THERPA: A small molecule database related to prion protein regulation and prion diseases progression

Prion diseases are fatal neurodegenerative disorders that affect humans and animals. Although various small molecules have been evaluated for application in the treatment of prion diseases, none have been shown to be efficacious. Expanding our knowledge of these molecules is important for understanding of the complex mechanisms of prion diseases. To improve access to the scattered information on small molecules related to prion diseases, we built a database of therapeutic molecules associated with prion diseases (THERPA, therpa.pythonanywhere.com). THERPA includes 119 small molecules and their 283 relationships with prion diseases. THERPA is an interactive visual database and useful for improving search efficiency which can help researchers identify intrinsic small molecules that can be used for developing therapeutics for prion diseases.     

Complete genome sequencing of sixteen Francisella noatunensis subsp. orientalis isolates: A genomic approach for molecular characterization and spread dynamics of this clonal population

Francisella noatunensis subsp. orientalis (FNO) is an important emerging pathogen associated with disease outbreaks in farm-raised Nile tilapia. FNO genetic diversity using PCR-based typing, no intra-species discrimination was achieved among isolates/strains from different countries, thus demonstrating a clonal behaviour pattern. In this study, we aimed to evaluate the population structure of FNO isolates by comparing whole-genome sequencing data. The analysis of recombination showed that Brazilian isolates group formed a clonal population; whereas other lineages are also supported by this analysis for isolates from foreign countries. The whole-genome multilocus sequence typing (wgMLST) analysis showed varying numbers of dissimilar alleles, suggesting that the Brazilian clonal population are in expansion. Each Brazilian isolate could be identified as a single node by high-resolution gene-by-gene approach, presenting slight genetic differences associated to mutational events. The common ancestry node suggests a single entry into the country before 2012, and the rapid dissemination of this infectious agent may be linked to market sales of infected fingerlings.     

Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons

The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q < 0.05; enrichment range 1.40–9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans?nosology pathways in diabetes and its co-morbidities.     

Public informatics resources for rice and other grasses

As an emerging model system, rice will benefit from an informatics infrastructure which organizes genome data and makes it available worldwide. RiceGenes and other Internet-accessible resources are evolving to meet these goals. Grass crops such as rice, maize, millet, sorghum and wheat are closely related but are represented by independent database projects; interlinking these resources would create a broad view of grass genetics and make it easier to compare data across genomes. The future success of grass informatics depends on the development of new comparative mapping displays as well as the participation of the research community in assembling and curating comparative map data.     

TiD: Standalone software for mining putative drug targets from bacterial proteome

TiD is a standalone application, which relies on basic assumption that a protein must be essential for pathogens survival and non-homologous with host to qualify as putative target. With an input bacterial proteome, TiD removes paralogous proteins, picks essential ones, and excludes proteins homologous with host organisms. The targets illustrate non-homology with at least 40 out of 84 gut microbes, considered safe for human. TiD classifies proposed targets as known, novel and virulent. Users can perform pathway analysis, choke point analysis, interactome analysis, subcellular localization and functional annotations through web servers cross-referenced with the application. Drug targets identified by TiD for Listeria monocytogenes, Bacillus anthracis and Pseudomonas aeruginosa have revealed significant overlaps with previous studies. TiD takes < 2 h to scan putative targets from a bacterial proteome with ~ 5000 proteins; hence, we propose it as a useful tool for rational drug design. TiD is available at http://bmicnip.in/TiD/.     

Reaction of haem containing proteins and enzymes with hydroperoxides: The radical view

The reaction between hydroperoxides and the haem group of proteins and enzymes is important for the function of many enzymes but has also been implicated in a number of pathological conditions where oxygen binding proteins interact with hydrogen peroxide or other peroxides. The haem group in the oxidized Fe³⁺ (ferric) state reacts with hydroperoxides with a formation of the Fe⁴⁺=O (oxoferryl) haem state and a free radical primarily located on the π-system of the haem. The radical is then transferred to an amino acid residue of the protein and undergoes further transfer and transformation processes. The free radicals formed in this reaction are reviewed for a number of proteins and enzymes. Their previously published EPR spectra are analysed in a comparative way. The radicals directly detected in most systems are tyrosyl radicals and the peroxyl radicals formed on tryptophan and possibly cysteine. The locations of the radicals in the proteins have been reported as follows: Tyr133 in soybean leghaemoglobin; αTyr42, αTrp14, βTrp15, βCys93, (αTyr24−αHis20), all in the α- and β-subunits of human haemoglobin; Tyr103, Tyr151 and Trp14 in sperm whale myoglobin; Tyr103, Tyr146 and Trp14 in horse myoglobin; Trp14, Tyr103 and Cys110 in human Mb. The sequence of events leading to radical formation, transformation and transfer, both intra- and intermolecularly, is considered. The free radicals induced by peroxides in the enzymes are reviewed. Those include: lignin peroxidase, cytochrome c peroxidase, cytochrome c oxidase, turnip isoperoxidase 7, bovine catalase, two isoforms of prostaglandin H synthase, Mycobacterium tuberculosis and Synechocystis PCC6803 catalase-peroxidases.     

Analysis of long-term ecological status of Lake Balaton based on the ALMOBAL phytoplankton database

Lake Balaton (Hungary), one of the largest lakes in Europe, has undergone eutrophication and restoration during the last two decades. The first quantitative phytoplankton records date back to the 1930s, and since that time thousands of data have been published or accumulated in counting protocols or computer sheets. These data provide material for both scientific analyses (e.g. effects of global change) and applications (e.g. estimation of reference state for the Water Framework Directive). The ALMOBAL phytoplankton database was developed to provide computing support for these applications. It stores data in standardized forms, handles synonyms and allows analyses to be conducted on the basis of floral records, numbers or biomass. The analysis includes records of about 3000 phytoplankton samples taken during the past 60 years from two representative basins in Lake Balaton. This article represents the first attempt at historical reconstruction of the ecological status and compares it with changes in trophic state and current water quality. The results indicate that the phytoplankton biomass and community structure found in the early 1960s could be regarded as reference conditions. Statistical analyses support the view that late summer phytoplankton assemblages are the most sensitive indicators of trophic change, and clearly show the eutrophication of the lake that occurred from the mid-1970s to the mid-1990s and the restoration during the last decade. An additional advantage is that, since quality estimation is based on relative biomass, the method can be used to reconstruct water quality in cases when counting protocols are available, but some basic data for quantitative estimates are missing.     

Structure-based drug design identifies novel LPA3 antagonists

Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA₃ antagonist (IC₅₀ = 4504 nM) in a virtual screening effort to optimize a dual LPA_{2 and 3} antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA₃ receptor by 200 nM LPA with IC₅₀ values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA₃ receptor antagonists. The results of the combined computational and experimental screening are reported.