On the upstream mobility scheme for two-phase flow in porous media

When neglecting capillarity, two-phase incompressible flow in porous media is modelled as a scalar nonlinear hyperbolic conservation law. A change in the rock type results in a change of the flux function. Discretizing in one-dimensional with a finite volume method, we investigate two numerical fluxes, an extension of the Godunov flux and the upstream mobility flux, the latter being widely used in hydrogeology and petroleum engineering. Then, in the case of a changing rock type, one can give examples when the upstream mobility flux does not give the right answer.Comment: A preprint to be published in Computational Geoscience

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes

Many cases of non-standard genetic codes are known in mitochondrial genomes. We carry out analysis of phylogeny and codon usage of organisms for which the complete mitochondrial genome is available, and we determine the most likely mechanism for codon reassignment in each case. Reassignment events can be classified according to the gain-loss framework. The gain represents the appearance of a new tRNA for the reassigned codon or the change of an existing tRNA such that it gains the ability to pair with the codon. The loss represents the deletion of a tRNA or the change in a tRNA so that it no longer translates the codon. One possible mechanism is Codon Disappearance, where the codon disappears from the genome prior to the gain and loss events. In the alternative mechanisms the codon does not disappear. In the Unassigned Codon mechanism, the loss occurs first, whereas in the Ambiguous Intermediate mechanism, the gain occurs first. Codon usage analysis gives clear evidence of cases where the codon disappeared at the point of the reassignment and also cases where it did not disappear. Codon disappearance is the probable explanation for stop to sense reassignments and a small number of reassignments of sense codons. However, the majority of sense to sense reassignments cannot be explained by codon disappearance. In the latter cases, by analysis of the presence or absence of tRNAs in the genome and of the changes in tRNA sequences, it is sometimes possible to distinguish between the Unassigned Codon and Ambiguous Intermediate mechanisms. We emphasize that not all reassignments follow the same scenario and that it is necessary to consider the details of each case carefully.Comment: 53 pages (45 pages, including 4 figures + 8 pages of supplementary information). To appear in J.Mol.Evo

Foot Bone in Vivo: Its Center of Mass and Centroid of Shape

This paper studies foot bone geometrical shape and its mass distribution and establishes an assessment method of bone strength. Using spiral CT scanning, with an accuracy of sub-millimeter, we analyze the data of 384 pieces of foot bones in vivo and investigate the relationship between the bone's external shape and internal structure. This analysis is explored on the bases of the bone's center of mass and its centroid of shape. We observe the phenomenon of superposition of center of mass and centroid of shape fairly precisely, indicating a possible appearance of biomechanical organism. We investigate two aspects of the geometrical shape, (i) distance between compact bone's centroid of shape and that of the bone and (ii) the mean radius of the same density bone issue relative to the bone's centroid of shape. These quantities are used to interpret the influence of different physical exercises imposed on bone strength, thereby contributing to an alternate assessment technique to bone strength.Comment: 9 pages, 4 figure

PRED_PPI: a server for predicting protein-protein interactions based on sequence data with probability assignment

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions (PPIs) are crucial for almost all cellular processes, including metabolic cycles, DNA transcription and replication, and signaling cascades. Given the importance of PPIs, several methods have been developed to detect them. Since the experimental methods are time-consuming and expensive, developing computational methods for effectively identifying PPIs is of great practical significance.</p> <p>Findings</p> <p>Most previous methods were developed for predicting PPIs in only one species, and do not account for probability estimations. In this work, a relatively comprehensive prediction system was developed, based on a support vector machine (SVM), for predicting PPIs in five organisms, specifically humans, yeast, <it>Drosophila</it>, <it>Escherichia coli</it>, and <it>Caenorhabditis elegans</it>. This PPI predictor includes the probability of its prediction in the output, so it can be used to assess the confidence of each SVM prediction by the probability assignment. Using a probability of 0.5 as the threshold for assigning class labels, the method had an average accuracy for detecting protein interactions of 90.67% for humans, 88.99% for yeast, 90.09% for <it>Drosophila</it>, 92.73% for <it>E. coli</it>, and 97.51% for <it>C. elegans</it>. Moreover, among the correctly predicted pairs, more than 80% were predicted with a high probability of ≥0.8, indicating that this tool could predict novel PPIs with high confidence.</p> <p>Conclusions</p> <p>Based on this work, a web-based system, Pred_PPI, was constructed for predicting PPIs from the five organisms. Users can predict novel PPIs and obtain a probability value about the prediction using this tool. Pred_PPI is freely available at <url>http://cic.scu.edu.cn/bioinformatics/predict_ppi/default.html</url>.</p

