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Atmospheric CO2 concentrations exert a strong influence on the susceptibility of plants to pathogens. However, the mechanisms involved in the CO2 -dependent regulation of pathogen resistance are largely unknown. Here we show that the expression of tomato (Solanum lycopersicum) β-CARBONIC ANHYDRASE 3 (βCA3) is induced by the virulent pathogen Pseudomonas syringae pv. tomato DC3000. The role of βCA3 in the high CO2 -mediated response in tomato and two other Solanaceae crops is distinct from that in Arabidopsis thaliana. Using βCA3 knock-out and over-expression plants, we demonstrate that βCA3 plays a positive role in the activation of basal immunity, particularly under high CO2 . βCA3 is transcriptionally activated by the transcription factor NAC43 and is also post-translationally regulated by the receptor-like kinase GRACE1. The βCA3 pathway of basal immunity is independent on stomatal- and salicylic-acid-dependent regulation. Global transcriptome analysis and cell wall metabolite measurement implicate cell wall metabolism/integrity in βCA3-mediated basal immunity under both CO2 conditions. These data not only highlight the importance of βCA3 in plant basal immunity under high CO2 in a well-studied susceptible crop-pathogen system, but they also point to new targets for disease management strategies in a changing climate.

Epidemiological and experimental animal studies indicate that there is a high risk for the incidence of neuropsychiatric disorders suffering from cardiovascular diseases such as myocardial infarction (MI). However, the potential mechanism of this association remains largely unknown. This study sought to evaluate whether epigenetic alterations in the hippocampus is associated with MI-induced anxiety-like behavior in rats. MI was induced by occlusion of the left anterior descending artery in adult female rats. Anxiety-like behavior was examined by elevated plus maze, light-dark box, and open field test. Relative gene and protein levels expression in the hippocampus were tested by qRT-PCR and western blotting, respectively. We found that MI rats exhibited anxiety-like behavior compared with those in controls, and there is a positive correlation between MI and anxiety-like behavior. We also found that MI decreased KDM6B while increased SIRT1 expression in the hippocampus of MI rats relative to those in controls. In addition, MI not only increased levels of IL-1β, bax, and cleaved-caspase 3, but also increased Iba-1 and GFAP expression in the hippocampus, as compared to those in controls, suggesting a promotion of neuro-inflammation and apoptosis in hippocampus. Co-immunoprecipitation assay illustrated that H3K27me3 functioned by counteracting with YAP activation in the hippocampus of MI rats relative to those in controls. Together, these results suggest a potential role of hippocampal epigenetic signaling in MI-induced anxiety-like behavior in rats, and pharmacological targeting KDM6B or SIRT1 could be a strategy to ameliorate anxiety-like behavior induced by MI.

Polyphyllin I (PPI) is a natural phytochemical drug isolated from plants which can inhibit the proliferation of cancer cells. One of the PPI tumor-inhibitory effects is through downregulating the expression of Cancerous Inhibitor of PP2A (CIP2A), the latter, is found upregulated in Alzheimer's disease (AD) brains and participates in the development of AD. In this study, we explored the application of PPI in experimental AD treatment in CIP2A-overexpressed cells and 3XTg-AD mice. In CIP2A-overexpressed HEK293 cells or primary neurons, PPI effectively reduced CIP2A level, activated PP2A, and decreased the phosphorylation of tau/APP and the level of Aβ. Furthermore, synaptic protein levels were restored by PPI in primary neurons overexpressing CIP2A. Animal experiments in 3XTg-AD mice revealed that PPI treatment resulted in decreased CIP2A expression and PP2A re-activation. With the modification of CIP2A-PP2A signaling, the hyperphosphorylation of tau/APP and Aβ overproduction were prevented, and the cognitive impairments of 3XTg-AD mice were rescued. In summary, PPI ameliorated AD-like pathology and cognitive impairment through modulating CIP2A-PP2A signaling pathway. It may be a potential drug candidate for the treatment of AD.

The intermediate filament protein Nestin, a specific marker for multifunctional, multilineage progenitor cells, is regulated during the progression of reparative and reactive fibrosis in the liver, heart and kidney. In this study, Nestin was found in both the mouse peritoneum and HPMCs derived from PD effluent (PDE) and HMrSV5. Moreover, these Nestin+ PMCs showed extensive proliferation for more than 20 passages. The mice that received chronic peritoneal dialysis solution (PDS) infusions showed typical features of peritoneal fibrosis (PF), including substantially increased perito­neal thickness, excessive matrix deposition, increased peritoneal permeability, and increased expression levels of α-smooth muscle actin (α-SMA) and collagen I (Col I). Nestin+ cells isolated from the peritoneum could significantly ameliorate these pathological changes. A parallel decrease in interleukin-33 (IL-33) and ST-2 accumulation in the peritoneum of Nestin+ cell-transplanted mice was observed. In addition, downregulation of IL-33 expression decreasedTGF-β1-induced accumulation of extracellular matrix (ECM) in the HPMCs. In conclusion, our findings discover a novel mechanism of Nestin+ cells in PF, that is, Nestin+ cells isolated from the peritoneum probably had a protective effect on high-glucose PDS-induced PF by suppressing IL-33/ST-2 signaling.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.

