R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins.

In-situ thermal conductive heating (TCH) for soil remediation: A review.

This paper provides a comprehensive overview of research works on in-situ thermal conductive heating (TCH), including heat transfer in soil, desorption behavior of pollutants, and mass transfer mechanism within the site. Each stage influences the effectiveness of subsequent stages. Comparison of simulation and experimental results demonstrates that heat transfer and temperature rise in soil are related to the hydrogeological conditions, wells layout and pollutants contents. Thermal desorption of pollutants from soil particles can be influenced by four aspects: energy input, pollutant properties, soil characteristics, and the binding state of pollutant in soil. The exponential decay kinetic model exhibits better applicability for fitting thermal desorption processes. After desorption, the pollutants migrate in soil driven by high temperature and extraction pressure, while hydrogeological conditions of the site determine the actual migration path and rate. Applying convection-dispersion model allows for quantitatively describing the complex migration behavior of pollutants in heterogeneous sites. Future research should focus more on the composite effects of multiple factors in TCH and develop multi-field coupling models through the combination of numerical simulation and in-situ experiments. Accurate characterization and prediction of entire TCH process can improve remediation efficiency, reduce energy costs, and achieve sustainable low-carbon remediation.

Mechanisms and extended kinetic model of thermal desorption in organic-contaminated soil.

Thermal desorption is a preferred technology for site remediation due to its various advantages. To ensure the effective removal of different pollutants in practical applications, it is necessary to understand the kinetic behaviors and removal mechanisms of pollutants in thermal desorption process. This paper explored the thermal desorption processes of five organic pollutants (nitrobenzene, naphthalene, n-dodecane, 1-nitronaphthalene, and phenanthrene) at 50-350 °C in two different subsoils with 6-18% moisture content. The results suggested that the thermal desorption process was well-fitted by the exponential decay model (R2 = 0.972-0.999) and could be divided into two distinct stages. The first stage was relatively fast and highly influenced by soil moisture, while the second stage showed a slower desorption rate due to the constraints imposed by the soil texture and structure. The influence of soil moisture on thermal desorption depended on the octanol/water partition coefficient (KOW) of pollutants. Pollutants with log KOW values lower than the critical value exhibited enhanced thermal desorption, while those with log KOW values higher than the critical value were inhibited. The critical value of log KOW might be between 3.33 and 4.46. Changes in soil texture and structure caused by heating promoted thermal desorption, especially for naphthalene, 1-nitronaphthalene and phenanthrene. The differences in texture and structure between the two soils diminished as the temperature increased. Finally, an extended kinetic model under changing temperature conditions was derived, and the simulation results for the two subsoils were very close to the actual thermogravimetric results, with the differences ranging from -1.28% to 0.94% and from -0.67% to 1.35%, respectively. These findings propose new insights into the influencing mechanisms of soil moisture and structure on the thermal desorption of organic pollutants. The extended kinetic model can provide reference for future kinetic research and guide practical site remediation.

An Image Detection Method for Image Stabilization Deviation of the Tank Gunner's Primary Sight.

The primary sight control system of a tank gunner has image stabilization as one of its primary functions. The image stabilization deviation in the aiming line is a key indicator for evaluating the operational status of Gunner's Primary Sight control system. Employing image detection technology to measure image stabilization deviation enhances the effectiveness and accuracy of the detection process and allows for the evaluation of image stabilization functionality. Hence, this paper proposes an image detection method aimed at the Gunner's Primary Sight control system of a specific tank which utilizes an enhanced You Only Look Once version 5 (YOLOv5) sight-stabilizing deviation algorithm. At first, a dynamic weight factor is integrated into SCYLLA-IoU (SIOU), creating δ-SIOU, which replaces Complete IoU (CIoU) as the loss function of YOLOv5. After that, the Spatial Pyramid Pool module of YOLOv5 was enhanced to improve the multi-scale feature fusion ability of the model, thereby elevating the performance of the detection model. Finally, the C3CA module was created by embedding the Coordinate Attention (CA) attention mechanism into the CSK-MOD-C3 (C3) module. The Bi-directional Feature Pyramid (BiFPN) network structure was also incorporated into the Neck network of YOLOv5 to improve the model's ability to learn target location information and image detection accuracy. Based on data collected by a mirror control test platform, experimental results indicate an improvement in the detection accuracy of the model by 2.1%. These findings offer valuable insights into measuring the image stabilization deviation in the aiming line and facilitating the development of the parameter measurement system for Gunner's Primary Sight control system.

