A pattern-based approach to a cell tracking ontology

Time-lapse microscopy has thoroughly transformed our understanding of biological motion and developmental dynamics from single cells to entire organisms. The increasing amount of cell tracking data demands the creation of tools to make extracted data searchable and interoperable between experiment and data types. In order to address that problem, the current paper reports on the progress in building the Cell Tracking Ontology (CTO): An ontology framework for describing, querying and integrating data from complementary experimental techniques in the domain of cell tracking experiments. CTO is based on a basic knowledge structure: the cellular genealogy serving as a backbone model to integrate specific biological ontologies into tracking data. As a first step we integrate the Phenotype and Trait Ontology (PATO) as one of the most relevant ontologies to annotate cell tracking experiments. The CTO requires both the integration of data on various levels of generality as well as the proper structuring of collected information. Therefore, in order to provide a sound foundation of the ontology, we have built on the rich body of work on top-level ontologies and established three generic ontology design patterns addressing three modeling challenges for properly representing cellular genealogies, i.e. representing entities existing in time, undergoing changes over time and their organization into more complex structures such as situations

Three dimensional shape comparison of flexible proteins using the local-diameter descriptor

<p>Abstract</p> <p>Background</p> <p>Techniques for inferring the functions of the protein by comparing their shape similarity have been receiving a lot of attention. Proteins are functional units and their shape flexibility occupies an essential role in various biological processes. Several shape descriptors have demonstrated the capability of protein shape comparison by treating them as rigid bodies. But this may give rise to an incorrect comparison of flexible protein shapes.</p> <p>Results</p> <p>We introduce an efficient approach for comparing flexible protein shapes by adapting a <it>local diameter </it>(LD) <it>descriptor</it>. The LD descriptor, developed recently to handle skeleton based shape deformations <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>, is adapted in this work to capture the invariant properties of shape deformations caused by the motion of the protein backbone. Every sampled point on the protein surface is assigned a value measuring the diameter of the 3D shape in the neighborhood of that point. The LD descriptor is built in the form of a one dimensional histogram from the distribution of the diameter values. The histogram based shape representation reduces the shape comparison problem of the flexible protein to a simple distance calculation between 1D feature vectors. Experimental results indicate how the LD descriptor accurately treats the protein shape deformation. In addition, we use the LD descriptor for protein shape retrieval and compare it to the effectiveness of conventional shape descriptors. A sensitivity-specificity plot shows that the LD descriptor performs much better than the conventional shape descriptors in terms of consistency over a family of proteins and discernibility across families of different proteins.</p> <p>Conclusion</p> <p>Our study provides an effective technique for comparing the shape of flexible proteins. The experimental results demonstrate the insensitivity of the LD descriptor to protein shape deformation. The proposed method will be potentially useful for molecule retrieval with similar shapes and rapid structure retrieval for proteins. The demos and supplemental materials are available on <url>https://engineering.purdue.edu/PRECISE/LDD</url>.</p

Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins

Major histocompatibility complex class I molecules (MHC I) present peptides to cytotoxic T-cells at the surface of almost all nucleated cells. The function of MHC I molecules is to select high affinity peptides from a large intracellular pool and they are assisted in this process by co-factor molecules, notably tapasin. In contrast to mammals, MHC homozygous chickens express a single MHC I gene locus, termed BF2, which is hypothesised to have co-evolved with the highly polymorphic tapasin within stable haplotypes. The BF2 molecules of the B15 and B19 haplotypes have recently been shown to differ in their interactions with tapasin and in their peptide selection properties. This study investigated whether these observations might be explained by differences in the protein plasticity that is encoded into the MHC I structure by primary sequence polymorphisms. Furthermore, we aimed to demonstrate the utility of a complimentary modelling approach to the understanding of complex experimental data. Combining mechanistic molecular dynamics simulations and the primary sequence based technique of statistical coupling analysis, we show how two of the eight polymorphisms between BF2*15:01 and BF2*19:01 facilitate differences in plasticity. We show that BF2*15:01 is intrinsically more plastic than BF2*19:01, exploring more conformations in the absence of peptide. We identify a protein sector of contiguous residues connecting the membrane bound ?3 domain and the heavy chain peptide binding site. This sector contains two of the eight polymorphic residues. One is residue 22 in the peptide binding domain and the other 220 is in the ?3 domain, a putative tapasin binding site. These observations are in correspondence with the experimentally observed functional differences of these molecules and suggest a mechanism for how modulation of MHC I plasticity by tapasin catalyses peptide selection allosterically

Connectable Components for Protein Design

Protein design requires reusable, trustworthy, and connectable parts in order to scale to complex challenges. The recent explosion of protein structures stored within the Protein Data Bank provides a wealth of small motifs we can harvest, but we still lack tools to combine them into larger proteins. Here I explore two approaches for connecting reusable protein components on two different length scales. On the atomic scale, I build an interactive search engine for connecting chemical fragments together. Protein fragments built using this search engine recapitulate native-like protein assemblies that can be integrated into existing protein scaffolds using backbone search engines such as MaDCaT. On the protein domain scale, I quantitatively dissect structural variations in two-component systems in order to extract general principles for engineering interfacial flexibility between modular four-helix bundles. These bundles exhibit large scissoring motions where helices move towards or away from the bundle axis and these motions propagate across domain boundaries. Together, these two approaches form the beginnings of a multiscale methodology for connecting reusable protein fragments where there is a constant interplay and feedback between design of atomic structure, secondary structure, and tertiary structure. Rapid iteration, visualization, and search glue these diverse length scales together into a cohesive whole

c-di-GMP modulates type IV MSHA pilus retraction and surface attachment in Vibrio cholerae.

Biofilm formation by Vibrio cholerae facilitates environmental persistence, and hyperinfectivity within the host. Biofilm formation is regulated by 3',5'-cyclic diguanylate (c-di-GMP) and requires production of the type IV mannose-sensitive hemagglutinin (MSHA) pilus. Here, we show that the MSHA pilus is a dynamic extendable and retractable system, and its activity is directly controlled by c-di-GMP. The interaction between c-di-GMP and the ATPase MshE promotes pilus extension, whereas low levels of c-di-GMP correlate with enhanced retraction. Loss of retraction facilitated by the ATPase PilT increases near-surface roaming motility, and impairs initial surface attachment. However, prolonged retraction upon surface attachment results in reduced MSHA-mediated surface anchoring and increased levels of detachment. Our results indicate that c-di-GMP directly controls MshE activity, thus regulating MSHA pilus extension and retraction dynamics, and modulating V. cholerae surface attachment and colonization

Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis.

The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy