Cardiomyocyte-specific regression of nitrosative stress-mediated S-Nitrosylation of IKKγ alleviates pathological cardiac hypertrophy.

IKKγ prototypically promotes NFκBp65 activity by regulating the assembly of the IKK holocomplex. In hypertrophied cardiomyocytes, the p65-p300 complex-induced regenerative efforts are neutralized by the p53-p300 complex-mediated apoptotic load resulting in compromised cardiac function. The present study reports that nitrosative stress leads to S-Nitrosylation of IKKγ in hypertrophied cardiomyocytes in a pre-clinical model. Using a cardiomyocyte-targeted nanoconjugate, IKKγ S-Nitrosylation-resistant mutant plasmids were delivered to the pathologically hypertrophied heart that resulted in improved cardiac function by amelioration of cardiomyocyte apoptosis and simultaneous induction of their cell cycle re-entry machinery. Mechanistically, in IKKγ S-Nitrosyl mutant-transfected hypertrophied cells, increased IKKγ-p300 binding downregulated the binding of p53 and p65 with p300. This shifted the binding preference of p65 from p300 to HDAC1 resulting in upregulated expression of cyclin D1 and CDK2 via the p27/pRb pathway. This approach has therapeutic advantage over mainstream anti-hypertrophic remedies which concomitantly reduce the regenerative prowess of resident cardiomyocytes during hypertrophy upon downregulation of myocyte apoptosis. Therefore, cardiomyocyte-targeted delivery of IKKγ S-Nitrosyl mutants during hypertrophy can be exploited as a novel strategy to re-muscularize the diseased heart.

High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis.

The High-performance Integrated Virtual Environment (HIVE) is a distributed storage and compute environment designed primarily to handle next-generation sequencing (NGS) data. This multicomponent cloud infrastructure provides secure web access for authorized users to deposit, retrieve, annotate and compute on NGS data, and to analyse the outcomes using web interface visual environments appropriately built in collaboration with research and regulatory scientists and other end users. Unlike many massively parallel computing environments, HIVE uses a cloud control server which virtualizes services, not processes. It is both very robust and flexible due to the abstraction layer introduced between computational requests and operating system processes. The novel paradigm of moving computations to the data, instead of moving data to computational nodes, has proven to be significantly less taxing for both hardware and network infrastructure.The honeycomb data model developed for HIVE integrates metadata into an object-oriented model. Its distinction from other object-oriented databases is in the additional implementation of a unified application program interface to search, view and manipulate data of all types. This model simplifies the introduction of new data types, thereby minimizing the need for database restructuring and streamlining the development of new integrated information systems. The honeycomb model employs a highly secure hierarchical access control and permission system, allowing determination of data access privileges in a finely granular manner without flooding the security subsystem with a multiplicity of rules. HIVE infrastructure will allow engineers and scientists to perform NGS analysis in a manner that is both efficient and secure. HIVE is actively supported in public and private domains, and project collaborations are welcomed. Database URL: https://hive.biochemistry.gwu.edu.