Systems Biology Markup Language (SBML) Level 2: Structures and Facilities for Model Definitions

With the rise of Systems Biology as a new paradigm for understanding biological processes, the development of quantitative models is no longer restricted to a small circle of theoreticians. The dramatic increase in the number of these models precipitates the need to exchange and reuse both existing and newly created models. The Systems Biology Markup Language (SBML) is a free, open, XML-based format for representing quantitative models of biological interest that advocates the consistent specification of such models and thus facilitates both software development and model exchange.

Principally oriented towards describing systems of biochemical reactions, such as cell signalling pathways, metabolic networks and gene regulation etc., SBML can also be used to encode any kinetic model. SBML offers mechanisms to describe biological components by means of compartments and reacting species, as well as their dynamic behaviour, using reactions, events and arbitrary mathematical rules. SBML also offers all the housekeeping structures needed to ensure an unambiguous understanding of quantitative descriptions.

This is Release 1 of the specification for SBML Level 2 Version 4, describing the structures of the language and the rules used to build a valid model. SBML XML Schema and other related documents and software are also available from the SBML project web site, "http://sbml.org/":http://sbml.org/

Systems Biology Markup Language (SBML) Level 2: Structures and Facilities for Model Definitions

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Mammalian Sperm Motility: Observation and Theory

Mammalian spermatozoa motility is a subject of growing importance because of rising human infertility and the possibility of improving animal breeding. We highlight opportunities for fluid and continuum dynamics to provide novel insights concerning the mechanics of these specialized cells, especially during their remarkable journey to the egg. The biological structure of the motile sperm appendage, the flagellum, is described and placed in the context of the mechanics underlying the migration of mammalian sperm through the numerous environments of the female reproductive tract. This process demands certain specific changes to flagellar movement and motility for which further mechanical insight would be valuable, although this requires improved modeling capabilities, particularly to increase our understanding of sperm progression in vivo. We summarize current theoretical studies, highlighting the synergistic combination of imaging and theory in exploring sperm motility, and discuss the challenges for future observational and theoretical studies in understanding the underlying mechanics.\ud Acronyms and Definitions\ud Acrosome: the cap of the sperm head containing enzymes allowing penetration of the zona pellucida via the acrosome reaction\ud Adenosine triphosphate (ATP): the currency unit of chemical energy transfer in living cells\ud Axoneme: a phylogenetically conserved structure within the eukaryotic flagellum consisting of a ring of nine microtubule doublets and a central pair, frequently referred to as 9 + 2\ud Bending moment density: the moment per unit length associated with flagellar bending; it can be divided into a hydrodynamic moment, an elastic moment (from the flagellar bending stiffness), an active moment (generated by dyneins exerting forces between adjacent microtubule doublets), and a passive moment resisting shear\ud Capacitation: the physiological state of a sperm required for fertilization, which is accompanied by the motility patterns associated with hyperactivation, characterized in saline by high-amplitude asymmetric beating\ud Central pair: a pair of microtubules along the length of the axoneme, symmetrically and slightly offset from the axoneme centerline\ud Cumulus oophorus: the outer vestment of the mammalian egg consisting of hundreds of cells radiating out from the egg embedded within a non-Newtonian hyaluronic acid gel\ud Dynein: a molecular motor within the axoneme, attached between adjacent microtubule doublets, that exerts a shearing force to induce axonemal bending\ud Flagellum: a motile cellular appendage that drives the swimming of sperm and other cells; this article focuses on the eukaryotic flagellum\ud Microtubule doublet: a pair of proteinaceous filament structures running the length of the axoneme; dyneins drive their bending, which induces flagellar motion\ud Mid-piece: the region of a sperm flagellum with a mitochondrial sheath, where ATP is generated\ud Oocyte: the egg\ud Outer dense fibers and fibrous sheath: accessory structures reinforcing the mammalian sperm flagellum; the combined axoneme and accessory structures are referred to as 9+9+2\ud Resistive-force theory: an approximation for the local drag of a slender filament element in Stokes flow (or a viscoelastic generalization thereof)\ud Rheotaxis: directed motility in response to the influence of fluid flow\ud Shear: in the context of the flagellum, the relative movement of adjacent microtubule doublets\ud Slender-body theory: an improved approximation for the local drag on a slender filament element in Stokes flow (or a viscoelastic generalization thereof)\ud Zona pellucida: a tough glycoprotein coat between the human egg and the cumulus oophorus, which a sperm must penetrate for successful fertilizatio

Spatiotemporal regulation of ATP and Ca2+ dynamics in vertebrate rod and cone ribbon synapses

PurposeIn conventional neurons, Ca2+ enters presynaptic terminals during an action potential and its increased local concentration triggers transient exocytosis. In contrast, vertebrate photoreceptors are nonspiking neurons that maintain sustained depolarization and neurotransmitter release from ribbon synapses in darkness and produce light-dependent graded hyperpolarizing responses. Rods transmit single photon responses with high fidelity, whereas cones are less sensitive and exhibit faster response kinetics. These differences are likely due to variations in presynaptic Ca2+ dynamics. Metabolic coupling and cross-talk between mitochondria, endoplasmic reticulum (ER), plasma membrane Ca2+ ATPase (PMCA), and Na+-Ca2+ exchanger (NCX) coordinately control presynaptic ATP production and Ca2+ dynamics. The goal of our structural and functional studies was to determine the spatiotemporal regulation of ATP and Ca2+ dynamics in rod spherules and cone pedicles.MethodsCentral retina tissue from C57BL/6 mice was used. Laser scanning confocal microscopy (LSCM) experiments were conducted on fixed-frozen vertical sections. Primary antibodies were selected for their tissue/cellular specificity and ability to recognize single, multiple or all splice variants of selected isoforms. Electron microscopy (EM) and 3-D electron tomography (ET) studies used our standard procedures on thin- and thick-sectioned retinas, respectively. Calibrated fluo-3-Ca2+ imaging experiments of dark- and light-adapted rod and cone terminals in retinal slices were conducted.ResultsConfocal microscopy showed that mitochondria, ER, PMCA, and NCX1 exhibited distinct retinal lamination patterns and differential distribution in photoreceptor synapses. Antibodies for three distinct mitochondrial compartments differentially labeled retinal areas with high metabolic demand: rod and cone inner segments, previously undescribed cone juxtanuclear mitochondria and the two plexiform layers. Rod spherule membranes uniformly and intensely stained for PMCA, whereas the larger cone pedicles preferentially stained for NCX1 at their active zones and PMCA near their mitochondria. EM and ET revealed that mitochondria in rod spherules and cone pedicles differed markedly in their number, location, size, volume, and total cristae surface area, and cristae junction diameter. Rod spherules had one large ovoid mitochondrion located near its active zone, whereas cone pedicles averaged five medium-sized mitochondria clustered far from their active zones. Most spherules had one ribbon synapse, whereas pedicles contained numerous ribbon synapses. Fluo-3 imaging studies revealed that during darkness rod spherules maintained a lower [Ca2+] than cone pedicles, whereas during light adaptation pedicles rapidly lowered their [Ca2+] below that observed in spherules.ConclusionsThese findings indicate that ATP demand and mitochondrial ATP production are greater in cone pedicles than rod spherules. Rod spherules employ high affinity/low turnover PMCA and their mitochondrion to maintain a relatively low [Ca2+] in darkness, which increases their sensitivity and signal-to-noise ratio. In contrast, cone pedicles utilize low affinity/high turnover NCX to rapidly lower their high [Ca2+] during light adaptation, which increases their response kinetics. Spatiotemporal fluo-3-Ca2+ imaging results support our immunocytochemical results. The clustering of cone pedicle mitochondria likely provides increased protection from Ca2+ overload and permeability transition. In summary, these novel studies reveal that several integrated cellular and subcellular components interact to regulate ATP and Ca2+ dynamics in rod and cone synaptic terminals. These results should provide a greater understanding of in vivo photoreceptor synaptic terminal exocytosis/endocytosis, Ca2+ overload and therapies for retinal degenerations

CDA Dairy Queen, Inc. v. State Ins. Fund Augmentaion Record Dckt. 38492

https://digitalcommons.law.uidaho.edu/idaho_supreme_court_record_briefs/4549/thumbnail.jp

ICAM-1 transmembrane signaling: involvement of TAXREB107 in ICAM-1-mediated signal transduction

The role of membrane ICAM-1 in intercellular adhesion, through interaction with the leukocyte beta2 integrin receptors LFA-1 and Mac-1, is well established. However, until recently, ICAM-1 was widely regarded as being simply an anchor molecule, promoting, for example, firm adhesion of lymphocytes to vascular endothelial cells. The demonstration that ICAM-1 is connected to the actin-based cytoskeleton through interactions with subcortical actin-binding proteins, such as alpha-actinin, enhanced this concept. However, ICAM-1 has been increasingly shown to have signaling properties of its own. Engagement of ICAM-1 extracellularly, either through its natural counter-receptors, LFA-1/Mac-1, or through antibody mediated clustering, can produce numerous changes within the cell. Recent evidence now confirms that ICAM-1 crosslinking induces multiple activation responses including: (1) phosphorylation of several cytoplasmic proteins, including cortactin, cdc2 kinase and lyn kinase; (2) activation of the Erk 1/2 MAP kinases; and (3) induction of various functional cellular responses such as oxidative burst from mononuclear leukocytes, neutrophil activation, and rho activation in endothelial cells. Although we know of several downstream targets of ICAM-1 engagement, very little is known about upstream events, i.e., the most proximal components of the signaling cascade involving direct protein interactions with the ICAM-1 cytodomain, or through indirect interactions in a multimeric unit.The specific aim of this project is to study the proximal aspects of ICAM-1 signaling. The hypothesis is that ICAM-1-mediated signal transduction requires interactions between currently unidentified intracellular proteins and the cytoplasmic domain of ICAM-1. In these studies, TAXREB107, a recently discovered protein, was specifically associated with the ICAM-1 cytodomain in GST-pulldown experiments using human endothelial cell extracts. This association was biochemically confirmed by co-immunoprecipitations of recombinantly expressed TAXREB107 and the ICAM-1 cytodomain, as well as endogenous TAXREB107 and ICAM-1. Recombinant TAXREB107, expressed in a wide spectrum of mammalian cell types, greatly augmented the ERK 1/2 MAPK activation induced by activating antibody or natural ligand (fibrinogen) engagement of ICAM-1. This amplifying effect was abolished by co-expression of the ICAM-1, but not VCAM-1 cytodomain. Furthermore, immunofluorescence studies demonstrated that TAXREB107, which possesses DNA-binding capability, is predominantly located in the cytoplasm in non-activated CHO or human endothelial cells, and rapidly translocates to the nucleus upon ICAM-1 engagement. These data demonstrate an interaction between the ICAM-1 cytoplasmic tail and TAXREB107, and support that this interaction can lead to a productive amplification of proximal ICAM-1-mediated signaling. This may consequently stimulate gene expression of TAXREB-responsive genes or promote a spectrum of ERK-mediated cellular responses, also including gene activation

Systems Biology Markup Language (SBML) Level 2: Structures and Facilities for Model Definitions

We present the Systems Biology Markup Language (SBML) SBML Level 2 Version 2, a model representation formalism for systems biology. SBML is oriented towards describing systems of biochemical reactions of the sort common in research on a number of topics, including cell signaling pathways, metabolic pathways, biochemical reactions, gene regulation, and many others. SBML is defined in a neutral fashion with respect to programming languages and software encoding; however, it is primarily oriented towards allowing models to be encoded using XML, the eXtensible Markup Language (Bosak and Bray, 1999; Bray et al., 2000). This document contains many examples of SBML models written in XML, as well as the text of an XML Schema (Biron and Malhotra, 2000; Fallside, 2000; Thompson et al., 2000) that defines SBML Level 2 Version 2. A downloadable copy of the XML Schema and other related documents and software are also available from the SBML project web site, http://sbml.org/. The SBML project is not an attempt to define a universal language for representing quantitative models. The rapidly evolving views of biological function, coupled with the vigorous rates at which new computational techniques and individual tools are being developed today, are incompatible with a one-size-fits-all idea of a universal language. A more realistic alternative is to acknowledge the diversity of approaches and methods being explored by different software tool developers, and seek a common intermediate format—a lingua franca—enabling communication of the most essential aspects of the models. The definition of the model description language presented here does not specify how programs should communicate or read/write SBML. We assume that for a simulation program to communicate a model encoded in SBML, the program will have to translate its internal data structures to and from SBML, use a suitable transmission medium and protocol, etc., but these issues are outside of the scope of this document

Evaluation of an Immunochromatographic Lateral Flow Assay (OXA-48 K-SeT) for Rapid Detection of OXA-48-Like Carbapenemases in Enterobacteriaceae

We evaluated an immunochromatographic lateral flow assay for the detection of OXA-48-like carbapenemases (OXA-48 K-SeT) in Enterobacteriaceae (n=82). 100% sensitivity and specificity was observed using bacteria recovered from both solid media and spiked blood culture bottles, with the result obtained in less than 10 minutes

Role of quantum chemical calculations in molecular biophysics with a historical perspective

We discuss how the basic principles of quantum chemistry and quantum mechanics can be and have been applied to a variety of problems in molecular biophysics. First, the historical development of quantum concepts in biophysics is discussed. Next, we describe a series of interesting applications of quantum chemical methods for studying biologically active molecules, molecular structures, and some of the important processes which play a role in living organisms. We discuss the application of quantum chemistry to such processes as energy storage and transformation, and the transmission of genetic information. Quantum chemical approaches are essential to comprehend and understand the molecular nature of these processes. To conclude our work, we present a short discussion of the perspectives of quantum chemical methods in modern biophysics, the field of experimental and theoretical chiral vibrational and electronic spectroscopy