Background: In Alzheimer’s disease (AD), activation of astrocyte participates in the development of neurodegenerative diseases through neuroinflammation and disturbs glia-neuron interaction. Cancerous Inhibitor of PP2A (CIP2A) is an endogenous PP2A inhibitor. CIP2A upregulation specifically in astrocytes causes reactive astrogliosis, synaptic degeneration and cognitive deficits. However, the underlying mechanism of CIP2A upregulation remains unclear. Methods: In 3xTg-AD mice, we determined ChK1 was activated and related to DNA damage upregulating CIP2A by WB. We transfected EGFP-ChK1 plasmid into HEK293-T cell to determine ChK1 induces CIP2A upregulation and PP2A inhibition. We incubated Aβ and infected GFAP-ChK1-LV into primary astrocytes to confirm the signaling pathway in astrocytes and astrogliosis in AD. GFAP-ChK1-AAV was injected into C57/BL6 mice to induce specific expression of target protein in astrocytes. ChK1 inhibitor (SB) was performed to reverse the ChK1 activity. Outcomes were assessed using molecular (immunofluorescent staining, Western Blot and Golgi staining) measures to estimate symptomatic pathology and behavioral (NORT, OLT, MWM and FCT) measures to assess cognitive function. For most experiments, subjects were randomly assigned to experimental groups, and data were collected under blinded experimental conditions.Results: We demonstrated that DNA damage related Checkpoint kinase 1 (ChK1) was activated in 3xTg-AD mice. ChK1-mediated CIP2A overexpression drove inhibition of PP2A and activated STAT3, then led to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induced reactive astrogliosis, degeneration of neurons and deterioration of AD through CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 might be a potential therapeutic approach for AD treatment.Conclusions: These results suggest that ChK1 is upregulated in 3xTg-AD mice, ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis, neurodegeneration and AD-like cognitive deficits in vitro and in vivo.

With global climate change, plants are frequently being exposed to various stresses, such as pathogen attack, drought, and extreme temperatures. Transcription factors (TFs) play crucial roles in numerous plant biological processes; however, the functions of many tomato (Solanum lycopersicum L.) TFs that regulate plant responses to multiple stresses are largely unknown. Here, using an RNA-seq approach, we identified SlNAP1, a NAC TF-encoding gene, which was strongly induced by various stresses. By generating SlNAP1 transgenic lines and evaluating their responses to biotic and abiotic stresses in tomato, we found that SlNAP1-overexpressing plants showed significantly enhanced defense against two widespread bacterial diseases, leaf speck disease, caused by Pseudomonas syringae pv. tomato (Pst) DC3000, and root-borne bacterial wilt disease, caused by Ralstonia solanacearum. In addition, SlNAP1 overexpression dramatically improved drought tolerance in tomato. Although the SlNAP1-overexpressing plants were shorter than the wild-type plants during the early vegetative stage, eventually, their fruit yield increased by 10.7%. Analysis of different hormone contents revealed a reduced level of physiologically active gibberellins (GAs) and an increased level of salicylic acid (SA) and abscisic acid (ABA) in the SlNAP1-overexpressing plants. Moreover, EMSAs and ChIP-qPCR assays showed that SlNAP1 directly activated the transcription of multiple genes involved in GA deactivation and both SA and ABA biosynthesis. Our findings reveal that SlNAP1 is a positive regulator of the tomato defense response against multiple stresses and thus may be a potential breeding target for improving crop yield and stress resistance.

Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide Ⅰ (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anti-cancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-β1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/β-catenin pathways. Besides, ATL-1 treatment repressed TGF-β1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-β1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.

