Improving anti-cancer drug response prediction using multi-task learning on graph convolutional networks.

Predicting the therapeutic effect of anti-cancer drugs on tumors based on the characteristics of tumors and patients is one of the important contents of precision oncology. Existing computational methods regard the drug response prediction problem as a classification or regression task. However, few of them consider leveraging the relationship between the two tasks. In this work, we propose a Multi-task Interaction Graph Convolutional Network (MTIGCN) for anti-cancer drug response prediction. MTIGCN first utilizes an graph convolutional network-based model to produce embeddings for both cell lines and drugs. After that, the model employs multi-task learning to predict anti-cancer drug response, which involves training the model on three different tasks simultaneously: the main task of the drug sensitive or resistant classification task and the two auxiliary tasks of regression prediction and similarity network reconstruction. By sharing parameters and optimizing the losses of different tasks simultaneously, MTIGCN enhances the feature representation and reduces overfitting. The results of the experiments on two in vitro datasets demonstrated that MTIGCN outperformed seven state-of-the-art baseline methods. Moreover, the well-trained model on the in vitro dataset GDSC exhibited good performance when applied to predict drug responses in in vivo datasets PDX and TCGA. The case study confirmed the model's ability to discover unknown drug responses in cell lines.

PFKFB3-driven vascular smooth muscle cell glycolysis promotes vascular calcification via the altered FoxO3 and lactate production.

A link between increased glycolysis and vascular calcification has recently been reported, but it remains unclear how increased glycolysis contributes to vascular calcification. We therefore investigated the role of PFKFB3, a critical enzyme of glycolysis, in vascular calcification. We found that PFKFB3 expression was upregulated in calcified mouse VSMCs and arteries. We showed that expression of miR-26a-5p and miR-26b-5p in calcified mouse arteries was significantly decreased, and a negative correlation between Pfkfb3 mRNA expression and miR-26a-5p or miR-26b-5p was seen in these samples. Overexpression of miR-26a/b-5p significantly inhibited PFKFB3 expression in VSMCs. Intriguingly, pharmacological inhibition of PFKFB3 using PFK15 or knockdown of PFKFB3 ameliorated vascular calcification in vD3 -overloaded mice in vivo or attenuated high phosphate (Pi)-induced VSMC calcification in vitro. Consistently, knockdown of PFKFB3 significantly reduced glycolysis and osteogenic transdifferentiation of VSMCs, whereas overexpression of PFKFB3 in VSMCs induced the opposite effects. RNA-seq analysis and subsequent experiments revealed that silencing of PFKFB3 inhibited FoxO3 expression in VSMCs. Silencing of FoxO3 phenocopied the effects of PFKFB3 depletion on Ocn and Opg expression but not Alpl in VSMCs. Pyruvate or lactate supplementation, the product of glycolysis, reversed the PFKFB3 depletion-mediated effects on ALP activity and OPG protein expression in VSMCs. Our results reveal that blockade of PFKFB3-mediated glycolysis inhibits vascular calcification in vitro and in vivo. Mechanistically, we show that FoxO3 and lactate production are involved in PFKFB3-driven osteogenic transdifferentiation of VSMCs. PFKFB3 may be a promising therapeutic target for the treatment of vascular calcification.

Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.

Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.

AST3DRNet: Attention-Based Spatio-Temporal 3D Residual Neural Networks for Traffic Congestion Prediction.

Traffic congestion prediction has become an indispensable component of an intelligent transport system. However, one limitation of the existing methods is that they treat the effects of spatio-temporal correlations on traffic prediction as invariable during modeling spatio-temporal features, which results in inadequate modeling. In this paper, we propose an attention-based spatio-temporal 3D residual neural network, named AST3DRNet, to directly forecast the congestion levels of road networks in a city. AST3DRNet combines a 3D residual network and a self-attention mechanism together to efficiently model the spatial and temporal information of traffic congestion data. Specifically, by stacking 3D residual units and 3D convolution, we proposed a 3D convolution module that can simultaneously capture various spatio-temporal correlations. Furthermore, a novel spatio-temporal attention module is proposed to explicitly model the different contributions of spatio-temporal correlations in both spatial and temporal dimensions through the self-attention mechanism. Extensive experiments are conducted on a real-world traffic congestion dataset in Kunming, and the results demonstrate that AST3DRNet outperforms the baselines in short-term (5/10/15 min) traffic congestion predictions with an average accuracy improvement of 59.05%, 64.69%, and 48.22%, respectively.

