Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction ...remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.
Hypertension affects 108 million in the United States, which is more common in African American (AA) population (54%). Several Genome‐Wide Association Studies (GWAS) showed a strong association ...between the apolipoprotein1 (apol1) gene and hypertension in AA adults. Nearly 45% of AAs carry a coding variant of the APOL1 gene either G1APOL1 or G2APOL1. The disease phenotypes associated with APOL1 RV are dependent on the cell type‐specific expression and toxicity of APOL1. Recently, we have reported that APOL1 is highly expressed in endothelial cells (EC) of the human kidneys using single‐cell analysis, single nuclei analysis, and in‐situ hybridization. People who carry G1 or G2 APOL1 RV have a high risk of chronic kidney disease and hypertensive kidney disease. However, the direct role of APOL1 in the development of hypertension and hypertensive kidney disease is clear. Therefore, the objective of the current study was to examine the role of endothelial‐specific inducible G2APOL1 risk variants in the development of hypertension and hypertensive kidney disease. To understand the role of APOL1 in endothelial cells, we generated mice with endothelial‐specific inducible expression of APOL1 (EC/G2‐APOL1) by crossing the TRE‐G2APOL1 mice with the Cdh5tTA animals. Cadherin 5 (VE‐cadherin or endothelial cadherin) is an endothelial‐specific gene, removal of doxycycline from the diet led to a significant expression of APOL1 in different vascular beds such as the lung, heart, and kidney, which was confirmed both by in situ hybridization and qRT‐PCR. After collecting the baseline data, we performed UNX surgery on both WT control and Cdh5tTA/TRE‐G2APOL1 five‐week‐old mice and kept them in 4% salt diet for 12 weeks after UNX surgery. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) (measured by tail‐cuff method) were significantly higher in Cdh5tTA/TRE‐G2APOL1 mice compared to control WT mice after 6 weeks of UNX surgery on a high salt diet. The significantly higher blood pressure in Cdh5tTA/TRE‐G2APOL1 mice was further associated with the increased urinary albumin/creatinine ratio and renal fibrosis. Interestingly, the blood pressure parameters SBP, DBP, and MAP were significantly reduced on STING, NLRP3, and gasdermin knock‐out mice on Cdh5tTA/TRE‐G2APOL1 background compared to Cdh5tTA/TRE‐G2APOL1 mice upon UNX‐surgery and 4% salt diet. Furthermore, the expression of the transcript of the mitochondrial gene including COX1, COX2, ATP6, and ND6 in the cytoplasm from kidney tissue obtained from Cdh5tTA/TRE‐G2APOL1 mice was significantly higher compared to control‐WT, which indicate that mitochondrial damage and leakage of the mitochondrial gene into the cytoplasm take place in the Cdh5tTA/TRE‐G2APOL1 mice upon UNX‐surgery and 4% salt‐diet. Therefore, EC specific apol1 gene induces mitochondrial damage, upregulates inflammasome and cGAS‐STING pathway to develop hypertension leading to hypertensive kidney disease. This project was supported by DK105821.
With the increasing complexity of data center networks, the operations, management and diagnosis of data centers is a critical problem. The need of a self-managing, self-configuring, and ...self-optimizing network is crucial which is known as Autonomic Networking concept. In this thesis, we propose an autonomic Diagnostics framework in Software-Defined Infrastructure running in the SAVI testbed. We have analyzed and discussed various design requirements and open challenges in literature. We have leveraged Graph Mining and Machine Learning techniques in our approach in order to detect different kinds of anomalies. We have studied different algorithm performance under different settings for detecting anomalies. We have tested our framework on several use cases: Standalone Webserver, Standalone Database, Webserver-Database workload pattern, bandwidth throttling between a pair of VMs, denial-of-service attack on a Webserver and Spark Job failure. Our framework was able to detect the aforementioned anomalies accurately.
Graph-based diagnosis in Software-Defined Infrastructure Wahba, Joseph; Soliman, Hazem; Bannazadeh, Hadi ...
Proceedings of the 12th Conference on International Conference on Network and Service Management,
11/2016
Conference Proceeding
Performing system diagnosis is a critical task in modern datacenters. Investigating individual resource behavior may not be efficient in detecting abnormal behavior in large and complex datacenters. ...In this paper, we propose a scalable graph based diagnosis framework to detect system anomalies in Software-Defined Infrastructure running in SAVI testbed. We have leveraged Graph Mining and Machine Learning techniques in our approach in order to detect different kinds of anomalies. We have experimentally tested our framework on several use cases: Webserver-Database workload pattern, bandwidth throttling between a pair of VMs, denial-of-service (DoS) attack on a webserver and Spark Job failure. Our framework was able to detect the aforementioned anomalies accurately.
Performing system diagnosis is a critical task in modern datacenters. Investigating individual resource behavior may not be efficient in detecting abnormal behavior in large and complex datacenters. ...In this paper, we propose a scalable graph based diagnosis framework to detect system anomalies in Software-Defined Infrastructure running in SAVI testbed. We have leveraged Graph Mining and Machine Learning techniques in our approach in order to detect different kinds of anomalies. We have experimentally tested our framework on several use cases: Webserver-Database workload pattern, bandwidth throttling between a pair of VMs, denial-of-service (DoS) attack on a webserver and Spark Job failure. Our framework was able to detect the aforementioned anomalies accurately.
RNA silencing is a highly conserved pathway in the network of interconnected defense responses that are activated during viral infection. As a counter-defense, many plant viruses encode proteins that ...block silencing, often also interfering with endogenous small RNA pathways. However, the mechanism of action of viral suppressors is not well understood and the role of host factors in the process is just beginning to emerge. Here we report that the ethylene-inducible transcription factor RAV2 is required for suppression of RNA silencing by two unrelated plant viral proteins, potyvirus HC-Pro and carmovirus P38. Using a hairpin transgene silencing system, we find that both viral suppressors require RAV2 to block the activity of primary siRNAs, whereas suppression of transitive silencing is RAV2-independent. RAV2 is also required for many HC-Pro-mediated morphological anomalies in transgenic plants, but not for the associated defects in the microRNA pathway. Whole genome tiling microarray experiments demonstrate that expression of genes known to be required for silencing is unchanged in HC-Pro plants, whereas a striking number of genes involved in other biotic and abiotic stress responses are induced, many in a RAV2-dependent manner. Among the genes that require RAV2 for induction by HC-Pro are FRY1 and CML38, genes implicated as endogenous suppressors of silencing. These findings raise the intriguing possibility that HC-Pro-suppression of silencing is not caused by decreased expression of genes that are required for silencing, but instead, by induction of stress and defense responses, some components of which interfere with antiviral silencing. Furthermore, the observation that two unrelated viral suppressors require the activity of the same factor to block silencing suggests that RAV2 represents a control point that can be readily subverted by viruses to block antiviral silencing.
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