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Cellular uptake, cytotoxicity and DNA-binding studies of the novel imidazoacridinone antineoplastic agent C1311

C1311 is a novel therapeutic agent with potent activity against experimental colorectal cancer that has been selected for entry into clinical trial. The compound has previously been shown to have DNA-binding properties and to inhibit the catalytic activity of topoisomerase II. In this study, cellular uptake and mechanisms by which C1311 interacts with DNA and exerts cytotoxic effects in intact colon carcinoma cells were investigated. The HT29 colon cancer cell line was chosen to follow cellular distribution of C1311 over a time course of 24 h at drug concentrations that just inhibited cell proliferation by 50% or 100%. Nuclear uptake of C1311 and co-localization with lysosomal or mitochondrial dyes was examined by fluorescence microscopy and effects on these cellular compartments were determined by measurement of acid phosphatase levels, rhodamine 123 release or DNA-binding behaviour. The strength and mode of DNA binding was established by thermal melting stabilization, direct titration and viscometric studies of host duplex length. The onset of apoptosis was followed using a TUNEL assay and DNA-fragmentation to determine a causal relationship of cell death. Growth inhibition of HT29 cells by C1311 was concomitant with rapid drug accumulation in nuclei and in this context we showed that the compound binds to duplex DNA by intercalation, with likely A/T sequence-preferential binding. Drug uptake was also seen in lysosomes, leading to lysosomal rupture and a marked increase of acid phosphatase activity 8 h after exposure to C1311 concentrations that effect total growth inhibition. Moreover, at these concentrations lysosomal swelling and breakdown preceded apoptosis, which was not evident up to 24 h after exposure to drug. Thus, the lysosomotropic effect of C1311 appears to be a novel feature of this anticancer agent. As it is unlikely that C1311-induced DNA damage alone would be sufficient for cytotoxic activity, lysosomal rupture may be a critical component for therapeutic efficacy. © 1999 Cancer Research Campaig

Technology-dependency among patients discharged from a children's hospital: a retrospective cohort study

BACKGROUND: Advances in medical technology may be increasing the population of children who are technology-dependent (TD). We assessed the proportion of children discharged from a children's hospital who are judged to be TD, and determined the most common devices and number of prescription medications at the time of discharge. METHODS: Chart review of 100 randomly selected patients from all services discharged from a children's hospital during the year 2000. Data were reviewed independently by 4 investigators who classified the cases as TD if the failure or withdrawal of the technology would likely have adverse health consequences sufficient to require hospitalization. Only those cases where 3 or 4 raters agreed were classified as TD. RESULTS: Among the 100 randomly sampled patients, the median age was 7 years (range: 1 day to 24 years old), 52% were male, 86% primarily spoke English, and 54% were privately insured. The median length of stay was 3 days (range: 1 to 103 days). No diagnosis accounted for more than 5% of cases. 41% were deemed to be technology dependent, with 20% dependent upon devices, 32% dependent upon medications, and 11% dependent upon both devices and medications. Devices at the time of discharge included gastrostomy and jejeunostomy tubes (10%), central venous catheters (7%), and tracheotomies (1%). The median number of prescription medications was 2 (range: 0–13), with 12% of cases having 5 or more medications. Home care services were planned for 7% of cases. CONCLUSION: Technology-dependency is common among children discharged from a children's hospital

The Multipartite Mitochondrial Genome of Liposcelis bostrychophila: Insights into the Evolution of Mitochondrial Genomes in Bilateral Animals

Booklice (order Psocoptera) in the genus Liposcelis are major pests to stored grains worldwide and are closely related to parasitic lice (order Phthiraptera). We sequenced the mitochondrial (mt) genome of Liposcelis bostrychophila and found that the typical single mt chromosome of bilateral animals has fragmented into and been replaced by two medium-sized chromosomes in this booklouse; each of these chromosomes has about half of the genes of the typical mt chromosome of bilateral animals. These mt chromosomes are 8,530 bp (mt chromosome I) and 7,933 bp (mt chromosome II) in size. Intriguingly, mt chromosome I is twice as abundant as chromosome II. It appears that the selection pressure for compact mt genomes in bilateral animals favors small mt chromosomes when small mt chromosomes co-exist with the typical large mt chromosomes. Thus, small mt chromosomes may have selective advantages over large mt chromosomes in bilateral animals. Phylogenetic analyses of mt genome sequences of Psocodea (i.e. Psocoptera plus Phthiraptera) indicate that: 1) the order Psocoptera (booklice and barklice) is paraphyletic; and 2) the order Phthiraptera (the parasitic lice) is monophyletic. Within parasitic lice, however, the suborder Ischnocera is paraphyletic; this differs from the traditional view that each suborder of parasitic lice is monophyletic

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission