (p-Akt)/Akt, Phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, and p62 expression were restored and LC-3II expression was increased. In addition, LC-3II expression was also restored after inhibition of Akt and mTOR signaling with MK2206 and rapamycin, respectively. Our results suggest that P2X7R expression is increased in podocytes in diabetes, and that P2X7R is involved in the inhibition of podocyte autophagy by high glucose, at least in part through the Akt-mTOR pathway, thereby exacerbating podocyte damage and promoting the onset of diabetic nephropathy. Targeting P2X7R may be a potential treatment for diabetic nephropathy.
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Nefropatías Diabéticas , Podocitos , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Nefropatías Diabéticas/genética , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Glucosa/metabolismo , Autofagia , Mamíferos/metabolismoRESUMEN
In intracellular transport, the cargo is usually simultaneously carried by two types of motor proteins that move oppositely, widely described as a "tug-of-war". We show theoretically that apart from the apparent competition, there is also a unintuitive cooperation between motors with opposite directionality. The model reproduces the in vivo experimental data with high accuracy. Under certain conditions, the cooperation can significantly increase the transport distance, rationalizing the choice of bidirectional over unidirectional transport in evolution. We further derive the exact analytical solution for the transport distance. Our results pave the road to understanding the physical nature of intracellular transport by motor proteins.
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Dineínas , Proteínas Motoras Moleculares , Transporte Biológico , Dineínas/metabolismo , Cinesinas , Modelos Biológicos , Proteínas Motoras Moleculares/metabolismoRESUMEN
Electronic skins and flexible pressure sensors are important devices for advanced healthcare and intelligent robotics. Sensitivity is a key parameter of flexible pressure sensors. Whereas introducing surface microstructures in a capacitive-type sensor can significantly improve its sensitivity, the signal becomes nonlinear and the pressure response range gets much narrower, significantly limiting the applications of flexible pressure sensors. Here, we designed a pressure sensor that utilizes a nanoscale iontronic interface of an ionic gel layer and a micropillared electrode, for highly linear capacitance-to-pressure response and high sensitivity over a wide pressure range. The micropillars undergo three stages of deformation upon loading: initial contact (0-6 kPa) and structure buckling (6-12 kPa) that exhibit a low and nonlinear response, as well as a post-buckling stage that has a high signal linearity with high sensitivity (33.16 kPa-1) over a broad pressure range of 12-176 kPa. The high linearity lies in the subtle balance between the structure compression and mechanical matching of the two materials at the gel-electrode interface. Our sensor has been applied in pulse detection, plantar pressure mapping, and grasp task of an artificial limb. This work provides a physical insight in achieving linear response through the design of appropriate microstructures and selection of materials with suitable modulus in flexible pressure sensors, which are potentially useful in intelligent robots and health monitoring.
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INTRODUCTION: Cognitive impairment (CI) is the common complications in maintenance haemodialysis (MHD) patients. Recently, the pathogenesis of CI has been discussed and oxidative stress is one of the main mechanisms in these patients. Thiamine and folic acid, which play an important role in relieving the production of reactive oxygen species, reducing homocysteine levels, improving oxidative stress in the nervous system. In pilot study, cognitive function was significantly improved in the group with thiamine and folic supplementation. Based on this result, we hypothesise that thiamine combined with folic acid supplementation may improve cognitive function in patients with MHD. METHODS AND ANALYSIS: In this prospective, randomised, placebo-controlled, double-blind, multicentre study, we will enrol patients undergoing haemodialysis who has the Montreal Cognitive Assessment score lower than 26 to treatment group (thiamine 90 mg/day combined with folic acid 30 mg/day) or control group (thiamine placebo 90 mg/day combined with folic acid placebo 30 mg/day). All subjects will be followed up for 96 weeks. The primary endpoint is the comparison of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score between treatment group and control group at 96 weeks of follow-up. The secondary endpoints include serum thiamine, folate, homocysteine levels, cranial functional MRI and survival. The central randomisation method will be adopted and the principles of placebo-controlled, double-blind randomised control will be followed. The comparisons among ADAS-Cog scores and other secondary endpoints over time within subjects is conducted by using repeated measure analysis of variance (ANOVA) or generalised estimating equations (GEE). Pairwise t-test with Bonferroni adjustment is performed for multiple comparisons. On the other hand, for comparisons between treatment and control group, simple one-way ANOVA, GEE or Wilcoxon rank sum test is used. The χ2 method is used for statistical analysis of the categorical data. Kaplan-Meier survival curve is used for survival analysis. A p<0.05 is considered statistically significant difference. ETHICS AND DISSEMINATION: This trial has been approved by Shanghai Jiao Tong University School of Medicine, Renji Hospital Ethics Committee (KY2019-199). After publication of study results, trial report will be published in peer-reviewed journals and/or in national or international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000029297.