A noninvasive method for the detection of foetal DNA in early pregnancy based on differential methylation pattern of Ras association domain family member 1A.

BACKGROUND: The detection of foetal DNA and extravillus trophoblasts (EVTs) in early pregnancy in cervical and uterine samples offers a potential pathway for non-invasive prenatal diagnostics. However, the challenge lies in effectively quantifying these samples. This study introduces a novel approach using the Ras association domain family 1 A (RASSF1A), which exhibits hypermethylation in foetal cells and hypomethylation in maternal cells. The differential methylation pattern of RASSF1A provides a unique biomarker for quantifying foetal cells in cervical and intrauterine samples. METHODS: This study was conducted between September 2022 and May 2023. In total, 23 samples (12 cervical cell samples and 11 intrauterine samples) were collected from women in the Sichuan Jinxin Women & Children Hospital, Jingxiu District, Chengdu, China. The cervical cell samples were collected via lavage and brush techniques, and the intrauterine cell samples were obtained via uterine lavage. These samples were collected as part of a broader effort to advance our understanding of foetal cell dynamics during early pregnancy. The sampling methods were chosen for their minimally invasive nature and their potential in capturing a representative cell population from the respective sites. After digestion of the cell samples using a methylation-sensitive restriction enzyme cocktail, a critical step to differentiate between maternal and foetal DNA, the quantitative polymerase chain reaction (qPCR) of RASSF1A and ß-actin (ACTB) were employed to measure foetal DNA and cell concentrations. Immunofluorescence techniques targeting histocompatibility complex, class I G (HLA-G) and GATA binding protein 3 (GATA-3) were employed to detect EVTs in the cell samples and in decidual tissue, with the latter providing an additional layer of confirmation for the presence of foetal cells. RESULTS: The results showed no hypermethylated RASSF1A was detected in any of the cervical samples, irrespective of whether the samples were obtained by brush or lavage. However, an average of 17,236 ± 7490 foetal cells per sample were detected in the uterine lavage samples. Foetal cells accounted for approximately 0.14% ± 0.10% of the total cell population in these samples. The presence of EVTs in these samples was confirmed by their expression of both HLA-G and GATA-3. CONCLUSION: The detection of foetal cells in uterine cavity samples based on hypermethylation of RASSF1A and quantification of foetal cells can be used to prenatal screening. GATA-3 can be used to label EVTs.

In the realm gestational foetal health, obtaining foetal cells or genetic information is important for detecting and managing potential genetic disorders. Although foetal cells can be obtained from the cervix or uterine cavity, methods to quantify the foetal cell and foetal DNA are lacking. We introduce an innovative technique that utilises DNA restriction endonucleases to selectively isolate foetal DNA and identify foetal cells. We used this technique to measure the number of foetal cells in a sample. Using this technique, we detected foetal cells collected via lavage in uterine but not cervical samples. This finding is significant as it paves the way towards early detection of chromosomal disorders in foetuses, potentially as early as the 10th week of pregnancy. Such early detection offers promising new screening options in early pregnancy, contributing to better prenatal care and outcomes.

PALMD regulates aortic valve calcification via altered glycolysis and NF-κB-mediated inflammation.

Recent genome-wide association and transcriptome-wide association studies have identified an association between the PALMD locus, encoding palmdelphin, a protein involved in myoblast differentiation, and calcific aortic valve disease (CAVD). Nevertheless, the function and underlying mechanisms of PALMD in CAVD remain unclear. We herein investigated whether and how PALMD affects the pathogenesis of CAVD using clinical samples from CAVD patients and a human valve interstitial cell (hVIC) in vitro calcification model. We showed that PALMD was upregulated in calcified regions of human aortic valves and calcified hVICs. Furthermore, silencing of PALMD reduced hVIC in vitro calcification, osteogenic differentiation, and apoptosis, whereas overexpression of PALMD had the opposite effect. RNA-Seq of PALMD-depleted hVICs revealed that silencing of PALMD reduced glycolysis and nuclear factor-κB (NF-κB)-mediated inflammation in hVICs and attenuated tumor necrosis factor α-induced monocyte adhesion to hVICs. Having established the role of PALMD in hVIC glycolysis, we examined whether glycolysis itself could regulate hVIC osteogenic differentiation and inflammation. Intriguingly, the inhibition of PFKFB3-mediated glycolysis significantly attenuated osteogenic differentiation and inflammation of hVICs. However, silencing of PFKFB3 inhibited PALMD-induced hVIC inflammation, but not osteogenic differentiation. Finally, we showed that the overexpression of PALMD enhanced hVIC osteogenic differentiation and inflammation, as opposed to glycolysis, through the activation of NF-κB. The present study demonstrates that the genome-wide association- and transcriptome-wide association-identified CAVD risk gene PALMD may promote CAVD development through regulation of glycolysis and NF-κB-mediated inflammation. We propose that targeting PALMD-mediated glycolysis may represent a novel therapeutic strategy for treating CAVD.

Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis.

BACKGROUND: Cisplatin is effective against various types of cancers. However, its clinical application is limited owing to its adverse effects, especially acute kidney injury (AKI). Dihydromyricetin (DHM), a flavonoid derived from Ampelopsis grossedentata, has varied pharmacological activities. This research aimed to determine the molecular mechanism for cisplatin-induced AKI. METHODS: A murine model of cisplatin-induced AKI (22 mg/kg, I.P.) and a HK-2 cell model of cisplatin-induced damage (30 µM) were established to evaluate the protective function of DHM. Renal dysfunction markers, renal morphology and potential signaling pathways were investigated. RESULTS: DHM decreased the levels of renal function biomarkers (blood urea nitrogen and serum creatinine), mitigated renal morphological damage, and downregulated the protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It upregulated the expression levels of antioxidant enzymes (superoxide dismutase and catalase expression), nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream proteins, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, thus eventually reducing cisplatin-induced reactive oxygen species (ROS) production. Moreover, DHM partially inhibited the phosphorylation of the active fragments of caspase-8 and -3 and mitogen-activated protein kinase and restored glutathione peroxidase 4 expression, which attenuated renal apoptosis and ferroptosis in cisplatin-treated animals. DHM also mitigated the activation of NLRP3 inflammasome and nuclear factor (NF)-κB, attenuating the inflammatory response. In addition, it reduced cisplatin-induced HK-2 cell apoptosis and ROS production, both of which were blocked by the Nrf2 inhibitor ML385. CONCLUSIONS: DHM suppressed cisplatin-induced oxidative stress, inflammation and ferroptosis probably through regulating of Nrf2/HO-1, MAPK and NF-κB signaling pathways.

Leptin differentially regulate cell apoptosis and cycle by histone acetylation in tibial and vertebral epiphyseal plates.

Leptin showed different apoptosis regulation effects on the chondrocytes from tibial and vertebral epiphyseal plates. However, the mechanism is still unclear. In this study, we tested the protein profile of tibial and vertebral epiphyseal plate chondrocytes with and without leptin stimulation by mass spectrometry and found that the histone acetylation level of tibial chondrocytes was decreased after leptin treatment, while increased in vertebral epiphyseal plates. COIP assay showed that leptin promoted H3, H4 histone acetylation by recruiting CREB binding protein (CBP)/P300 to activate histone acetyl transferases (HATs) activity in vertebral disc chondrocytes. But in tibial plate cartilage cells, leptin did not recruit CBP and p300, thus differently affect the apoptosis of epiphyseal plate chondrocytes. Through explored the mechanism of histone acetylation modulated by leptin, and its effect on cartilage cell apoptosis and cell cycle regulation, This provides a novel target therapy possibility therapeutic approach to for the related disease.

Occurrence and Distribution of Major Viruses Infecting Passion Fruit in Guizhou Province, China, and Molecular Characterization of Two Potyviruses.

The planting of passion fruit (Passiflora edulis) in Guizhou Province has gradually increased, and the area under cultivation ranks third in China. However, the cultivation and production of passion fruit is severely affected by viral diseases. In 2021 and 2022, we investigated the occurrence of multiple viral diseases in major cultivation areas, identified the main viruses and conducted field surveys in different growing areas of passion fruit in Guizhou Province, China. In total, 308 samples were randomly collected from 10 different passion fruit cultivation areas, and seven viral diseases were identified using electron microscopy, small RNA sequencing, and reverse-transcription polymerase chain reaction. Among them, the infection rate of Telosma mosaic virus (TeMV) was the highest (50%), followed by East Asian Passiflora virus (EAPV) (19%), and cucumber mosaic virus (CMV) (15%). The detection rates of the other four viruses were lower: Passiflora latent virus (PLV) (1%), turnip mosaic virus (TuMV) (0.6%), Passiflora virus Y (PaVY) (0.3%), and Euphorbia leaf curl virus (ELCV) (6%). In addition, high rates of mixed TeMV + CMV + EAPV infections were found in the province. Notably, 79% of EAPV-infected plants were also infected with TeMV. Finally, the molecular characteristics of the two highly detected potyviruses, TeMV and EAPV, were analyzed. To our knowledge, this study is the first systematic survey of viral diseases of passion fruit in Guizhou Province, China.

