ALBERT

Description: In law, inferences of causation are sometimes made through a structured process in which multiple participants play various roles, and make decisions concerning various logical components of the overall inference (such as legal rules, policy objectives, presumptions, evidence, burdens of proof and findings of fact). This article illustrates such a process using empirical research into compensation decisions in the USA for injuries allegedly caused by vaccinations. Empirical research into actual legal processes is essential, in order to discover how various players approach their sub-tasks of decision-making. It also provides insights for areas outside of law, such as non-monotonic logic, cognitive science, sociology and artificial intelligence.

Description: Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org . Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Drosophila melanogaster (fruit fly) has been a popular model organism in animal genetics due to the high accessibility of reverse-genetics tools. In addition, the close relationship between the Drosophila and human genomes rationalizes the use of Drosophila as an invertebrate model for human neurobiology and disease research. A platform technology for predicting candidate genes or functions would further enhance the usefulness of this long-established model organism for gene-to-phenotype mapping. Recently, the power of network prioritization for gene-to-phenotype mapping has been demonstrated in many organisms. Here we present a network prioritization server dedicated to Drosophila that covers ~95% of the coding genome. This server, dubbed FlyNet, has several distinctive features, including (i) prioritization for both genes and functions; (ii) two complementary network algorithms: direct neighborhood and network diffusion; (iii) spatiotemporal-specific networks as an additional prioritization strategy for traits associated with a specific developmental stage or tissue and (iv) prioritization for human disease genes. FlyNet is expected to serve as a versatile hypothesis-generation platform for genes and functions in the study of basic animal genetics, developmental biology and human disease. FlyNet is available for free at http://www.inetbio.org/flynet .

Description: We calculate and analyse the distribution of period ratios observed in systems of Kepler exoplanet candidates including studies of both adjacent planet pairs and all planet pairs. These distributions account for both the geometrical bias against detecting more distant planets and the effects of incompleteness due to planets missed by the data reduction pipeline. In addition to some of the known features near first-order mean-motion resonances (MMRs), there is a significant excess of planet pairs with period ratios near 2.2. The statistical significance of this feature is assessed using Monte Carlo simulation. We also investigate the distribution of period ratios near first-order MMR and compare different quantities used to measure this distribution. We find that beyond period ratios of ~2.5, the distribution of all period ratios follows a power law with an exponent –1.26 ± 0.05. We discuss implications that these results may have on the formation and dynamical evolution of Kepler -like planetary systems–systems of sub-Neptune/super-Earth planets with relatively short orbital periods.

Description: Here, we report a resistance mechanism that is induced through the modulation of 16S ribosomal RNA (rRNA) processing on the exposure of Escherichia coli cells to aminoglycoside antibiotics. We observed decreased expression levels of RNase G associated with increased RNase III activity on rng mRNA in a subgroup of E. coli isolates that transiently acquired resistance to low levels of kanamycin or streptomycin. Analyses of 16S rRNA from the aminoglycoside-resistant E. coli cells, in addition to mutagenesis studies, demonstrated that the accumulation of 16S rRNA precursors containing 3–8 extra nucleotides at the 5’ terminus, which results from incomplete processing by RNase G, is responsible for the observed aminoglycoside resistance. Chemical protection, mass spectrometry analysis and cell-free translation assays revealed that the ribosomes from rng -deleted E. coli have decreased binding capacity for, and diminished sensitivity to, streptomycin and neomycin, compared with wild-type cells. It was observed that the deletion of rng had similar effects in Salmonella enterica serovar Typhimurium strain SL1344. Our findings suggest that modulation of the endoribonucleolytic activity of RNase III and RNase G constitutes a previously uncharacterized regulatory pathway for adaptive resistance in E. coli and related gram-negative bacteria to aminoglycoside antibiotics.

Description: The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breitbach, Caroline J -- Burke, James -- Jonker, Derek -- Stephenson, Joe -- Haas, Andrew R -- Chow, Laura Q M -- Nieva, Jorge -- Hwang, Tae-Ho -- Moon, Anne -- Patt, Richard -- Pelusio, Adina -- Le Boeuf, Fabrice -- Burns, Joe -- Evgin, Laura -- De Silva, Naomi -- Cvancic, Sara -- Robertson, Terri -- Je, Ji-Eun -- Lee, Yeon-Sook -- Parato, Kelley -- Diallo, Jean-Simon -- Fenster, Aaron -- Daneshmand, Manijeh -- Bell, John C -- Kirn, David H -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Aug 31;477(7362):99-102. doi: 10.1038/nature10358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jennerex Inc., 450 Sansome Street, 16th floor, San Francisco, California 94111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21886163" target="_blank"〉PubMed〈/a〉

