Predicting Secondary Structures, Contact Numbers, and Residue-wise Contact Orders of Native Protein Structure from Amino Acid Sequence by Critical Random Networks

Prediction of one-dimensional protein structures such as secondary structures and contact numbers is useful for the three-dimensional structure prediction and important for the understanding of sequence-structure relationship. Here we present a new machine-learning method, critical random networks (CRNs), for predicting one-dimensional structures, and apply it, with position-specific scoring matrices, to the prediction of secondary structures (SS), contact numbers (CN), and residue-wise contact orders (RWCO). The present method achieves, on average, $Q_3$ accuracy of 77.8% for SS, correlation coefficients of 0.726 and 0.601 for CN and RWCO, respectively. The accuracy of the SS prediction is comparable to other state-of-the-art methods, and that of the CN prediction is a significant improvement over previous methods. We give a detailed formulation of critical random networks-based prediction scheme, and examine the context-dependence of prediction accuracies. In order to study the nonlinear and multi-body effects, we compare the CRNs-based method with a purely linear method based on position-specific scoring matrices. Although not superior to the CRNs-based method, the surprisingly good accuracy achieved by the linear method highlights the difficulty in extracting structural features of higher order from amino acid sequence beyond that provided by the position-specific scoring matrices.Comment: 20 pages, 1 figure, 5 tables; minor revision; accepted for publication in BIOPHYSIC

Ultrastructural study of the effects of tranexamic acid and urokinase on metastasis of Lewis lung carcinoma.

Lewis lung carcinoma cells were implanted in the foot-pads of mice and the effects of the plasminogen-plasmin inhibitor tranexamic acid (t-AMCHA) and of the plasminogen activator urokinase on metastasis were examined by electron microscopy. The intravascular tumour cells were not associated with thrombus formation in either control or urokinase-treated mice. Polymerized fibrin deposition around tumour cells and thrombi composed of fibrin and platelets was observed only in the mice given t-AMCHA. This suggests that the inhibition of fibrinolysis by tACC caused fibrin deposition and thrombus formation around intravascular tumour cells, which prevented release of the cells from primary foci to form secondary tumours. On the other hand, fibrinolysis induced by urokinase prevented thrombus formation, and accelerated cell release from primary foci

Fast and efficient critical state modelling of field-cooled bulk high-temperature superconductors using a backward computation method

Abstract: A backward computation method has been developed to accelerate modelling of the critical state magnetization current in a staggered-array bulk high-temperature superconducting (HTS) undulator. The key concept is as follows: (i) a large magnetization current is first generated on the surface of the HTS bulks after rapid field-cooling (FC) magnetization; (ii) the magnetization current then relaxes inwards step-by-step obeying the critical state model; (iii) after tens of backward iterations the magnetization current reaches a steady state. The simulation results show excellent agreement with the H -formulation method for both the electromagnetic and electromagnetic-mechanical coupled analyses, but with significantly faster computation speed. The simulation results using the backward computation method are further validated by the recent experimental results of a five-period Gd–Ba–Cu–O (GdBCO) bulk undulator. Solving the finite element analysis (FEA) model with 1.8 million degrees of freedom (DOFs), the backward computation method takes less than 1.4 h, an order of magnitude or higher faster than other state-of-the-art numerical methods. Finally, the models are used to investigate the influence of the mechanical stress on the distribution of the critical state magnetization current and the undulator field along the central axis

SPRITE and ASSAM: web servers for side chain 3D-motif searching in protein structures

Similarities in the 3D patterns of amino acid side chains can provide insights into their function despite the absence of any detectable sequence or fold similarities. Search for protein sites (SPRITE) and amino acid pattern search for substructures and motifs (ASSAM) are graph theoretical programs that can search for 3D amino side chain matches in protein structures, by representing the amino acid side chains as pseudo-atoms. The geometric relationship of the pseudo-atoms to each other as a pattern can be represented as a labeled graph where the pseudo-atoms are the graph's nodes while the edges are the inter-pseudo-atomic distances. Both programs require the input file to be in the PDB format. The objective of using SPRITE is to identify matches of side chains in a query structure to patterns with characterized function. In contrast, a 3D pattern of interest can be searched for existing occurrences in available PDB structures using ASSAM. Both programs are freely accessible without any login requirement. SPRITE is available at http://mfrlab.org/grafss/sprite/while ASSAM can be accessed at http://mfrlab.org/grafss/assam/

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

CREB is a critical regulator of normal hematopoiesis and leukemogenesis

The cAMP-responsive element binding protein (CREB) is a 43-kDa nuclear transcription factor that regulates cell growth, memory, and glucose homeostasis. We showed previously that CREB is amplified in myeloid leukemia blasts and expressed at higher levels in leukemia stem cells from patients with myeloid leukemia. CREB transgenic mice develop myeloproliferative disease after 1 year, but not leukemia, suggesting that CREB contributes to but is not sufficient for leukemogenesis. Here, we show that CREB is most highly expressed in lineage negative hematopoietic stem cells (HSCs). To understand the role of CREB in hematopoietic progenitors and leukemia cells, we examined the effects of RNA interference (RNAi) to knock down CREB expression in vitro and in vivo. Transduction of primary HSCs or myeloid leukemia cells with lentiviral CREB shRNAs resulted in decreased proliferation of stem cells, cell- cycle abnormalities, and inhibition of CREB transcription. Mice that received transplants of bone marrow transduced with CREB shRNA had decreased committed progenitors compared with control mice. Mice injected with Ba/F3 cells expressing either Bcr-Abl wild-type or T315I mutation with CREB shRNA had delayed leukemic infiltration by bioluminescence imaging and prolonged median survival. Our results suggest that CREB is critical for normal myelopoiesis and leukemia cell proliferation

Unique Interplay between Sugar and Lipid in Determining the Antigenic Potency of Bacterial Antigens for NKT Cells

Structural and biophysical studies reveal the induced-fit mechanism underlying the stringent specificity of invariant natural killer T cells for unique glycolipid antigens from the pathogen Streptococcus pneumoniae

Inverse analysis of critical current density in a bulk high-temperature superconducting undulator

In order to optimise the design of undulators using high-temperature superconductor (HTS) bulks we have developed a method to estimate the critical current density (Jc) of each bulk from the overall measured magnetic field of an undulator. The vertical magnetic field was measured along the electron-beam axis in a HTS bulk-based undulator consisting of twenty Gd-Ba-Cu-O (GdBCO) bulks inserted in a 12-T solenoid. The Jc values of the bulks were estimated by an inverse analysis approach in which the magnetic field was calculated by the forward simulation of the shielding currents in each HTS bulk with a given Jc. Subsequently the Jc values were iteratively updated using the pre-calculated response matrix of the undulator magnetic field to Jc. We demonstrate that it is possible to determine the Jc of each HTS bulk with sufficient accuracy for practical application within around 10 iterations. The pre-calculated response matrix, created in advance, enables the inverse analysis to be performed within a practically short time, on the order of several hours. The measurement error, which destroys the uniqueness of the solution, was investigated and the points to be noted for future magnetic field measurements were clarified. The results show that this inverse-analysis method allows the estimation of the Jc of each bulk comprising an HTS bulk undulator.CHART (Swiss Accelerator Research and Technology Collaboration); EPSRC Early Career Fellowship, EP/P020313/