Using the canonical modelling approach to simplify the simulation of function in functional-structural plant models

Functional-structural plant models that include detailed mechanistic representation of underlying physiological processes can be expensive to construct and the resulting models can also be extremely complicated. On the other hand, purely empirical models are not able to simulate plant adaptability and response to different conditions. In this paper, we present an intermediate approach to modelling plant function that can simulate plant response without requiring detailed knowledge of underlying physiology. Plant function is modelled using a 'canonical' modelling approach, which uses compartment models with flux functions of a standard mathematical form, while plant structure is modelled using L-systems. Two modelling examples are used to demonstrate that canonical modelling can be used in conjunction with L-systems to create functional-structural plant models where function is represented either in an accurate and descriptive way, or in a more mechanistic and explanatory way. We conclude that canonical modelling provides a useful, flexible and relatively simple approach to modelling plant function at an intermediate level of abstraction.

Functional-structural plant modelling using a combination of architectural analysis, L-systems and a canonical model of function

This paper presents a new method for producing a functional-structural plant model that simulates response to different growth conditions, yet does not require detailed knowledge of underlying physiology. The example used to present this method is the modelling of the mountain birch tree. This new functional-structural modelling approach is based on linking an L-system representation of the dynamic structure of the plant with a canonical mathematical model of plant function. Growth indicated by the canonical model is allocated to the structural model according to probabilistic growth rules, such as rules for the placement and length of new shoots, which were derived from an analysis of architectural data. The main advantage of the approach is that it is relatively simple compared to the prevalent process-based functional-structural plant models and does not require a detailed understanding of underlying physiological processes, yet it is able to capture important aspects of plant function and adaptability, unlike simple empirical models. This approach, combining canonical modelling, architectural analysis and L-systems, thus fills the important role of providing an intermediate level of abstraction between the two extremes of deeply mechanistic process-based modelling and purely empirical modelling. We also investigated the relative importance of various aspects of this integrated modelling approach by analysing the sensitivity of the standard birch model to a number of variations in its parameters, functions and algorithms. The results show that using light as the sole factor determining the structural location of new growth gives satisfactory results. Including the influence of additional regulating factors made little difference to global characteristics of the emergent architecture. Changing the form of the probability functions and using alternative methods for choosing the sites of new growth also had little effect. (c) 2004 Elsevier B.V. All rights reserved.

Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function

The mammalian transcriptome contains many nonprotein-coding RNAs (ncRNAs), but most of these are of unclear significance and lack strong sequence conservation, prompting suggestions that they might be non-functional. However, certain long functional ncRNAs such as Air and Xist are also poorly conserved. In this article, we systematically analyzed the conservation of several groups of functional ncRNAs, including miRNAs, snoRNAs and longer ncRNAs whose function has been either documented or confidently predicted. As expected, miRNAs and snoRNAs were highly conserved. By contrast, the longer functional non-micro, non-sno ncRNAs were much less conserved with many displaying rapid sequence evolution. Our findings suggest that longer ncRNAs are under the influence of different evolutionary constraints and that the lack of conservation displayed by the thousands of candidate ncRNAs does not necessarily signify an absence of function.

Expression and role of complex carbohydrates in axon guidance in the olfactory system

Primary sensory neurons in the vertebrate olfactory systems are characterised by the differential expression of distinct cell surface carbohydrates. We show here that the histo-blood groups Sda (or CT1 antigen) and H are expressed by primary sensory neurons in the olfactory system, while the blood group A carbohydrate is expressed by a subset of vomeronasal neurons only in the developing accessory olfactory system. We have used both loss-of-function and gain-of-function approaches to manipulate expression of these carbohydrates in the olfactory system. In null mutant mice lacking the alpha(1,2)fucosyltransferase FUT1, the blood group H and A carbohydrates were not expressed in the olfactory systems which caused delayed development of the nerve fibre and glomerular layers in the main olfactory bulb. In contrast, ubiquitous expression of blood group A on olfactory axons in gain-of-function transgenic mice perturbed the ability of vomeronasal axons to terminate in the accessory olfactory bulb and affected the selective targeting of axons in the main olfactory bulb. During regeneration following bulbectomy, vomeronasal axons were unable to effectively sort out from the main olfactory axons when blood group A was misexpressed. These results provide in vivo evidence for a role of specific cell surface carbohydrates during development and regeneration of the olfactory nerve pathways.