B7-H6 as an efficient target for T cell-induced cytotoxicity in haematologic malignant cells.

T cells play crucial roles in the antitumour immune response. However, their dysfunction leads to inefficient tumour eradication. New members of the B7 family have moved to the fore of cancer research because of their involvement in T cell-mediated immune escape and tumorigenesis. Recently, bispecific antibodies (Bi-Abs) have become attractive because of their ability to activate T cells to target tumours. In this study, we examined the expression of new B7 family members B7-H4, B7-H5, B7-H6, and B7-H7 in human haematological tumour cells. Furthermore, we explored whether B7-H6 is an efficient target for T cell-induced cytotoxicity in haematologic malignant cells. We determined the capability of T cells armed with the bispecific antibody anti-CD3 × anti-B7-H6 (B7-H6Bi-Ab) to target haematological tumours in K562, Thp-1, Daudi, Jurkat, and U266 cells. Compared with their T cell counterparts, B7-H6Bi-Ab-armed T cells demonstrated significant cytotoxicity induction in B7-H6+ haematological tumour cells, according to quantitative luciferase and lactate dehydrogenase assays, and their activity was accompanied by increased levels of the secreted killing mediators granzyme B and perforin. Moreover, B7-H6Bi-Ab-armed T cells produced more T cell-derived cytokines: TNF-α, IFN-γ, and IL-2. In addition, compared to the control T cells, a higher level of the activation marker CD69 was detected on the B7-H6Bi-Ab-armed T cells. Taken together, these data suggest that the antitumour effect of B7-H6Bi-Ab-armed T cells may be a promising immunotherapy for use in future haematologic treatments.

Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo.

Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3+ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

A Two Phases Multiobjective Trajectory Optimization Scheme for Multi-UGVs in the Sight of the First Aid Scenario.

Timely delivery of first aid supplies is significant to saving lives when an accident happens. Among the promising solutions provided for such scenarios, the application of unmanned vehicles has attracted ever more attention. However, such scenarios are often very complex, while the existing studies have not fully addressed the trajectory optimization problem of multiple unmanned ground vehicles (multi-UGVs) against the scenario. This study focuses on multi-UGVs trajectory optimization in the sight of first aid supply delivery tasks in mass accidents. A two-stage completely decoupling fuzzy multiobjective optimization strategy is designed. On the first stage, with the proposed timescale involved tridimensional tunneled collision-free trajectory (TITTCT) algorithm, collision-free coarse tunnels are build within a tridimensional coordinate system, respectively, for the UGVs as the corresponding configuration space for a further multiobjective optimization. On the second stage, a fuzzy multiobjective transcription method is designed to solve the decoupled optimal control problem (OCP) within the configuration space with the consideration of priority constrains. Following the two-stage design, the computational time is significantly reduced when achieving an optimal solution of the multi-UGV trajectory planning, which is crucial in a first aid task. In addition, other objectives are optimized with the aspiration level reflected. Simulation studies and experiments have been curried out to testify the effectiveness and the improved computational performance of the proposed design.

Switching Anti-Windup Synthesis for Linear Systems With Asymmetric Actuator Saturation.

This article proposes a switching anti-windup strategy for linear, time-invariant (LTI) systems subject to asymmetric actuator saturation and L2 -disturbances, the core idea behind which is to make full use of the available range of control input space by switching among multiple anti-windup gains. The asymmetrically saturated LTI system is converted to a switched system with symmetrically saturated subsystems, and a dwell time switching rule is presented to govern the switching between different antiwindup gains. Based on multiple Lyapunov functions, we derive sufficient conditions for guaranteeing the regional stability and weighted L2 performance of the closed-loop system. The switching anti-windup synthesis that designs a separate anti-windup gain for each subsystem is cast as a convex optimization problem. In comparison with the design of a single anti-windup gain, our method can induce less conservative results since the asymmetric character of the saturation constraint is fully utilized in the switching anti-windup design. Two numerical examples, and an application to aeroengine control (the experiments are conducted on a semiphysical test bench), demonstrate the superiority and practicality of the proposed scheme.

Premature senescence in cells from patients with autosomal recessive hypercholesterolemia (ARH): evidence for a role for ARH in mitosis.

OBJECTIVE: The defective gene causing autosomal recessive hypercholesterolemia (ARH) encodes ARH, a clathrin-associated adaptor protein required for low-density-lipoprotein receptor endocytosis in most cells but not in skin fibroblasts. The aim here was to elucidate why ARH fibroblasts grow slowly and undergo premature senescence. METHODS AND RESULTS: Knockdown of ARH by RNA interference in IMR90 cells produces the same phenotype, indicated by increased p16 expression, γ-H2AX-positive foci, and enlarged flattened morphology. We showed that ARH contributes to several aspects of mitosis: it localizes to mitotic microtubules, with lamin B1 on the nuclear envelope and spindle matrix, and with clathrin heavy chain on mitotic spindles. Second, ARH is phosphorylated in G(2)/M phase by a roscovitine-sensitive kinase, probably cdc2. Third, cells lacking ARH show disfigured nuclei and defective mitotic spindles. Defects are most marked in ARH W22X cells, where translation starts at Met46, so the protein lacks a phosphorylation site at Ser14, identified by mass spectrometry of wild-type ARH. CONCLUSIONS: The ARH protein is involved in cell cycle progression, possibly by affecting nuclear membrane formation through interaction with lamin B1 or other mitotic proteins, and its absence affects cell proliferation and induces premature senescence, which may play a role in the development of atherosclerosis in ARH.

Modeling and controller design of a micro gas turbine for power generation.

This paper investigates the modeling and controller design of a micro gas turbine in power generation scenario. From the perspective of the controller design, it is well recognized that an accurate model in possession of the complex dynamic characteristics of a micro gas turbine is paramount. Thus, a nominal nonlinear model originated from integrating the start-up model and the component characteristic map model together is established to depict the main operating modes of the full operation envelope, containing the start-up mode, loading mode and unloading mode. The start-up model is got by the combination of polynomial fitting method with identification method. The component characteristic map model is achieved by combining inter-component volume method with experiment data. The proposed nominal nonlinear model is realized in MATLAB/Simulink environment. Furthermore, nonlinear and linear active disturbance rejection controllers and a PID controller are designed respectively. Such controllers not only realize the speed tracking control from the idle speed to the nominal speed, but also achieve the load tracking control at the nominal speed by numerical simulations and hardware-in-the-loop tests. In addition, the nonlinear active disturbance rejection controller has the best control performance, which is validated through the simulation results and hardware-in-the-loop tests.

Active fault tolerant tracking control of turbofan engine based on virtual actuator.

In this paper, an active fault-tolerant tracking control scheme for the turbofan engine under dynamic and simultaneous actuator faults and sensor faults under disturbances is proposed. First, based on the linear parameter-varying model of the turbofan engine, an H∞ state feedback nominal controller is designed so as to achieve rotor speed tracking control with adaptive gain scheduling characteristics at different working conditions for the turbofan engine. Next, for the control system with simultaneous multiplicative actuator faults and additive sensor faults, a virtual actuator based active fault-tolerant tracking control strategy is developed to reconfigure the system such that it can obtain the similar behavior to the fault-free system without modifying the nominal controller. Specifically, in addition to handle the actuator fault by the virtual actuator, the reconfigured controller adopts a feedforward control signal to compensate for the sensor fault. Besides, in order to guarantee the reconfigured system, a sufficiency criterion is proposed. Finally, simulations have been conducted on a twin-spool turbofan engine to verify the effectiveness of the strategy.

Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control.

OBJECTIVE: To produce transgenic mice expressing the D374Y variant of the human proprotein convertase subtilisin/kexin type 9 (PCSK9) gene at physiological levels to investigate the mechanisms causing hypercholesterolemia and accelerated atherosclerosis. METHODS AND RESULTS: A bacterial artificial chromosome containing PCSK9 and its flanking regions was modified to introduce the D374Y mutation and a C-terminal myc(2) tag. Transgenic mice that expressed 1 copy of the mutant or wild-type (WT) PCSK9 bacterial artificial chromosome were produced. Human PCSK9 mRNA was expressed at levels comparable to endogenous pcsk9 and with the same tissue specificity. The expression of D374Y or WT human PCSK9 increased the serum cholesterol level and reduced hepatic low-density lipoprotein receptor protein levels in the transgenic mice compared with bacterial artificial chromosome-negative controls; however, the effects were more marked in D374Y mice. The effect of a high-cholesterol diet on increasing serum cholesterol level was greater in D374Y mice, and atherosclerotic plaques after 15 weeks were more extensive in mice expressing D374Y than in WT PCSK9. D374Y mice secreted more triglyceride-rich lipoproteins into the circulation than WT mice. CONCLUSIONS: The expression of human D374Y PCSK9 at physiological levels produced a phenotype that closely matched that found in heterozygous D374Y patients and suggested that reduced low-density lipoprotein receptor activity is not the sole cause of their hypercholesterolemia.

Advanced hepatocellular carcinoma treated by radiofrequency ablation combined with oncolytic virus and anti-PD-1 antibody therapy: a case report and literature review.

The development of an effective therapy for advanced hepatocellular carcinoma (HCC) represents an important global concern. In recent years, the combination of multiple treatment methods with immunotherapy has achieved great progress in patients with advanced HCC. Patient survival has been significantly prolonged, but cases of complete response (CR) remain rare. Here, we report two cases in which CR was achieved by radiofrequency ablation combined with an oncolytic virus (recombinant human adenovirus type 5) and anti-programmed cell death protein 1 antibody. Additionally, a literature review is presented to describe similar advancements in this field and explore viable methods for the treatment of advanced HCC.

Size-Dependent Increase in RNA Polymerase II Initiation Rates Mediates Gene Expression Scaling with Cell Size.

Cell size varies during the cell cycle and in response to external stimuli. This requires the tight coordination, or "scaling," of mRNA and protein quantities with the cell volume in order to maintain biomolecule concentrations and cell density. Evidence in cell populations and single cells indicates that scaling relies on the coordination of mRNA transcription rates with cell size. Here, we use a combination of single-molecule fluorescence in situ hybridization (smFISH), time-lapse microscopy, and mathematical modeling in single fission yeast cells to uncover the precise molecular mechanisms that control transcription rates scaling with cell size. Linear scaling of mRNA quantities is apparent in single fission yeast cells during a normal cell cycle. Transcription of both constitutive and periodic genes is a Poisson process with transcription rates scaling with cell size and without evidence for transcriptional off states. Modeling and experimental data indicate that scaling relies on the coordination of RNA polymerase II (RNAPII) transcription initiation rates with cell size and that RNAPII is a limiting factor. We show using real-time quantitative imaging that size increase is accompanied by a rapid concentration-independent recruitment of RNAPII onto chromatin. Finally, we find that, in multinucleated cells, scaling is set at the level of single nuclei and not the entire cell, making the nucleus a determinant of scaling. Integrating our observations in a mechanistic model of RNAPII-mediated transcription, we propose that scaling of gene expression with cell size is the consequence of competition between genes for limiting RNAPII.

Single-cell imaging and RNA sequencing reveal patterns of gene expression heterogeneity during fission yeast growth and adaptation.