Background The intermediate filament protein Nestin, a specific marker for multifunctional, multilineage progenitor cells, is regulated during the progression of reparative and reactive fibrosis in the liver, heart and kidney. However, whether Nestin regulates peritoneal fibrosis via suppressing IL-33/ST-2 signaling is unclear. Methods High-glucose peritoneal dialysis solution (PDS) or TGF-β1 was administered to a mouse peritoneal dialysis (PD) model to induce peritoneal fibrosis (PF) in vivo and to human peritoneal mesothelial cells (HPMCs) in vitro to stimulate accumulation of extracellular matrix (ECM). Nestin+ cells isolated from the peritoneum of Nestin-green fluorescent protein (GFP) transgenic mice were transplanted in vivo, and adeno-associated virus (AAV)-RNAi was used to silence IL-33 in vitro. Results Notably, Nestin was found in both the mouse peritoneum and HPMCs derived from PD effluent (PDE) and HMrSV5. These Nestin+ PMCs showed extensive proliferation for more than 20 passages. The mice that received chronic PDS infusions showed typical features of PF, including substantially increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and increased expression levels of α-smooth muscle actin (α-SMA) and collagen I (Col I). Nestin+ cells isolated from the peritoneum could significantly ameliorate these pathological changes. A parallel decrease in interleukin-33 (IL-33) and ST-2 accumulation in the peritoneum of Nestin+ cell-transplanted mice was observed. In addition, downregulation of IL-33 expression increased TGF-β1-induced ECM in the HPMCs. Conclusion Nestin+ cells isolated from the peritoneum had a clear protective effect on high-glucose PDS-induced PF by suppressing IL-33/ST-2 signaling.

Atmospheric CO

Background Sodium glucose cotransporter-2 (SGLT-2) inhibitors have been widely used in the clinic to reduce blood glucose levels by enhancing glucose excretion. However, whether such agents might also reduce glucose absorption via the peritoneal function of human peritoneal mesothelial cells (HPMCs) that also express SGLT-2 is not clear. Methods An acute peritoneal dialysis (PD) model in nonuremic rats was established. Ratios of peritoneal glucose uptake at D4/D0 of Sprague-Dawley rats treated with the SGLT-2 inhibitor, empagliflozin were tested to evaluate the effect of this inhibitor on peritoneal glucose absorption. An in vitro model of HPMCs obtained from peritoneal dialysate effluent in patients undergoing PD was used. HPMCs were exposed to high glucose (60 mM) in the presence and absence of empagliflozin. Glucose uptake and glucose consumption, which were used to estimate the activity of SGLT-2 in HPMCs, were measured by flow cytometry and hexokinase respectively. The expression of SGLT-2 in both peritoneum and HPMCs was also observed by real-time polymerase chain reaction (PCR), western blot, and immunofluorescence staining. Results Both ratios of peritoneal glucose uptake at D4/D0 and ultrafiltration of rats treated with 3 mg kg−1 of empagliflozin for 3 days increased significantly compared to those of the control group (0.32 ± 0.40 vs. 0.11 ± 0.11 mM, P = 0.001；17.00 ± 3.58 vs. -13.67 ± 17.25 ml, P = 0.002). Compared to the control group, the expression of mRNA and protein in SGLT-2 increased significantly in the rats treated with 3 mg kg−1 of empagliflozin for 3 days. Both glucose consumption and uptake of HPMCs incubated with 1 μM of empagliflozin for 24 h decreased significantly compared to control values (8.69 ± 1.77 vs. 11.48 ± 1.00 mM, P = 0.004; 31.97 ± 4.81 vs. 43.98 ± 1.38, P = 0.002). Conclusion An SGLT-2 inhibitor was able to exert a glucose-lowering effect in peritoneum exposed to PD solution by inhibiting the activity of SGLT-2.

Sleep disorders are very common among dialysis patients, leading patients to frequently take sedative–hypnotic medications; however, the effects of sleep disorders and the use of such drugs on health-related quality of life (HRQOL) have rarely been investigated. The Pittsburgh Sleep Quality Index and Short Form-12 were used to assess sleep quality and patient health situations, respectively. Logistic regression was employed to identify factors associated with deterioration of the mental component summary (MCS) score and the physical component summary (PCS) score. A total of 461 patients undergoing dialysis were recruited. The prevalence of sleep disorders was 67.0%. Among the study population, 30.4% of patients took sedative–hypnotic medications to improve their sleep quality. Both the PCS (81.25 vs. 71.88, p

Background and aim Serum lactate levels are routinely measured in critically ill patients with cirrhosis, and hyperlactatemia is a common finding, but its prognostic value remains controversial. Our aim was to examine whether serum lactate level could be used as a predictor of outcome in critically ill patients with cirrhosis (CICP) with acute kidney injury (AKI). Patients and methods In this study, we included 480 consecutive patients with cirrhosis admitted to ICU, complicated with AKI, and were followed up for 365 days. Patients were divided into four groups (Q1-Q4) by serum lactate quartiles: Q1≤1.8 mg/dl, Q2=1.9-2.4 mg/dl, Q3=2.5-4.0 mg/dl, and Q4≥4.1 mg/dl. The hazard ratio (HR) and 95% confidence intervals (CIs) for hospital mortality were calculated across each quartile of serum lactate, using the Q1 as reference, and four models were built to adjust for the HR of mortality. Results Compared with patients in the survival group, nonsurvivors had higher serum lactate levels. Mortality rate increased progressively as the serum lactate level increased (Q1: 56.06%, Q2: 62.16%, Q3: 72.73% and Q4: 75.86%), and this relationship remained statistically significant after rigorous control of confounding factors in Q2, Q3, and Q4 with HRs of 1.03 (95% CI: 0.73-1.46), 1.40 (95% CI: 1.01-1.95), and 1.84 (95% CI: 1.28-2.64), respectively. Conclusion Our study brings a new perspective to the role of lactate monitoring in CICP with AKI. Elevated serum lactate levels are associated with a higher mortality rate in CICP with AKI. Elevated serum lactate levels should be part of rapid diagnosis and initiation of therapy to improve clinical outcome.

