The role of KIBRA in reconstructive episodic memory

In order to retrieve episodic past events, the missing information needs to be reconstructed using information stored in semantic memory. Failures in these reconstructive processes are expressed as false memories. KIBRA single nucleotide polymorphism (rs17070145) has been linked to episodic memory performance as well as an increased risk of Alzheimer’s disease and post-traumatic stress disorder (PTSD). Here, the role of KIBRA rs17070145 polymorphism (male and female CC vs. CT/TT carriers) in reconstructive episodic memory in the Deese-Roediger-McDermott (DRM) paradigm was investigated in N = 219 healthy individuals. Female participants outperformed males in the free recall condition. Furthermore, a trend towards a gender x genotype interaction was found for false recognition rates. Female CT/TT carriers exhibited a lower proportion of false recognition rates for associated critical lures as compared to male CT/TT. Additionally, an association between KIBRA rs17070145 genotype, familiarity and recollection based recognition performance was found. In trials with correct recognition of listed items CT/TT carriers showed more “remember”, but fewer “know” responses as compared to CC carriers. Our findings suggest that the T-allele of KIBRA rs17070145 supports recollection based episodic memory retrieval and contributes to memory accuracy in a gender dependent manner. Findings are discussed in the context of the specific contribution of KIBRA related SNPs to reconstructive episodic memory and its implications for cognitive and emotional symptoms in dementia and PTS

Dual Chromatin and Cytoskeletal Remodeling by SETD2

Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy. These data now identify SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton and show a requirement for methylation in maintenance of genomic stability and the integrity of both the tubulin and histone codes

A Conceptual Architecture for Reproducible On-demand Data Integration for Complex Diseases

Eosinophilic Esophagitis, which is a complex and emerging condition characterized by poorly defined phenotypes, and associated with both genetic and environmental conditions. Understanding such diseases requires researchers to seamlessly navigate across multiple scales (e.g., metabolome, proteome, genome, phenome, exposome) and models (sources using different stores, formats, and semantics), interrogate existing knowledge bases, and obtain results in formats of choice to answer different types of research questions. All of these would need to be performed to support reproducibility and sharability of methods used for selecting data sources, designing research queries, as well as query execution, understanding results and their quality. We present a higher level of formalizations for building multi-source data platforms on-demand based on the principles of meta-process modeling and provide reproducible and sharable data query and interrogation workflows and artifacts. A framework based on these formalizations consists of a layered abstraction of processes to support administrative and research end users: Top layer (meta-process): An extendable library of computable generic process concepts (PC) stored in a metadata repository1 (MDR) and describe steps/phases in the translational research life cycle. Middle layer (process): Methods to generate on-demand queries by assembling instantiated PC into query processes and rules. Researchers design query processes using PC, and evaluate their feasibility and validity by leveraging metadata content in the MDR. Bottom layer (execution): Interaction with a hyper-generalized federation platform (e.g. OpenFurther1) that performs complex interrogation and integration queries that require consideration of interdependencies and precedence across the selected sources. This framework can be implemented using process exchange formats (e.g., DAX, BPMN); and scientific workflow systems (e.g., Pegasus2, Apache Taverna3). All content (PC, rules, and workflows), assembling, and executing mechanism are sharable. The content, design, and development of the framework is informed by user-centered design methodology and consists of researcher and integration-centric components to provide robust and reproducible workflows. References 1. Gouripeddi R, Facelli JC, et al. FURTHeR: An Infrastructure for Clinical, Translational and Comparative Effectiveness Research. AMIA Annual Fall Symposium. 2013; Wash, DC. 2. Pegasus. The Pegasus Project. 2016; https://pegasus.isi.edu/. 3. Apache Software Foundation. Apache Taverna. 2016; https://taverna.incubator.apache.org/