Description: Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that alpha-ketoglutarate (alpha-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit beta is identified as a novel binding protein of alpha-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that alpha-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by alpha-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by alpha-KG requires ATP synthase subunit beta and is dependent on target of rapamycin (TOR) downstream. Endogenous alpha-KG levels are increased on starvation and alpha-KG does not extend the lifespan of dietary-restricted animals, indicating that alpha-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263271/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263271/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chin, Randall M -- Fu, Xudong -- Pai, Melody Y -- Vergnes, Laurent -- Hwang, Heejun -- Deng, Gang -- Diep, Simon -- Lomenick, Brett -- Meli, Vijaykumar S -- Monsalve, Gabriela C -- Hu, Eileen -- Whelan, Stephen A -- Wang, Jennifer X -- Jung, Gwanghyun -- Solis, Gregory M -- Fazlollahi, Farbod -- Kaweeteerawat, Chitrada -- Quach, Austin -- Nili, Mahta -- Krall, Abby S -- Godwin, Hilary A -- Chang, Helena R -- Faull, Kym F -- Guo, Feng -- Jiang, Meisheng -- Trauger, Sunia A -- Saghatelian, Alan -- Braas, Daniel -- Christofk, Heather R -- Clarke, Catherine F -- Teitell, Michael A -- Petrascheck, Michael -- Reue, Karen -- Jung, Michael E -- Frand, Alison R -- Huang, Jing -- DP2 OD008398/OD/NIH HHS/ -- P01 HL028481/HL/NHLBI NIH HHS/ -- P40 OD010440/OD/NIH HHS/ -- T32 CA009120/CA/NCI NIH HHS/ -- T32 GM007104/GM/NIGMS NIH HHS/ -- T32 GM007185/GM/NIGMS NIH HHS/ -- T32 GM008496/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):397-401. doi: 10.1038/nature13264. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA. ; Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2] UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828042" target="_blank"〉PubMed〈/a〉

Description: Saccharomyces cerevisiae , i.e. baker’s yeast, is a widely studied model organism in eukaryote genetics because of its simple protocols for genetic manipulation and phenotype profiling. The high abundance of publicly available data that has been generated through diverse ‘omics’ approaches has led to the use of yeast for many systems biology studies, including large-scale gene network modeling to better understand the molecular basis of the cellular phenotype. We have previously developed a genome-scale gene network for yeast, YeastNet v2, which has been used for various genetics and systems biology studies. Here, we present an updated version, YeastNet v3 (available at http://www.inetbio.org/yeastnet/ ), that significantly improves the prediction of gene–phenotype associations. The extended genome in YeastNet v3 covers up to 5818 genes (~99% of the coding genome) wired by 362 512 functional links. YeastNet v3 provides a new web interface to run the tools for network-guided hypothesis generations. YeastNet v3 also provides edge information for all data-specific networks (~2 million functional links) as well as the integrated networks. Therefore, users can construct alternative versions of the integrated network by applying their own data integration algorithm to the same data-specific links.

Description: Protein sequences evolve under selection pressures imposed by functional and biophysical requirements, resulting in site-dependent rates of amino acid substitution. Relative solvent accessibility (RSA) and local packing density (LPD) have emerged as the best candidates to quantify structural constraint. Recent research assumes that RSA is the main determinant of sequence divergence. However, it is not yet clear which is the best predictor of substitution rates. To address this issue, we compared RSA and LPD with site-specific rates of evolution for a diverse data set of enzymes. In contrast with recent studies, we found that LPD measures correlate better than RSA with evolutionary rate. Moreover, the independent contribution of RSA is minor. Taking into account that LPD is related to backbone flexibility, we put forward the possibility that the rate of evolution of a site is determined by the ease with which the backbone deforms to accommodate mutations.

Description: An objective measurement of cutaneous topographical information is important for quantifying the degree of skin aging. Our aim was to improve methods for measuring microrelief patterns using a three-dimensional analysis based on silicone replicas and scanning electron microscope (SEM). Another objective was to compare the results with those obtained using a two-dimensional analysis method based on dermoscopy. Silicone replicas were obtained from forearms, dorsum of the hands and fingers of 51 volunteers. Cutaneous profiles obtained by SEM with silicone replicas showed more consistent correlations with age than data obtained by dermoscopy. This indicates the advantage of three-dimensional topography analysis using silicone replicas and SEM over the widely used dermoscopic assessment. The cutaneous age was calculated using stepwise linear regression, and the result was 57.40–9.47  x  (number of furrows on dorsum of the hand)  x  (width of furrows on dorsum of the hand).