Phytosulfokine (PSK) is a disulfated pentapeptide that is an important signaling molecule. Although it has recently been implicated in plant defenses to pathogen infection, the mechanisms involved remain poorly understood. Using surface plasmon resonance and gene silencing approaches, we showed that the tomato (Solanum lycopersicum) PSK receptor PSKR1, rather than PSKR2, functioned as the major PSK receptor in immune responses. Silencing of PSK signaling genes rendered tomato more susceptible to infection by the economically important necrotrophic pathogen Botrytis cinerea Analysis of tomato mutants defective in either defense hormone biosynthesis or signaling demonstrated that PSK-induced immunity required auxin biosynthesis and associated defense pathways. Here, using aequorin-expressing tomato plants, we provide evidence that PSK perception by tomato PSKR1 elevated cytosolic [Ca2+], leading to auxin-dependent immune responses via enhanced binding activity between calmodulins and the auxin biosynthetic YUCs. Thus, our data demonstrate that PSK acts as a damage-associated molecular pattern and is perceived mainly by PSKR1, which increases cytosolic [Ca2+] and activates auxin-mediated pathways that enhance immunity of tomato plants to B. cinerea.

How one trait developmentally varies as a function of others shapes a spectrum of biological phenomena. Despite its importance to trait dissection, the understanding of whether and how genes mediate such developmental covariation is poorly understood. We integrate developmental allometry equations into the functional mapping framework to map specific QTLs that govern the correlated development of different traits. Based on evolutionary game theory, we assemble and contextualize these QTLs into an intricate but organized network coded by bidirectional, signed, and weighted QTL-QTL interactions. We use this approach to map shoot height-diameter allometry QTLs in an ornamental woody species, mei (Prunus mume). We detect "pioneering" QTLs (piQTLs) and "maintaining" QTLs (miQTLs) that determine how shoot height varies with diameter and how shoot diameter varies with height, respectively. The QTL networks inferred can visualize how each piQTL regulates others to promote height growth at a cost of diameter growth, how miQTL regulates others to benefit radial growth at a cost of height growth, and how piQTLs and miQTLs regulate each other to form a pleiotropic web of primary and secondary growth in trees. Our approach provides a unique gateway to explore the genetic architecture of developmental covariation, a widespread phenomenon in nature.

The aim of the present study was to explore the role of ataxia-telangiectasia mutated (ATM) in lipopolysaccharide (LPS)-induced in vitro model of septic acute kidney injury (AKI) and the association between ATM, tubular epithelial inflammatory response and autophagy. The renal tubular epithelial cell HK-2 cell line was cultured and passaged, with HK-2 cell injury induced by LPS. The effects of LPS on HK-2 cell morphology, viability, ATM expression and inflammation were observed. Lentiviral vectors encoding ATM shRNA were constructed to knock down ATM expression in HK-2 cells. The efficiency of ATM knockdown in HK-2 cells was detected by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR). HK-2 cells transfected with the ATM shRNA lentivirus were used for subsequent experiments. Following ATM knockdown, corresponding controls were set up, and the effects of ATM on inflammation and autophagy were detected in HK-2 cells using RT-qPCR, western blotting and ELISA. After LPS stimulation, the HK-2 cells were rounded into a slender or fusiform shape with poorly defined outlines. LPS treatment reduced cell viability in a partly dose-dependent manner. LPS increased the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6, with the levels reaching its highest value at 10 µg/ml. IL-6 and IL-1β expression increased with increasing LPS concentration. These findings suggest that LPS reduced HK-2 cell viability whilst increasing the expression of inflammatory factors. Following transfection with ATM shRNA, expression levels of key autophagy indicators microtubule associated protein 1 light chain 3α I/II ratio and beclin-1 in the two ATM shRNA groups were also significantly reduced compared with the NC shRNA group. In summary, downregulation of ATM expression in HK-2 cells reduced LPS-induced inflammation and autophagy in sepsis-induced AKI in vitro, suggesting that LPS may induce autophagy in HK-2 cells through the ATM pathway leading to the upregulation of inflammatory factors.