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Disfunción Cognitiva , Ácido Fólico , China , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Método Doble Ciego , Ácido Fólico/uso terapéutico , Humanos , Estudios Multicéntricos como Asunto , Proyectos Piloto , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Tiamina/uso terapéuticoRESUMEN
Extracellular adenosine triphosphate (ATP) and its receptor, P2X7 receptor (P2X7R), are playing an important role in the pathological process of renal ischemia-reperfusion injury, but their underlying mechanism remains unclear. Also, the effects of tubular epithelium-expressed P2X7 receptor on ischemia acute kidney injury is still unknown. The aim of this study is to clarify if this mechanism involves the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the renal tubular epithelial cells. In our research, we used male C57BL/6 wild type and P2X7R (-/-) mice, cultured human proximal tubular epithelial cells, and kidneys from acute kidney injury patients. Mice underwent for unilateral nephrectomy combined with the lateral renal pedicle clamping. Cultured cells were subjected to hypoxia/reoxygenation or ATP. Apyrase and A438079 were used to block the extracellular ATP/P2X7 receptor pathway. We also constructed radiation-induced bone marrow (BM) chimeras by using P2X7R (-/-) mice and P2X7R (+/+) wild-type mice. P2X7 receptor deficiency protected from renal ischemia-reperfusion injury and attenuated the formation of NLRP3 inflammasome. By using BM chimeras, we found a partial reduction of serum creatinine and less histological impairment in group wild-type BM to P2X7R (-/-) recipient, compared with group wild-type BM to wild-type recipient. In renal tubular epithelial cells, hypoxia/reoxygenation induced ATP release and extracellular ATP depletion reduced the expression of active IL-1ß. ATP activated the NLRP3 inflammasome in renal tubular epithelial cells, which were blunted by transient silence of P2X7 receptor, as well as by P2X7 receptor blocking with A438079. In human samples, we found that patients with Stage 3 AKI had higher levels of P2X7 receptor expression than patients with Stage 1 or Stage 2. Extracellular ATP/P2X7 receptor axis blocking may protect renal tubular epithelial cells from ischemia-reperfusion injury through the regulation of NLRP3 inflammasome.
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Lesión Renal Aguda/metabolismo , Inflamación/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Daño por Reperfusión/fisiopatología , Lesión Renal Aguda/patología , Animales , Femenino , Humanos , Inflamación/patología , Masculino , Ratones , Transducción de Señal , Análisis de Supervivencia , TransfecciónRESUMEN
Sensitivity is a crucial parameter for flexible pressure sensors and electronic skins. While introducing microstructures (e.g., micro-pyramids) can effectively improve the sensitivity, it in turn leads to a limited pressure-response range due to the poor structural compressibility. Here, we report a strategy of engineering intrafillable microstructures that can significantly boost the sensitivity while simultaneously broadening the pressure responding range. Such intrafillable microstructures feature undercuts and grooves that accommodate deformed surface microstructures, effectively enhancing the structural compressibility and the pressure-response range. The intrafillable iontronic sensor exhibits an unprecedentedly high sensitivity (Smin > 220 kPa-1) over a broad pressure regime (0.08 Pa-360 kPa), and an ultrahigh pressure resolution (18 Pa or 0.0056%) over the full pressure range, together with remarkable mechanical stability. The intrafillable structure is a general design expected to be applied to other types of sensors to achieve a broader pressure-response range and a higher sensitivity.
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Human-computer interfaces, smart glasses, touch screens, and some electronic skins require highly transparent and flexible pressure-sensing elements. Flexible pressure sensors often apply a microstructured or porous active material to improve their sensitivity and response speed. However, the microstructures or small pores will result in high haze and low transparency of the device, and thus it is challenging to balance the sensitivity and transparency simultaneously in flexible pressure sensors or electronic skins. Here, for a capacitive-type sensor that consists of a porous polyvinylidene fluoride (PVDF) film sandwiched between two transparent electrodes, the challenge is addressed by filling the pores with ionic liquid that has the same refractive index with PVDF, and the transmittance of the film dramatically boosts from 0 to 94.8% in the visible range. Apart from optical matching, the ionic liquid also significantly improves the signal intensity as well as the sensitivity due to the formation of an electric double layer at the dielectric-electrode interfaces, and improves the toughness and stretchability of the active material benefiting from a plasticization effect. Such transparent and flexible sensors will be useful in smart windows, invisible bands, and so forth.
