Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens.

Front Microbiol. 2016;7:570

Authors: Guthke R, Gerber S, Conrad T, Vlaic S, Durmuş S, Çakır T, Sevilgen FE, Shelest E, Linde J

Abstract
In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.

PMID: 27148247 [PubMed]

Research Infrastructure for Collaborative Team Science: Challenges in Technology-Supported Workflows in and Across Laboratories, Institutions, and Geographies.

Semin Nephrol. 2015 May;35(3):291-302

Authors: Mirel B, Luo A, Harris M

Abstract
Collaborative research has many challenges. One under-researched challenge is how to align collaborators' research practices and evolving analytical reasoning with technologies and configurations of technologies that best support them. The goal of such alignment is to enhance collaborative problem solving capabilities in research. Toward this end, we draw on our own research and a synthesis of the literature to characterize the workflow of collaborating scientists in systems-level renal disease research. We describe the various phases of a hypothetical workflow among diverse collaborators within and across laboratories, extending from their primary analysis through secondary analysis. For each phase, we highlight required technology supports, and. At time, complementary organizational supports. This survey of supports matching collaborators' analysis practices and needs in research projects to technological support is preliminary, aimed ultimately at developing a research capability framework that can help scientists and technologists mutually understand workflows and technologies that can help enable and enhance them.

PMID: 26215866 [PubMed - indexed for MEDLINE]

APOL1 Kidney Disease Risk Variants: An Evolving Landscape.

Semin Nephrol. 2015 May;35(3):222-36

Authors: Dummer PD, Limou S, Rosenberg AZ, Heymann J, Nelson G, Winkler CA, Kopp JB

Abstract
Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.

PMID: 26215860 [PubMed - indexed for MEDLINE]

Identification of miR-34a-target interactions by a combined network based and experimental approach.

Oncotarget. 2016 Apr 29;

Authors: Hart M, Rheinheimer S, Leidinger P, Backes C, Menegatti J, Fehlmann T, Grässer F, Keller A, Meese E

Abstract
Circulating miRNAs have been associated with numerous human diseases. The lack of understanding the functional roles of blood-born miRNAs limits, however, largely their value as disease marker. In a systems biology analysis we identified miR-34a as strongly associated with pathogenesis. Genome-wide analysis of miRNAs in blood cell fractions highlighted miR-34a as most significantly up-regulated in CD3+ cells of lung cancer patients. By our in silico analysis members of the protein kinase C family (PKC) were indicated as miR-34a target genes. Using a luciferase assay, we confirmed binding of miR-34a-5p to target sequences within the 3'UTRs of five PKC family members. To verify the biological effect, we transfected HEK 293T and Jurkat cells with miR-34a-5p causing reduced endogenous protein levels of PKC isozymes. By combining bioinformatics approaches with experimental validation, we demonstrate that one of the most relevant disease associated miRNAs has the ability to control the expression of a gene family.

PMID: 27144431 [PubMed - as supplied by publisher]

Spatial Cross-Talk Between Oxidative Stress and DNA Replication in Human Fibroblasts.

J Proteome Res. 2016 May 4;

Authors: Radulovic M, Baqader NO, Stoeber K, Godovac-Zimmermann J

Abstract
MS-based proteomics has been applied to a differential network analysis of the nuclear-cytoplasmic subcellular distribution of proteins between cell cycle arrest: (a) at the origin activation checkpoint for DNA replication, or (b) in response to oxidative stress. Significant changes were identified for 401 proteins. Cellular response combines changes in trafficking and in total abundance to vary the local compartmental abundances that are the basis of cellular response. Appreciable changes for both perturbations were observed for 245 proteins, but cross-talk between oxidative stress and DNA replication is dominated by 49 proteins that show strong changes for both. Many nuclear processes are influenced by a spatial switch involving the proteins {KPNA2, KPNB1, PCNA, PTMA, SET} and heme/iron proteins HMOX1 and FTH1. Dynamic spatial distribution data is presented for proteins involved in caveolae, extracellular matrix remodelling, TGFβ signalling, IGF pathways, emerin complexes, mitochondrial protein import complexes, spliceosomes, proteasomes, etc. The data indicates that for spatially heterogeneous cells, cross-compartmental communication is integral to their systems biology, that coordinated spatial redistribution for crucial protein networks underlies many functional changes, and that information on dynamic spatial redistribution of proteins is essential to obtain comprehensive pictures of cellular function. We describe how spatial data of the type presented here can provide priorities for further investigation of crucial features of high-level spatial coordination across cells. We suggest that the present data is related to increasing indications that much of subcellular protein transport is constitutive and that perturbation of these constitutive transport processes may be related to cancer and other diseases. A quantitative, spatially resolved nucleus-cytoplasm interaction network is provided for further investigations.

PMID: 27142241 [PubMed - as supplied by publisher]