Phenotypic cell-to-cell variability is a fundamental determinant of microbial fitness that contributes to stress adaptation and drug resistance. Gene expression heterogeneity underpins this variability but is challenging to study genome-wide. Here we examine the transcriptomes of >2,000 single fission yeast cells exposed to various environmental conditions by combining imaging, single-cell RNA sequencing and Bayesian true count recovery. We identify sets of highly variable genes during rapid proliferation in constant culture conditions. By integrating single-cell RNA sequencing and cell-size data, we provide insights into genes that are regulated during cell growth and division, including genes whose expression does not scale with cell size. We further analyse the heterogeneity of gene expression during adaptive and acute responses to changing environments. Entry into the stationary phase is preceded by a gradual, synchronized adaptation in gene regulation that is followed by highly variable gene expression when growth decreases. Conversely, sudden and acute heat shock leads to a stronger, coordinated response and adaptation across cells. This analysis reveals that the magnitude of global gene expression heterogeneity is regulated in response to different physiological conditions within populations of a unicellular eukaryote.

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFß1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFß1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

An Equation Based on Fuzzy Mathematics to Assess the Timing of Haemodialysis Initiation.

In order to develop an equation that integrates multiple clinical factors including signs and symptoms associated with uraemia to assess the initiation of dialysis, we conducted a retrospective cohort study including 25 haemodialysis centres in Mainland China. Patients with ESRD (n = 1281) who commenced haemodialysis from 2008 to 2011 were enrolled in the development cohort, whereas 504 patients who began haemodialysis between 2012 and 2013 were enrolled in the validation cohort comprised. An artificial neural network model was used to select variables, and a fuzzy neural network model was then constructed using factors affecting haemodialysis initiation as input variables and 3-year survival as the output variable. A logistic model was set up using the same variables. The equation's performance was compared with that of the logistic model and conventional eGFR-based assessment. The area under the bootstrap-corrected receiver-operating characteristic curve of the equation was 0.70, and that of two conventional eGFR-based assessments were 0.57 and 0.54. In conclusion, the new equation based on Fuzzy mathematics, covering laboratory and clinical variables, is more suitable for assessing the timing of dialysis initiation in a Chinese ESRD population than eGFR, and may be a helpful tool to quantitatively evaluate the initiation of haemodialysis.

Assessment of dialysis initiation by a fuzzy mathematics equation (ADIFE): a study protocol for a randomised controlled trial.

INTRODUCTION: Starting dialysis early or late both result in a low quality of life and a poor prognosis in patients undergoing haemodialysis. However, there remains no consensus on the optimal timing of dialysis initiation, mainly because of a lack of suitable methods to assess variations in dialysis initiation time. We have established a novel equation named DIFE (Dialysis Initiation based on Fuzzy-mathematics Equation) through a retrospective, multicentre clinical cohort study in China to determine the most suitable timing of dialysis initiation. The predictors of the DIFE include nine biochemical markers and clinical variables that together influence dialysis initiation. To externally validate the clinical accuracy of DIFE, we designed the assessment of DIFE (ADIFE) study as a prospective, open-label, multicentre, randomised controlled trial to assess the clinical outcomes among patients who initiate dialysis in an optimal start dialysis group and a late-start dialysis group, based on DIFE. METHODS AND ANALYSIS: A total of 388 enrolled patients with end-stage renal disease will be randomised 1:1 to the optimal start dialysis group, with a DIFE value between 30 and 35, or the late-start dialysis group, with a DIFE value less than 30, using the Randomization and Trial Supply Management system. Participants will be assessed for changes in signs and symptoms, dialysis mode and parameters, biochemical and inflammatory markers, Subjective Global Assessment, Kidney Disease Quality of Life Short Form, Cognitive Assessment, medical costs, adverse events and concomitant medication at baseline, predialysis visiting stage and postdialysis visiting stage, every 12-24 weeks. The following data will be recorded on standardised online electronic case report forms. The primary endpoint is 3-year all-cause mortality. The secondary endpoints include non-fatal cerebrocardiovascular events, annual hospitalisation rate, quality of life, medical costs and haemodialysis related complications. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Dalian Medical University China (registration no: YJ-KY-2017-119) and the ethics committees of all participating centres. The final results of the ADIFE trial will be presented to the study sponsor, clinical researchers and the patient and public involvement reference group. Findings will be disseminated through peer-reviewed journals, Clinical Practice Guidelines and at scientific meetings. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov. Registry (NCT03385902); pre-results.