Plant adaptation to high altitudes has long been a substantial focus of ecological and evolutionary research. However, the genetic mechanisms underlying such adaptation remain poorly understood. Here, we address this issue by sampling, genotyping, and comparing populations of Tibetan poplar, Populus szechuanica var. tibetica, distributed from low (~2,000 m) to high altitudes (~3,000 m) of Sejila Mountain on the Qinghai–Tibet Plateau. Population structure analyses allow clear classification of two groups according to their altitudinal distributions. However, in contrast to the genetic variation within each population, differences between the two populations only explain a small portion of the total genetic variation (3.64%). We identified asymmetrical gene flow from high‐ to low‐altitude populations. Integrating population genomic and landscape genomic analyses, we detected two hotspot regions, one containing four genes associated with altitudinal variation, and the other containing ten genes associated with response to solar radiation. These genes participate in abiotic stress resistance and regulation of reproductive processes. Our results provide insight into the genetic mechanisms underlying high‐altitude adaptation in Tibetan poplar., In this article, we address this issue by sampling, genotyping, and comparing populations of Tibetan poplar, Populus szechuanica var. tibetica, distributed at low (~2,000 m) and high altitudes (~3,000 m) of Sejila Mountain on the Qinghai‐Tibet Plateau. We identified clearly classification of these two populations according to altitudinal distribution, and we also detected low population divergence and robust asymmetry gene flows between them. Finally, we identified a hot spot region under selection and associated with environmental variables through scanning of the whole Tibetan poplar genome.

Background and Aims: The metabolic acid-base disorders have a high incidence of acute kidney injury (AKI) in critically ill cirrhotic patients (CICPs). The aims of our study were to ascertain the composition of metabolic acidosis of CICPs with AKI and explore its relationship with hospital mortality. Methods: Three-hundred and eighty consecutive CICPs with AKI were eligible for the cohort study. Demographic, clinical and laboratory parameters were recorded and arterial acid-base state was analyzed by the Stewart and Gilfix methodology. Results: Net metabolic acidosis, lactic acidosis, acidosis owing to unmeasured anions, acidemia, and dilutional acidosis were less frequent in the non-survival group compared to the survival group of CICPs. The presence of acidemia, acidosis owing to unmeasured anions, and lactic acidosis were independently associated with increased risk of intensive care unit 30-day mortality, with hazard ratios of 2.11 (95% confidence interval (CI): 1.43–3.12), 3.38 (95% CI: 2.36–4.84), and 2.16 (95% CI: 1.47–3.35), respectively. After full adjustment for confounders, the relationship between acidosis owing to unmeasured anions with hospital mortality was still significant, with hazard ratio of 2.29 (95% CI: 1.22–4.30). Furthermore, arterial lactate concentration in combination with chronic liver failure-sequential organ failure assessment and BEUMA had the strongest ability to differentiate 30-day mortality (area under the receiver operating characteristic curve: 0.79, 95% CI: 0.74–0.83). Conclusions: CICPs with AKI exhibit a complex metabolic acidosis during intensive care unit admission. Lactic acidosis and BEUMA, novel markers of acid-base disorders, show promise in predicting mortality rate of CICPs with AKI.

Chronic inflammation is a major contributor to obesity-related renal damage. Recent studies have demonstrated that microRNA (miR)-155 is closely associated with hyperglycemia-induced nephropathy, but whether renal miR-155 participates in the inflammatory response and development of obesity-related nephropathy is unknown. In present study, we investigated the pathophysiological role of renal miR-155 in palmitic acid (PA)-treated endothelial cell and high-fat-diet (HFD)-fed mouse models by specific miR-155 sponge. Mice fed with HFD exhibited higher levels of renal miR-155, which positively correlated with urine microalbumin and blood urea nitrogen. In vitro study, mouse renal vascular endothelial cells stimulated with PA also showed higher miR-155 levels, accompanied with increased inflammatory response. Suppression of renal miR-155 effectively attenuated HFD-induced renal structural damages and dysfunction. MiR-155 sponge treatment also significantly decreased NF-κB signaling and downstream gene expression in vitro and in vivo. The obesity-increased macrophage infiltration and lipotoxicity was decreased in mouse kidney after miR-155 sponge treatment. Mechanistically, miR-155 directly targeted 3'-UTR of SHIP1/INPP5D and suppressed its expression in vitro and in vivo, whereas silence of SHIP1/INPP5D abolished the renal protective benefits of miR-155 sponge in obese mice. Taken together, present findings for the first time provided evidence for the potential role of miR-155 in obesity-related nephropathy and clarified that SHIP1/NF-κB signaling was a potential molecular mechanism.

Sodium glucose cotransporter-2 (SGLT-2) inhibitor has been reported to exert a glucose-lowering effect in the peritoneum exposed to peritoneal dialysis solution. However, whether SGLT-2 inhibitors can regulate peritoneal fibrosis by suppressing TGF-β/Smad signaling is unclear. We aimed to (i) examine the effect of the SGLT-2 inhibitor empagliflozin in reducing inflammatory reaction and preventing peritoneal dialysis solution-induced peritoneal fibrosis and (ii) elucidate the underlying mechanisms. High-glucose peritoneal dialysis solution or transforming growth factor β1 (TGF-β1) was used to induce peritoneal fibrosis in vivo, in a mouse peritoneal dialysis model (C57BL/6 mice) and in human peritoneal mesothelial cells in vitro, to stimulate extracellular matrix accumulation. The effects of empagliflozin and adeno-associated virus-RNAi, which is used to suppress SGLT-2 activity, on peritoneal fibrosis and extracellular matrix were evaluated. The mice that received chronic peritoneal dialysis solution infusions showed typical features of peritoneal fibrosis, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and upregulated α-smooth muscle actin and collagen I expression. Empagliflozin treatment or downregulation of SGLT-2 expression significantly ameliorated these pathological changes. Inflammatory cytokines (TNF-α, IL-1β, IL-6) and TGF-β/Smad signaling-associated proteins, such as TGF-β1 and phosphorylated Smad (p-Smad3), decreased in the empagliflozin-treated and SGLT-2 downregulated groups. In addition, empagliflozin treatment and downregulation of SGLT-2 expression reduced the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), TGF-β1, α-smooth muscle actin, collagen I, and p-Smad3 accumulation in human peritoneal mesothelial cells. Collectively, these results indicated that empagliflozin exerted a clear protective effect on high-glucose peritoneal dialysis-induced peritoneal fibrosis via suppressing TGF-β/Smad signaling.

Xinxin Chen,1 Huan Tong,2 Yu Chen,3 Chaosheng Chen,1 Jingjing Ye,2 Qingfei Mo,2 Guangju Zhao,2 Guangliang Hong,2 Chenfei Zheng,1 Zhongqiu Lu2 1Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 2Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 3Department of Nephrology, Wenzhou Hospital of Traditional Chinese Medicine Affiliated with Zhejiang Chinese Medical University, Wenzhou, Zhejiang, China Background: The role of Klotho (KL) in sepsis-induced acute kidney injury (AKI) and the potential relationship between KL and autophagy in septic AKI were investigated. Materials and methods: A murine model of sepsis-induced AKI was established by cecal ligation and puncture (CLP). Mice undergoing CLP and immortalized proximal tubular epithelial human HK-2 cells that were exposed to lipopolysaccharide (LPS) were treated with recombinant KL, autophagy stimulator rapamycin (Rap), and autophagy suppressor 3-methyladenine (3-MA). Results: Autophagy activation and KL reduction reached maximum levels in mice 24 hours after CLP. Recombinant KL and/or Rap significantly attenuated CLP-induced renal dysfunction (P

The aim of this study was to establish a stable rat model of autogenous arteriovenous fistula (AVF) with chronic renal function insufficiency. Forty Sprague-Dawley rats were randomly divided into an experimental group (n=20) and sham surgery group (n=20) and a 5/6 nephrectomy model was established in the rats. One week later, in the experimental group, the ipsilateral caroid artery was inserted into the external jugular vein by a cuff technique to establish a carotid arteriovenous fistula; in the sham group, the external jugular vein and carotid artery were dissociated. At 7 and 28 days following the establishment of the AVF, the renal functions of the two groups were measured. Hematoxylin and eosin staining and double collagen and elastin staining were conducted to evaluate the area of intimal hyperplasia in the external jugular vein, and the expression of α-smooth muscle actin in the vein was investigated by immunohistochemistry. The creatinine and urea nitrogen levels in the experimental group at each time-point were significantly higher than those in the sham surgery group (P

N-decanoyl-homoserine lactone activates plant systemic resistance against Botrytis cinerea in tomato plants, which is largely dependent on jasmonic acid biosynthesis and signal transduction pathways. Rhizosphere bacteria secrete N-acylated-homoserine lactones (AHLs), a type of specialized quorum-sensing signal molecule, to coordinate their population density during communication with their eukaryotic hosts. AHLs behave as low molecular weight ligands that are sensed by plants and promote the host’s resistance against foliar pathogens. In this study, we report on N-decanoyl-homoserine lactone (DHL), which is a type of AHL that induces systemic immunity in tomato plants and protects the host organism against the necrotrophic fungus Botrytis cinerea. Upon DHL treatment, tomato endogenous jasmonic acid (JA) biosynthesis (rather than salicylic acid biosynthesis) and signal transduction were significantly activated. Strikingly, the DHL-induced systemic resistance against B. cinerea was blocked in the tomato JA biosynthesis mutant spr2 and JA signaling gene-silenced plants. Our findings highlight the role of DHL in systemic resistance against economically important necrotrophic pathogens and suggest that DHL-induced immunity against B. cinerea is largely dependent on the JA signaling pathway. Manipulation of DHL-induced resistance is an attractive disease management strategy that could potentially be used to enhance disease resistance in diverse plant species.