Characterization of histone deacetylases and their roles in response to abiotic and PAMPs stresses in Sorghum bicolor.

BACKGROUND: Histone deacetylases (HDACs) play an important role in the regulation of gene expression, which is indispensable in plant growth, development, and responses to environmental stresses. In Arabidopsis and rice, the molecular functions of HDACs have been well-described. However, systematic analysis of the HDAC gene family and gene expression in response to biotic and abiotic stresses has not been reported for sorghum. RESULTS: We conducted a systematic analysis of the sorghum HDAC gene family and identified 19 SbHDACs mainly distributed on eight chromosomes. Phylogenetic tree analysis of SbHDACs showed that the gene family was divided into three subfamilies: RPD3/HDA1, SIR2, and HD2. Tissue-specific expression results showed that SbHDACs displayed different expression patterns in different tissues, indicating that these genes may perform different functions in growth and development. The expression pattern of SbHDACs under different stresses (high and low temperature, drought, osmotic and salt) and pathogen-associated molecular model (PAMPs) elf18, chitin, and flg22) indicated that SbHDAC genes may participate in adversity responses and biological stress defenses. Overexpression of SbHDA1, SbHDA3, SbHDT2 and SbSRT2 in Escherichia coli promoted the growth of recombinant cells under abiotic stress. Interestingly, we also showed that the sorghum acetylation level was enhanced when plants were under cold, heat, drought, osmotic and salt stresses. The findings will help us to understand the HDAC gene family in sorghum, and illuminate the molecular mechanism of the responses to abiotic and biotic stresses. CONCLUSION: We have identified and classified 19 HDAC genes in sorghum. Our data provides insights into the evolution of the HDAC gene family and further support the hypothesis that these genes are important for the plant responses to abiotic and biotic stresses.

The role of Gα protein signaling in the membrane estrogen receptor-mediated signaling.

Estrogens exert rapid, extranuclear effects by their action on the plasma membrane estrogen receptors (mERs). Gα protein associated with the cell membrane is involved in many important processes regulated by estrogens. However, the Gα's role in the mER-mediated signaling and the signaling pathways involved are poorly understood. This review aims to outline the Gα's role in the mER-mediated signaling. Immunoblotting, immunofluorescence, co-immunoprecipitation, and RNA interference were carried out using vascular endothelial cells (ECs) and human breast carcinoma cell lines as experimental models. Electrophysiology and immunocytochemistry were carried out using guinea pigs as animal models. Recent advances suggest that the signaling of mERα through Gα is required for vascular EC migration or endothelial H2S release, while Gα13 is involved in estrogen-induced breast cancer cell invasion. Besides, the Gαq-coupled PLC-PKC-PKA pathway is critical for the neural regulation of energy homeostasis. This review summarizes the contributions of Gα to mER-mediated signaling, including cardiovascular protection, breast cancer metastasis, neural regulation of homeostatic functions, and osteogenesis.

Histone deacetylase SbHDT701 in Sorghum bicolor reveals functions in response to stress factors by enhancing acetylation.

Histone acetylation plays important roles in eukaryotic chromatin modification and gene expression regulation. Acetylation levels are modulated by histone deacetylases (HDACs), which function as key epigenetic factors that regulate gene expression in response to various stresses. HDT701, a member of the HD2 subfamily of HDACs, plays crucial roles in plant responses to abiotic stress and pathogen infection. Here, we analysed the expression pattern of SbHDT701 in sorghum. Real-time fluorescence quantitative PCR (RT-qPCR) results showed that expression of SbHDT701 was tissue-specific, and up-regulated under drought (d-mannitol) and salt (NaCl) stresses. We also determined the optimal expression conditions for SbHDT701 protein accumulation, and successfully expressed and purified SbHDT701 protein. Besides, overexpression of SbHDT701 in could promote the growth of recombinant cells under abiotic stress. SbHDT701 expression in Escherichia coli also increased acetylation modification levels following treatment with 750 mM NaCl, and 100 mM or 300 mM d-mannitol. In summary, the sorghum HDAC SbHDT701 mediates stress responses by enhancing acetylation modification levels.