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BACKGROUND: Diabetic nephropathy (DN) is one of the principal complications of diabetes and podocyte injury plays an important role in the DN pathogenesis. Wnt/ß-catenin signaling overactivation confers podocyte injury and promotes multiple types of renal disease. However, the underlying mechanism of Wnt/ß-catenin signaling activation in DN progression has not been fully elucidated. Long noncoding RNA (lncRNA) is a large class of endogenous RNA molecules lacking functional code capacity and which participates in the pathogenesis of human disease, including DN. METHOD: A diabetes model was constructed by intraperitoneal injection of Streptozotocin in rats. The MPC5 cells were used to create the in vitro model. Western blot and Quantitative reverse-transcriptase-PCR were used to examine the expression of protein and mRNA. The migrated capacity was analyzed by Transwell migration assay. The cell viability was detected by CCK8. RESULTS: In the present study, we revealed the association of lncRNA Maternally Expressed Gene 3 (MEG3) with aberrant activation of Wnt/ß-catenin signaling and the role of MEG3/Wnt axis in podocyte injury. We found that high glucose (HG) treatment suppressed MEG3 expression in cultured podocytes, activated Wnt/ß-catenin signaling and caused podocyte injury as indicated by the downregulation of podocyte-specific markers (podocin and synaptopodin) and the upregulation of snail1 and α-smooth muscle actin. Overexpression of MEG3 attenuated HG-induced podocyte injury by reducing Wnt/ß-catenin activity, repressing cell migration, reactive oxygen species production and increasing the viability of podocytes. Furthermore, we provided evidences that restoration of Wnt/ß-catenin signaling by specific agonist impeded the protective effect of MEG3 on podocyte injury. Current results demonstrated that MEG3/Wnt axis plays an important role in fostering podocyte injury and may serve as a potential therapeutic target for the treatment of DN. CONCLUSION: lncRNA MEG3 ameliorates podocyte injury in DN via inactivating Wnt/ß-catenin signaling.
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BACKGROUND This study was designed to observe incidence and risk factors of low oxygenation after orthotropic liver transplantation (OLT). MATERIAL AND METHODS We retrospectively evaluated all adult patients who underwent living-donor OLT between January 1, 2017 and December 31, 2017. Postoperative low oxygenation was defined as PaO2/FiO2 <300 mmHg within 24 hours after surgery. Early acute kidney injury (AKI) after OLT was also defined when AKI was happened with 24 hours after operative. RESULTS A total of 301 patients, aged 50.35±10.29 years were enrolled. Of these patients, 100 patients (33.2%) suffered postoperative low oxygenation (PaO2/FiO2=251.80±35.84). Compared with the normal oxygenation group, body mass index (BMI) (24.48±3.53 versus 23.1±3.27 kg/m², P=0.001), preoperative hemoglobin (115.79±29.27 versus 111.52±29.80 g/L, P=0.033), preoperative MELD (22.25±6.54 versus 20.24±5.74, P=0.008), and intraoperative urinary volume (1.25 [0.76, 1.89] versus 2.04 [1.49, 3.68] mL/kg/h, P=0.003) were higher in low oxygenation group. There were more cases of earlier AKIs that occurred after OLT in low oxygenation patients than that in normal group (47% versus 23.4%, P<0.001). Logistic analysis showed that the preoperative BMI (hazard ration [HR]=1.107, [1.010, 1.212], P=0.029) and early AKI after OLT (HR=2.115, [1.161, 3.855], P=0.014) were independent risk factors for postoperative low oxygenation. CONCLUSIONS The incidence of postoperative low oxygenation after liver transplantation in adults was 33.2%. BMI and early AKI after OLT were correlated with postoperative hypoxemia.
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Enfermedad Hepática en Estado Terminal/cirugía , Hipoxia/epidemiología , Hipoxia/etiología , Trasplante de Hígado/efectos adversos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Podocytes are terminally differentiated cells with little proliferative capacity. The high expression levels of cell cycle inhibitory proteins, including p21, p27, and p57, play an important role in maintaining the low level of proliferation of mature podocytes. In the present study, we aimed to explore the role of yes-associated protein (YAP) signalling in adriamycin-induced podocyte re-entry into the cell cycle and dedifferentiation. Proliferating cell nuclear antigen (PCNA)-, cyclin-dependent kinase 4 (CDK4)-, and Cyclin D1-positive podocytes were found in mice with adriamycin-induced nephropathy. In vitro, adriamycin administration increased the percentage of cells in S phase and the upregulation of mesenchymal-related marker proteins. CDK4 and cyclin D1 were significantly up-regulated after incubation with adriamycin. Overexpression of YAP in podocytes promoted their entry into the cell cycle; up-regulated cyclin D1, desmin, and snail2 expression and down-regulated Wilms' tumour 1 (WT1) and nephrin production. Recombinant murine FGF-basic induced podocytes to re-enter the cell cycle, inhibited WT1 and nephrin, and increased desmin and snail2 expression. Pretreating podocytes with verteporfin, an inhibitor of YAP/ TEA domain transcription factor (TEAD), decreased the adriamycin-induced overexpression of cyclin D1 and reduced the ratio of S-phase podocytes. This result was further verified by knocking down YAP expression using RNA interference. In conclusion, adriamycin induced podocytes to re-enter the cell cycle via upregulation of CDK4 and cyclin D1 expression, which was at least partly mediated by YAP signalling. Re-entry into the cell cycle induced the over-expression of mesenchymal markers in podocytes.