State observer is an essential component in computerized control loops for greenhouse-crop systems. However, the current accomplishments of observer modeling for greenhouse-crop systems mainly focus on mass/energy balance, ignoring physiological responses of crops. As a result, state observers for crop physiological responses are rarely developed, and control operations are typically made based on experience rather than actual crop requirements. In addition, existing observer models require a large number of parameters, leading to heavy computational load and poor application feasibility. To address these problems, we present a new state observer modeling strategy that takes both environmental information and crop physiological responses into consideration during the observer modeling process. Using greenhouse cucumber seedlings as an instance, we sample 10 physiological parameters of cucumber seedlings at different time point during the exponential growth stage, and employ them to build growth state observers together with 8 environmental parameters. Support vector machine (SVM) acts as the mathematical tool for observer modeling. Canonical correlation analysis (CCA) is used to select the dominant environmental and physiological parameters in the modeling process. With the dominant parameters, simplified observer models are built and tested. We conduct contrast experiments with different input parameter combinations on simplified and un-simplified observers. Experimental results indicate that physiological information can improve the prediction accuracies of the growth state observers. Furthermore, the simplified observer models can give equivalent or even better performance than the un-simplified ones, which verifies the feasibility of CCA. The current study can enable state observers to reflect crop requirements and make them feasible for applications with simplified shapes, which is significant for developing intelligent greenhouse control systems for modern greenhouse production.

Serum creatinine measurement demonstrates a poor specificity and sensitivity for the early diagnosis of acute kidney injury (AKI) in patients with cirrhosis. The existing model for end-stage liver disease (MELD) score reveals multiple pitfalls in critically ill patients with cirrhosis and acute kidney injury (CAKI). The aim of this study was to re-evaluate the role of creatinine values in the existing MELD score and to develop a novel score for CAKI, named the "acute kidney injury-model for end-stage liver disease score" (AKI-MELD score). We extracted 651 CAKI from the Multiparameter Intelligent Monitoring in Intensive Care database. A time-dependent Cox regression analysis was performed for developing remodeled MELD scores (Reweight-MELD score, Del-Cr-MELD score, and AKI-MELD score). The area under the receiver operating characteristic curve provided the discriminative power of scoring models related to outcome. The hazard ratio of creatinine was 1.104 (95% confidence interval [CI], 0.945-1.290; P = 0.211). Reweight-MELD score and Del-Cr-MELD score (decreasing the weight of creatinine) were superior to the original MELD score (all P < 0.001). The new AKI-MELD score consists of bilirubin, the international normalized ratio, and the ratio of creatinine in 48 hours to creatinine at admission. It had competitive discriminative ability for predicting mortality (area under the receiver operating characteristic curve, 0.720 [95% CI, 0.653-0.762] at 30 days, 0.688 [95% CI, 0.630-0.742] at 90 days, and 0.671 [95% CI, 0.612-0.725] at 1 year). Further, AKI-MELD score had significantly higher predictive ability in comparison with MELD score, MELD-Na score, and Updated MELD score (all P < 0.001). Conclusion: The predictive value of creatinine for CAKI should be re-evaluated. AKI-MELD score is a potentially reliable tool to determine the prognosis for mortality of CAKI. (Hepatology Communications 2017;1:748-756).

Vegetative phase changes in plants describes the transition between juvenile and adult phases of vegetative growth before flowering. It is one of the most fundamental mechanisms for plants to sense developmental signals, presenting a complex process involving many still-unknown determinants. Several studies in annual and perennial plants have identified the conservative roles of miR156 and its targets, SBP/SPL genes, in guiding the switch of plant growth from juvenile to adult phases. Here, we review recent progress in understanding the regulation of miR156 expression and how miR156-SPLs mediated plant age affect other processes in Arabidopsis. Powerful high-throughput sequencing techniques have provided rich data to systematically study the regulatory mechanisms of miR156 regulation network. From this data, we draw an expanded miR156-regulated network that links plant developmental transition and other fundamental biological processes, gaining novel and broad insight into the molecular mechanisms of plant-age-related processes in Arabidopsis.

Critically ill cirrhotic patients with acute kidney injury (AKI) are associated with high mortality rates. The aims of this study were to develop a specific prognostic score for critically ill cirrhotic patients with AKI, the acute kidney injury - Chronic Liver Failure - Sequential Organ Failure- Assessment score (AKI-CLIF-SOFA) score. This study focused on 527 cirrhotic patients with AKI admitted to intensive care unit and constructed a new scoring system, the AKI-CLIF-SOFA, which can be used to prognostically assess mortality in these patient population. Parameters included in this model were analysed by cox regression. The area under the receiver operating characteristic curve (auROC) of AKI-CLIF-SOFA scoring system was 0.74 in 30 days, 0.74 in 90 days, 0.72 in 270 days and 0.72 in 365 days. Additionally, this study demonstrated that the new model had more discriminatory power than chronic liver failure- sequential organ failure assessment score (CLIF-SOFA), SOFA, model for end stage liver disease (MELD), kidney disease improving global outcomes (KDIGO) and simplified acute physiology score II (SAPS II) (auROC: 0.72, 0.66, 0.64, 0.62, 0.63 and 0.65 respectively, all P < 0.05) for the prediction of the 365-days mortality. Therefore, AKI-CLIF-SOFA demonstrated a valuable discriminative ability compared with KDIGO, CLIF-SOFA, MELD, SAPS II and SOFA in critically ill cirrhotic patients with AKI.

The aim of this study was to investigate the value of hematocrit (HCT) level in predicting the outcomes of critically ill patients with acute kidney injury (AKI). A retrospective study of a total of 14,350 intensive care unit (ICU) patients, who were selected from Beth Israel Deaconess Medical Center (Boston, MA, USA) and met the inclusion criteria, was carried out. And the patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3 (MIMIC-III v1.3). In our study, HCT quintiles were used to categorize the subjects into groups. The clinical outcomes were 30- and 90-day mortality in the ICU. Cox proportional-hazards models were used to evaluate the association between the HCT and survival. A total of 2827 30-day deaths and 3828 90-day deaths occurred. In univariate analysis, low HCT was significantly associated with increased 30- and 90-day mortality among females, which, however, was not observed in multivariate analysis adjusted for age, ethnicity, dialysate, continuous renal replacement therapy (CRRT), use of insulin, use of ventilator, AKI stages, and report of obesity. In subgroup analysis, an inverse association between HCT levels and risk of mortality for 90-day outcome was observed for female patients by exclusion of dialysate use, receiving CRRT, and obesity reports. Therefore, these findings suggest that lower HCT was associated with an increased risk of mortality in critically ill patients with AKI, and the effect appears to be stronger among women than men. The prognostic value of HCT seems dependent on other factors, for example, dialysate use, CRRT, and obesity. Further multicenter study is in demand to confirm the validity of the results presented in this article.

The purpose of this study was to investigate the cancer incidence in patients with end-stage aristolochic acid nephropathy (AAN).A total of 102 patients with end-stage AAN treated in our hospital between 2004 and 2013 were included in this study. The correlation of cancer incidence with age, gender, dosage of aristolochic acid (AA), the type of renal replacement therapies, and the polymorphisms of quinone oxidoreductase 1 (NQO1) C609T and cytochrome P450 1A1 (CYP1A1) A4889G was examined.The cancer incidence rate in our patients was 41.2% (42 in 102) including 39 cases of urinary cancer. The mortality rate in the patients with cancer was significantly higher than that in the patients without cancer (31%, 13/42 vs. 11.7%, 7/60, p0.05). Thirteen patients developed cancer before entering end-stage renal disease (ESRD). Cancer incidence was significantly associated with the dosage of AA consumption (p=0.091). Hemodialysis, peritoneal dialysis and renal transplant did not affect the cancer incidence in our patients differently, but appeared to be associated with cancer at particular locations of urinary system. The patients undergoing hemodialysis seemed to more likely have bladder cancer (72.72%), while the patients receiving peritoneal dialysis appeared to develop cancer predominantly in the upper urinary tract (66.67%).The cancer initiation in our patients seems significantly correlate with the dosage of AA consumption. Different renal replacement therapies appear to be associated with cancer at particular locations of urinary system in our patients.

To explore the influences of slim exercise prescription on body fat mass, blood sugar and plasma resistin for overweight and obesity students.Subjects were 9 males and 13 females for simple overweight and obesity students of freshman and junior. The function capacity (FC) were defined after examine of body shape, physical function and exercise capacity. The slim goals and exercise projects were determined according to different objects. The exercise intensity was 60%-70% of FC and 13-15 levels of RPE. Exercise with each time was 60 min, exercise frequency was 5 times perweek, energy metabolism was 500-600 kcal at a time. The relative indexes were detected after 8 weeks.Implementing programmes of slim exercise prescription for 8 weeks, before and after the experiment in the males and females group. The weight, BMI, percentage of body fat (FAT%), waist and hip circumference ratio (WHR), body surface area (BS), fat indexes, the density of body for overweight and obesity the male and female students were significantly decreased (P0.01). Body fat mass (FM) and blood sugar were significantly decreased (P0.01). Plasma resistin of the male students were significant different (P0.01), but the female students were significant different (P0.05). Analysis of Bivariate Correlation was Pearson Correlation, plasma resistin and BMI, WHR the male students had correlation, but the female had no correlation.The exercise prescription was safe and sure, and could improve weight, BMI, FAT%, FM, WHR, BS, fat indexes, the density of body, blood sugar, plasma resistin in obesity without the diet control.