Imaging Multidimensional Therapeutically Relevant Circadian Relationships

Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies

Imaging Multidimensional Therapeutically Relevant Circadian Relationships

Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies

An Ensemble Approach for Annotating Source Code Identifiers with Part-of-speech Tags

This paper presents an ensemble part-of-speech tagging approach for source code identifiers. Ensemble tagging is a technique that uses machine-learning and the output from multiple part-of-speech taggers to annotate natural language text at a higher quality than the part-of-speech taggers are able to obtain independently. Our ensemble uses three state-of-the-art part-of-speech taggers: SWUM, POSSE, and Stanford. We study the quality of the ensemble\u27s annotations on five different types of identifier names: function, class, attribute, parameter, and declaration statement at the level of both individual words and full identifier names. We also study and discuss the weaknesses of our tagger to promote the future amelioration of these problems through further research. Our results show that the ensemble achieves 75\% accuracy at the identifier level and 84-86\% accuracy at the word level. This is an increase of +17\% points at the identifier level from the closest independent part-of-speech tagger

In-situ local phase-transitioned MoSe2 in La0.5Sr0.5CoO3-?? heterostructure and stable overall water electrolysis over 1000 hours

Developing efficient bifunctional catalysts for overall water splitting that are earth-abundant, cost-effective, and durable is of considerable importance from the practical perspective to mitigate the issues associated with precious metal-based catalysts. Herein, we introduce a heterostructure comprising perovskite oxides (La0.5Sr0.5CoO3?????) and molybdenum diselenide (MoSe2) as an electrochemical catalyst for overall water electrolysis. Interestingly, formation of the heterostructure of La0.5Sr0.5CoO3????? and MoSe2 induces a local phase transition in MoSe2, 2???H to 1???T phase, and more electrophilic La0.5Sr0.5CoO3????? with partial oxidation of the Co cation owing to electron transfer from Co to Mo. Together with these synergistic effects, the electrochemical activities are significantly improved for both hydrogen and oxygen evolution reactions. In the overall water splitting operation, the heterostructure showed excellent stability at the high current density of 100???mA???cm???2 over 1,000???h, which is exceptionally better than the stability of the state-of-the-art platinum and iridium oxide couple

ProteinHistorian: Tools for the Comparative Analysis of Eukaryote Protein Origin

The evolutionary history of a protein reflects the functional history of its ancestors. Recent phylogenetic studies identified distinct evolutionary signatures that characterize proteins involved in cancer, Mendelian disease, and different ontogenic stages. Despite the potential to yield insight into the cellular functions and interactions of proteins, such comparative phylogenetic analyses are rarely performed, because they require custom algorithms. We developed ProteinHistorian to make tools for performing analyses of protein origins widely available. Given a list of proteins of interest, ProteinHistorian estimates the phylogenetic age of each protein, quantifies enrichment for proteins of specific ages, and compares variation in protein age with other protein attributes. ProteinHistorian allows flexibility in the definition of protein age by including several algorithms for estimating ages from different databases of evolutionary relationships. We illustrate the use of ProteinHistorian with three example analyses. First, we demonstrate that proteins with high expression in human, compared to chimpanzee and rhesus macaque, are significantly younger than those with human-specific low expression. Next, we show that human proteins with annotated regulatory functions are significantly younger than proteins with catalytic functions. Finally, we compare protein length and age in many eukaryotic species and, as expected from previous studies, find a positive, though often weak, correlation between protein age and length. ProteinHistorian is available through a web server with an intuitive interface and as a set of command line tools; this allows biologists and bioinformaticians alike to integrate these approaches into their analysis pipelines. ProteinHistorian's modular, extensible design facilitates the integration of new datasets and algorithms. The ProteinHistorian web server, source code, and pre-computed ages for 32 eukaryotic genomes are freely available under the GNU public license at http://lighthouse.ucsf.edu/ProteinHistorian/

MycoRRdb: A Database of Computationally Identified Regulatory Regions within Intergenic Sequences in Mycobacterial Genomes

The identification of regulatory regions for a gene is an important step towards deciphering the gene regulation. Regulatory regions tend to be conserved under evolution that facilitates the application of comparative genomics to identify such regions. The present study is an attempt to make use of this attribute to identify regulatory regions in the Mycobacterium species followed by the development of a database, MycoRRdb. It consist the regulatory regions identified within the intergenic distances of 25 mycobacterial species. MycoRRdb allows to retrieve the identified intergenic regulatory elements in the mycobacterial genomes. In addition to the predicted motifs, it also allows user to retrieve the Reciprocal Best BLAST Hits across the mycobacterial genomes. It is a useful resource to understand the transcriptional regulatory mechanism of mycobacterial species. This database is first of its kind which specifically addresses cis-regulatory regions and also comprehensive to the mycobacterial species. Database URL: http://mycorrdb.uohbif.in

Synonymous Codon Ordering: A Subtle but Prevalent Strategy of Bacteria to Improve Translational Efficiency

Background: In yeast coding sequences, once a particular codon has been used, subsequent occurrence of the same amino acid tends to use codons sharing the same tRNA. Such a phenomenon of co-tRNA codons pairing bias (CTCPB) is also found in some other eukaryotes but it is not known whether it occurs in prokaryotes. Methodology/Principal Findings: In this study, we focused on a total of 773 bacterial genomes to investigate their synonymous codon pairing preferences. After calculating the actual frequencies of synonymous codon pairs and comparing them with their expected values, we detected an obvious pairing bias towards identical codon pairs. This seems consistent with the previously reported CTCPB phenomenon, since identical codons are certainly read by the same tRNA. However, among co-tRNA but non-identical codon pairs, only 22 were often found overrepresented, suggesting that many co-tRNA codons actually do not preferentially pair together in prokaryotes. Therefore, the previously reported co-tRNA codons pairing rule needs to be more rigorously defined. The affinity differences between a tRNA anticodon and its readable codons should be taken into account. Moreover, both within-gene-shuffling tests and phylogenetic analyses support the idea that translational selection played an important role in shaping the observed synonymous codon pairing pattern in prokaryotes. Conclusions: Overall, a high level of synonymous codon pairing bias was detected in 73 % investigated bacterial species

Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only