17ß-Estradiol nongenomically induces vascular endothelial H2S release by promoting phosphorylation of cystathionine γ-lyase.

Estrogen exerts its cardiovascular protective role at least in part by regulating endothelial hydrogen sulfide (H2S) release, but the underlying mechanisms remain to be fully elucidated. Estrogen exerts genomic effects, i.e. those involving direct binding of the estrogen receptor (ER) to gene promoters in the nucleus, and nongenomic effects, mediated by interactions of the ER with other proteins. Here, using human umbilical vein endothelial cells (HUVECs), immunological detection, MS-based analyses, and cGMP and H2S assays, we show that 17ß-estradiol (E2) rapidly enhances endothelial H2S release in a nongenomic manner. We found that E2 induces phosphorylation of cystathionine γ-lyase (CSE), the key enzyme in vascular endothelial H2S generation. Mechanistically, E2 enhanced the interaction of membrane ERα with the Gα subunit Gαi-2/3, which then transactivated particulate guanylate cyclase-A (pGC-A) to produce cGMP, thereby activating protein kinase G type I (PKG-I). We also found that PKG-Iß, but not PKG-Iα, interacts with CSE, leading to its phosphorylation, and rapidly induces endothelial H2S release. Furthermore, we report that silencing of either CSE or pGC-A in mice attenuates E2-induced aorta vasodilation. These results provide detailed mechanistic insights into estrogen's nongenomic effects on vascular endothelial H2S release and advance our current understanding of the protective activities of estrogen in the cardiovascular system.

Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

Increasing evidence supports the important role of H2S in renal physiology and the pathogenesis of kidney injury. Whether H2S regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of H2S in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS), 2 major enzymes for endogenous H2S production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow H2S donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (V2R) antagonist tolvaptan. Inhibition of endogenous H2S production impaired urine concentration in mice, whereas an exogenous H2S donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. H2S upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

Identifying possible risk factors for cesarean scar pregnancy based on a retrospective study of 291 cases.

AIM: Cesarean scar pregnancy (CSP) is a rare but life-threatening type of ectopic pregnancy. This study's aim is to investigate the clinical characteristics and possible risk factors for cesarean scar pregnancy. METHODS: A clinically randomized, unpaired and retrospective case-control study was implemented. A study group of 291 CSP patients and a control group of 317 full-term pregnant women with a history of cesarean section (CS) were recruited in our hospital from May 2013 to October 2018. Their demographic characteristics and medical and obstetric history were collected. RESULTS: Only symptoms suggestive of an impending abortion, such as vaginal bleeding with or without abdominal pain, were identified as the clinical characteristics of CSP. Maternal age older than 35 years, gravidity higher than 3 (especially gravidity higher than 5), more than two induced abortions (especially more than five abortions), an interval of less than 5 years (especially less than 2 years) between the current pregnancy and the last CS, history of CS performed in a rural hospital, history of induced abortions after CS and retroposition of the uterus were possible independent risk factors for CSP. CONCLUSION: CSP is a result of a combination of multiple factors associated with CS. There are no unique early clinical features of CSP. As a unique type of ectopic pregnancy, early diagnosis, early termination and early clearance should be the treatment principles. Further research is needed to evaluate the relationship between the cesarean scar defect and CSP in the future.

(Pro)renin receptor contributes to pregnancy-induced sodium-water retention in rats via activation of intrarenal RAAS and α-ENaC.