Genetic manipulation of blood group carbohydrates alters development and pathfinding of primary sensory axons of the olfactory systems

Primary sensory neurons in the vertebrate olfactory systems are characterised by the differential expression of distinct cell surface carbohydrates. We show here that the histo-blood group H carbohydrate is expressed by primary sensory neurons in both the main and accessory olfactory systems while the blood group A carbohydrate is expressed by a subset of vomeronasal neurons in the developing accessory olfactory system. We have used both loss-of-function and gain-of-function approaches to manipulate expression of these carbohydrates in the olfactory system. In null mutant mice lacking the alpha(1,2)fucosyltransferase FUT1, the absence of blood group H carbohydrate resulted in the delayed maturation of the glomerular layer of the main olfactory bulb. In addition, ubiquitous expression of blood group A on olfactory axons in gain-of-function transgenic mice caused mis-routing of axons in the glomerular layer of the main olfactory bulb and led to exuberant growth of vomeronasal axons in the accessory olfactory bulb. These results provide in vivo evidence for a role of specific cell surface carbohydrates during development of the olfactory nerve pathways. (c) 2006 Elsevier Inc. All rights reserved.

A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin--Vps17p--is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.

Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo

Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane-bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) × Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system.

Achievable performance gain of IEEE 802.11 multi-rate link adaptation algorithm with cross-layer design

Link quality-based rate adaptation has been widely used for IEEE 802.11 networks. However, network performance is affected by both link quality and random channel access. Selection of transmit modes for optimal link throughput can cause medium access control (MAC) throughput loss. In this paper, we investigate this issue and propose a generalised cross-layer rate adaptation algorithm. It considers jointly link quality and channel access to optimise network throughput. The objective is to examine the potential benefits by cross-layer design. An efficient analytic model is proposed to evaluate rate adaptation algorithms under dynamic channel and multi-user access environments. The proposed algorithm is compared to link throughput optimisation-based algorithm. It is found rate adaptation by optimising link layer throughput can result in large performance loss, which cannot be compensated by the means of optimising MAC access mechanism alone. Results show cross-layer design can achieve consistent and considerable performance gains of up to 20%. It deserves to be exploited in practical design for IEEE 802.11 networks.

A novel role of plasma membrane calcium atpase 4 as a negative-regulator of VEGF-induced angiogenesis

Current anti-angiogenic treatments involve the attenuation of signalling via the pro-angiogenic vascular endothelial growth factor/receptor (VEGF/VEGFR) axis. Stimulation of angiogenesis by VEGF requires the activation of the calcineurin/nuclear factor of activated T-cells (NFAT) signal transduction pathway which is inhibited by Plasma Membrane Calcium ATPase 4 (PMCA4), an endogenous calcium extrusion pump. However, PMCA4s role in calcineurin/NFAT-dependent angiogenesis is unknown. Using “gain of function” studies, we show here that adenoviral overexpression of PMCA4 in human umbilical vein endothelial cells (HUVEC) inhibited NFAT activity, decreased the expression of NFAT-dependent pro-angiogenic proteins (regulator of calcineurin 1.4 (RCAN1.4) and cyclooxygenase-2) and diminished in vitro cell migration and tube formation in response to VEGF-stimulation. Furthermore, in vivo blood vessel formation was attenuated in a matrigel plug assay by ectopic expression of PMCA4. Conversely, “loss of function” experiments by si-RNA-mediated knockdown of PMCA4 in HUVEC or isolation of mouse lung endothelial cells from PMCA4−/− mice showed increased VEGF-induced NFAT activity, RCAN1.4 expression, in vitro endothelial cell migration, tube formation and in vivo blood vessel formation. Additionally, in an in vivo pathological angiogenesis model of limb ischemia, the reperfusion of the ischemic limb of PMCA4−/− mice was augmented compared to wild-type. Disruption of the interaction between endogenous PMCA4 and calcineurin by adenoviral overexpression of the region of PMCA4 that interacts with calcineurin (residues 428–651) increased NFAT activity, RCAN1.4 protein expression and in vitro tube formation. These results identify PMCA4 as an inhibitor of VEGF-induced angiogenesis, highlighting its potential as a new therapeutic target for anti-angiogenic treatments.

Molecular Mechanisms Involved in Regulating the Mucoid-to-Nonmucoid Conversion of Pseudomonas aeruginosa Associated with Cystic Fibrosis Patients

Pseudomonas aeruginosa is an opportunistic pathogen that has received attention because of its close association with cystic fibrosis (CF). Chronic pulmonary infection with the mucoid P. aeruginosa is the leading cause of mortality in CF patients. This bacterium has the ability to sense and adapt to the harsh environment in the CF lung by converting from a nonmucoid to a mucoid state. The mucoid phenotype is caused by overproduction of a polysaccharide called alginate. Alginate production is regulated by the algT/U operon containing five genes, algT/U-mucA-mucB-mucC-mucD. Alginate overproduction in CF isolates has been partially attributed to a loss-of-function mutation in mucA that results in the overexpression of algT. This mucoid phenotype is unstable, reverting to the nonmucoid form when the isolates are cultured outside of the CF lung. This study was undertaken to determine the mechanisms involved in the conversion from the mucoid to the nonmucoid form. Thirty-six spontaneous nonmucoid variants of a known mucoid isolate with a mucA mutation were analyzed. Ten of these isolates were complemented in trans by plasmids containing the algT operon and the algT gene. Chromosomal DNA was extracted and the mucA and algT genes were amplified by the polymerase chain reaction. Sequence analysis of the genes showed that these mutants retained the original mucA mutation but acquired secondary mutations in the algT gene.

A loss-of-function allele of OsHMA3 associated with high cadmium accumulation in shoots and grain of Japonica rice cultivars

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Position measurements at five permanent GPS stations in the Bavarian Alps as part of the Geodetic Alpine Integrated Network (GAIN) of the ALPS-GPSQUAKENET project

In the frame of the transnational ALPS-GPSQUAKENET project, a component of the Alpine Space Programme of the European Community Initiative Programme (CIP) INTERREG III B, the Deutsches Geodätisches Forschungsinstitut (DGFI) in Munich, Germany, installed in 2005 five continuously operating permanent GPS stations located along the northern Alps boundary in Bavaria. The main objective of the ALPS-GPSQUAKENET project was to build-up a high-performance transnational space geodetic network of Global Positioning System (GPS) receivers in the Alpine region (the so-called Geodetic Alpine Integrated Network, GAIN). Data from this network allows for studying crustal deformations in near real-time to monitor Earthquake hazard and improve natural disaster prevention. The five GPS stations operatied by DGFI are mounted on concrete pillars attached to solid rock. The names of the stations are (from west to east) Hochgrat (HGRA), Breitenberg (BREI), Fahrenberg (FAHR), Hochries (HRIE) and Wartsteinkopf (WART). The provided data series start from October 7, 2005. Data are stored with a temporal spacing of 15 seconds in daily RINEX files.

A Rare Loss-of-Function Variant in Scavenger Receptor Class B Type I (SCARB1) Raises HDL Cholesterol and Increases Risk of Coronary Disease

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL)
cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a
lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI
knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased
atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains
unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328
individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function
variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene
encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and
abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells
derived from induced pluripotent stem cells from the homozygous subject, and in mice.
Large population-based studies revealed that subjects who are heterozygous carriers of
the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have
a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is
statistically significant).