Monitoring allograft function during the early stages is crucial, and therefore requires biomarkers more sensitive than serum creatinine (Scr). Kidney injury molecular-1 (KIM-1) is a potent biomarker; however, disparities exist in the literature concerning its predictive value in allograft function. Therefore, this study aimed to evaluate its predictive value for the long-term prognosis of kidney transplantation patients.A prospective study with a cohort comprising 160 patients scheduled for kidney transplantation was conducted to evaluate the predictive power of urinary KIM-1 (uKIM-1) and other renal ischemia-reperfusion biomarkers including urinary L-type fatty acid binding protein (uL-FABP), urinary N-acetyl-β-D glucosaminidase (uNAG), and urinary neutrophil gelatinase-related lipoprotein (uNGAL) for allograft prognosis.One hundred and forty kidney recipients who were admitted to our hospital between September 2014 and December 2017 with a median follow-up of 30.3 months were included. Thirty-seven recipients had functional delayed graft function (fDGF) in the first week post transplantation, and 42 recipients had progressed to allograft dysfunction [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2] by the end of the study, while nine recipients deteriorated into allograft loss (defined by the initiation of dialysis). The levels of uKIM-1 in the fDGF group were higher than those in the immediate graft function (IGF) recipients (P<0.05) at 0 hour post transplantation [5.885 (4.420-7.913) vs. 4.605 (3.417-5.653) ng/mmol], and on the first day post transplantation [5.569 (4.181-6.722) vs. 4.002 (3.222-6.488) ng/mmol]. The levels of uL-FABP in the fDGF group were also higher than those in the IGF group at 0 hour post transplantation (89.818±39.332 vs. 69.187±37.926 µg/mmol) and on the third day post transplantation [77.835 (60.368-100.678) vs. 66.841 (28.815-89.783) µg/mmol]. Multivariate Cox regression analysis demonstrated that recipients with higher uKIM-1 levels on the first day post transplantation had a 23.5% increase in the risk of developing fDGF and a 27.3% increase in the risk of prolonged renal allograft dysfunction.uKIM-1 on the first day post transplantation can predict short-term graft function and is a potent biomarker for the long-term prognosis of graft function.
Abstract Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity.
Floating Offshore Wind Turbine (FOWT) is commonly used in harnessing wind energy in offshore regions. As a source of green energy, governments are paying more attention to the development of offshore wind farms worldwide. However, there are no offshore wind farms built in Australia. This study developed a conceptual design of FOWT based on the Bass Strait region which has the greatest potential for offshore wind farm development. Numerical simulations have been conducted using ANSYS AQWA to investigate the motion response of the concept in both the frequency and time domain. Both the uncoupled response amplitude operators and coupled motion behaviour were studied so as to determine an optimal design with respect to heave and pitch motions. The results obtained from the investigation provided a good understanding of the motion response of the structure. Response amplitude operators found from the frequency domain simulations agreed with similar concepts in existing literature, while results from the coupled analysis showed that mooring lines could influence the response of the structure. Therefore, it can be concluded that the FOWT concept can safely produce electricity with a significant wave height up to 4 metres in the Bass Strait region.
Acute kidney injury (AKI) is a critical clinical condition that causes kidney fibrosis, and it currently lacks specific treatment options. In this research, we investigate the role of the SENP1-Sirt3 signaling pathway and its correlation with mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) using folic acid (FA) and ischemia-reperfusion-induced (IRI) AKI models. Our findings reveal that Sirt3 SUMOylation site mutation (Sirt3 KR) or pharmacological stimulation (metformin) protected mice against AKI and subsequent kidney inflammation and fibrosis by decreasing the acetylation level of mitochondrial SOD2, reducing mitochondrial reactive oxygen species (mtROS), and subsequently restoring mitochondrial ATP level, reversing mitochondrial morphology and alleviating cell apoptosis. In addition, AKI in mice was similarly alleviated by reducing mtROS levels using N-acetyl-L-cysteine (NAC) or MitoQ. Metabolomics analysis further demonstrated an increase in antioxidants and metabolic shifts in Sirt3 KR mice during AKI, compared with Sirt3 wild-type (WT) mice. Activation of the AMPK pathway using metformin promoted the SENP1-Sirt3 axis and protected PTECs from apoptosis. Hence, the augmented deSUMOylation of Sirt3 in mitochondria, activated through the metabolism-related AMPK pathway, protects against AKI and subsequently mitigated renal inflammation and fibrosis through Sirt3-SOD2-mtROS, which represents a potential therapeutic target for AKI.
The FGF signal is important for cell survival, proliferation, differentiation and migration. It is not clear how the FGF signalling cascade is regulated. In order to identify genes downstream of FGF signalling, a gain-of-function (GOF) screen was conducted using the Drosophila compound eye as a model system. The screen was based on the observation that expression of an activated form of the FGF receptor and Dof together in the Drosophilia eye ('GMR>λ-fgfr, dof'), produces a rough eye phenotype, whereas expressing either alone has no effect. This implies that at least some of the components in the signalling cascade are present during Drosophila eye development. When one copy of raf, rhoA or rhoGEF was mutated, the rough eye phenotype of 'GMR>λ-fgfr, dof' flies was enhanced. In the screen, 'GMR>λ-fgfr, dof' flies were crossed to the EP collection and the progeny were screened for the modification of the rough eye phenotype. In total, 24 suppressors and 26 enhancers were obtained, which may affect 38 annotated genes. 8 lines did not have any interactions with other signalling pathways that I have tested, which are the PDGF and EGF signalling pathways, and pathways involving Cdc42 or Rac1. Nor were they found in any of the published GOF screens. In order to investigate the interaction of the candidates with the endogenous FGF signalling pathway, imprecise excisions of three candidates - EP719, EP3575 and EP863 - were generated and the mutant phenotypes were studied.
MicroRNAs (miRNAs) regulate several biological processes, including tumorigenesis. In order to comprehend the roles of miRNAs in cancer, various screens were performed to investigate the changes in the expression levels of miRNAs that occur in different types of cancer. The present review focuses on the results of five recent screens, whereby a number of overlapping miRNAs were identified to be downregulated or differentially regulated, whereas no miRNAs were observed to be frequently upregulated. Furthermore, the majority of the miRNAs that were common to >1 screen were involved in signaling networks, including wingless‑related integration site, receptor tyrosine kinase and transforming growth factor‑β, or in cell cycle checkpoint control. The present review will discuss the aforementioned miRNAs implicated in cell cycle checkpoint control and signaling networks.
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