The (pro)renin receptor (PRR) is a new component of the renin-angiotensin-aldosterone system (RAAS) and regulates renin activity. The objective of the present study was to test potential roles of the renal PRR and intrarenal RAAS in the physiological status of late pregnancy. Late pregnant Sprague-Dawley rats were studied 19-21 days after sperm was observed in vaginal smears. Experiments were performed using age-matched virgin rats and late pregnant rats treated with the specific PRR inhibitor PRO20 (700 µg·kg-1·day-1 sc for 14 days, 3 times/day for every 8 h) or vehicle. The indices of RAAS, including PRR, renin, angiotensin II, and aldosterone levels, were examined by immunoblotting, qRT-PCR, or ELISA. Further analyses of renal epithelial sodium channel (ENaC) expression, sodium-water retention, and plasma volume were performed. We first present evidence for the activation of intrarenal RAAS in late pregnant rats, including increases in urinary renin activity, active and total renin content, and prorenin content, angiotensin II and aldosterone excretion, in parallel with increased renal PRR expression and urinary soluble PRR excretion. Functional evidence demonstrated that PRR antagonism with PRO20 effectively suppressed the indices of intrarenal RAAS in late pregnant rats. In addition, our results revealed that renal α-ENaC expression, sodium-water retention, and plasma volume were elevated during late pregnancy, which were all attenuated by PRO20. In summary, the present study examined the renal mechanism of sodium-water retention and plasma volume expansion in late pregnant rats and identified a novel role of PRR in regulation of intrarenal RAAS and α-ENaC and thus sodium and fluid retention associated with pregnancy.

ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function.

Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Ser473 and eNOS at Ser1177. Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis, and improving microvascular endothelial dysfunction. rhADAMTS13 could be a promising strategy to treat AKI in clinical settings.

Notch signaling in bone marrow-derived FSP-1 cells initiates neointima formation in arteriovenous fistulas.

Neointima formation is a major contributor to arteriovenous fistula (AVF) failure. We have previously shown that activation of the Notch signaling pathway contributes to neointima formation by promoting the migration of vascular smooth muscle cells (VSMCs) into the venous anastomosis. In the current study we investigated the mechanisms underlying the dedifferentiation and migration of VSMCs, and in particular the role of bone marrow-derived fibroblast specific protein 1 (FSP-1)+ cells, another cell type found in models of vascular injury. Using VSMC-specific reporter mice, we found that most of the VSMCs participating in AVF neointima formation originated from dedifferentiated VSMCs. We also observed infiltration of bone marrow-derived FSP-1+ cells into the arterial anastomosis where they could interact with VSMCs. In vitro, conditioned media from FSP-1+ cells stimulated VSMC proliferation and phenotype switching. Activated Notch signaling transformed FSP-1+ cells into type I macrophages and stimulated secretion of cytokines and growth factors. Pretreatment with a Notch inhibitor or knockout of the canonical downstream factor RBP-Jκ in bone marrow-derived FSP1+ cells decreased FSP1+ cell infiltration into murine AVFs, attenuating VSMC dedifferentiation and neointima formation. Our results suggest that targeting Notch signaling could provide a new therapeutic strategy to improve AVF patency.

A cloud-based framework for large-scale traditional Chinese medical record retrieval.

INTRODUCTION: Electronic medical records are increasingly common in medical practice. The secondary use of medical records has become increasingly important. It relies on the ability to retrieve the complete information about desired patient populations. How to effectively and accurately retrieve relevant medical records from large- scale medical big data is becoming a big challenge. Therefore, we propose an efficient and robust framework based on cloud for large-scale Traditional Chinese Medical Records (TCMRs) retrieval. METHODS: We propose a parallel index building method and build a distributed search cluster, the former is used to improve the performance of index building, and the latter is used to provide high concurrent online TCMRs retrieval. Then, a real-time multi-indexing model is proposed to ensure the latest relevant TCMRs are indexed and retrieved in real-time, and a semantics-based query expansion method and a multi- factor ranking model are proposed to improve retrieval quality. Third, we implement a template-based visualization method for displaying medical reports. RESULTS: The proposed parallel indexing method and distributed search cluster can improve the performance of index building and provide high concurrent online TCMRs retrieval. The multi-indexing model can ensure the latest relevant TCMRs are indexed and retrieved in real-time. The semantics expansion method and the multi-factor ranking model can enhance retrieval quality. The template-based visualization method can enhance the availability and universality, where the medical reports are displayed via friendly web interface. CONCLUSIONS: In conclusion, compared with the current medical record retrieval systems, our system provides some advantages that are useful in improving the secondary use of large-scale traditional Chinese medical records in cloud environment. The proposed system is more easily integrated with existing clinical systems and be used in various scenarios.

Tempol Protects Against Acute Renal Injury by Regulating PI3K/Akt/mTOR and GSK3ß Signaling Cascades and Afferent Arteriolar Activity.

BACKGROUND/AIMS: Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3ß (GSK3ß) pathways as well as the coordinating apoptosis and inflammation related proteins. METHODS: The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3ß pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice. RESULTS: The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O2.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3ß, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole. CONCLUSION: Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3ß pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity.