34 research outputs found
(1+1) REMPI spectroscopy and high-level ab initio study of the complex formed between NO and CO
No full text
Retracted. A theoretical study of the ligand-exchange reactions of Na+·X complexes (X = O, O-2, N-2, CO2 and H2O): implications for the upper atmosphere (vol 64, pg 863, 2002)
No full textThis article has been retracted at the request of the editor.Reason: The publisher regrets that several errors appeared in this paper and that it therefore has been retracted. A correct version of the complete paper has been published in Volume 64, Issue 7, pages 863–870 of the Journal of Atmospheric and Solar-Terrestrial Physics
The (A)over-tilde <-(X)over-tilde(1+1)REMPI spectrum and high-level ab initio calculations of the complex between NO and N-2
No full textThe results of two separate studies of the complex between NO and N-2 are reported. The (1+1) REMPI spectrum of the (A) over tilde <--(X) over tilde transition of the complex between NO and N-2 is presented of improved quality over that reported previously, and the appearance of the spectrum is discussed. The results of high-level ab initio calculations [RCCSD(T)/aug-cc-pVQZ//QCISD/6-311+G(2d)] on the (X) over tilde (2)Pi state are also reported. The indications are that the NO moiety is more freely rotating in the complex than is N-2, and that a wide angular space is sampled in the zero-point energy level. The appearance of the REMPI spectrum suggests that the (A) over tilde (2)Sigma (+) state is (close to) linear, and RCCSD(T)//QCISD calculations on the (A) over tilde state, using Rydberg-function-augmented basis sets, suggest that the lowest energy linear isomer is the ON .N-2 linear orientation. It is clear, however, that the understanding of this complex, and its spectroscopy, is far from complete, and will be challenging
Mind the Gap: Modeling Synaptic Development and Degeneration in Caenorhabditis elegans
No full textThe nervous system is composed of a complex network of neural circuits, relying on synaptic connections throughout to ensure proper signal transmission. Disorders of the nervous system typically fall into two categories, developmental disorders, failure of the system to properly form circuits, or senile disorders, failure of the system to properly maintain their circuits. As such, the formation, modification, and maintenance of synaptic connections is crucial to nervous system function, and a failure in any stage may lead to disease. Here we will use C. elegans to look at both sides of the process, examining the molecules important in the development of synapses, as well as examining the consequences on synaptic maintenance found in tauopathies, a class of neurodegenerative disorders. Synaptic development is a multi-step dynamic process, relying on a precise balance between adhesion-mediated stability and calcium-driven expansion. In chapter III, we show that synaptic expansion relies on the presence of the C. elegans ortholog of the calcium and integrin binding protein, CALM-1. We show that mutations in a predictive phosphorylation site of CALM-1 result in over-elongated synapses, suggesting that phosphorylation of CALM-1 might be necessary for proper synaptic growth and maintenance. In chapter IV, we show that the C. elegans neuromuscular junction can be used to model tauopathies, a subset of neurodegenerative disorders defined by the presence of abnormally aggregated clusters of tau. We show that expression of wildtype human 2N4R tau protein in the GABAergic motor neurons is well-tolerated, with no effects on synapse size, shape, or number. In contrast, expression of two mutated variants of human tau, a known disease-causing variant, P301, and an aggressively assembling variant, 3PO, induced progressive synaptic loss associated with the animal aging, notably without causing other forms of neurodegeneration, such as cell death or axon degradation. We show that synaptic loss is not merely a loss of vesicle trafficking, as use of another marker for synaptic active zones also demonstrated progressive synaptic loss in tau variant animals. Finally, we show that synaptic loss is not limited to the GABAergic motor neurons, as expression of mutant tau in another subset of neurons, the cholinergic neurons, also induced progressive synaptic loss. In Chapter V we look to further expand our model, by examining the consequences of genetic and chemical modifiers on the synaptic loss phenotype shown in mutant tau variants. We show that our model of synaptic degeneration can be used to screen genetic risk factors for tauopathies, as loss of function of a proposed Alzheimer’s disease risk factor, ptp-3, strongly enhanced the synaptic loss seen in tau mutant animals. We also show that expression of a risk factor for a primary tauopathy, Progressive Supranuclear Palsy, induced axon defects that were significantly enhanced by the presence of P301 tau, indicating the utility of our model to look beyond just synaptic consequences of tauopathy risk factors. Additionally, we show that our model can be used to screen for chemical modifiers of tauopathies, as we show that treatment of animals with a proposed tau aggregation inhibitor, ANTC15, partially rescues the synaptic loss in 3PO and P301 animals. Finally, in Chapter VI we begin to examine potential mechanisms of tau-mediated synaptic degeneration. We show that synaptic loss is not due to interference with the endogenous C. elegans tau-like protein, ptl-1, and that disruption of the normal method of calcium driven synaptic expansion does not significantly alter the synaptic loss phenotype, suggesting that the loss of synapses is a result of a toxic gain of function consequence of the addition of the mutated tau variants. Finally, we show that any interference with microtubule stability, through the over stabilization or destabilization of tubulin, is sufficient to induce a progressive decrease in synapses, suggesting that the synaptic loss seen in tau mutant animals may be a result of the mutation interfering with tau’s ability to bind and stabilize microtubules. Overall, this report strengthens our understanding of synaptic development, homeostasis, and age-related declines. More importantly, it establishes the first C. elegans model where we can examine synapse degeneration as a function of aging as it relates to human disease
NOVEL INSIGHTS INTO THE ROLE OF THE UNC-6/NETRIN RECEPTOR UNC-5 IN REGULATING GROWTH CONE POLARITY AND PROTRUSION
No full textThe central nervous system (CNS) is a complex network of connected neurons. In the developing nervous system, axons must reach their target for the formation of functional neuronal connections. During embryonic and postnatal development of a nervous system, neuronal precursor cells must migrate to their final destinations, and axons must navigate to the correct target to establish normal connectivity. Failure of axons to properly reach their target leads to incomplete development of a brain, resulting in several neurodevelopmental disorders such as mental retardation and autism, horizontal gaze palsy with progressive scoliosis (HGPPS) and schizophrenia (GUAN AND RAO 2003; NUGENT et al. 2012). Proper functioning of the nervous system depends on the development of proper neuronal connections, which in turn depends on the proper guidance of neurites from their neuronal cells of origin to their eventual synaptic targets. The outgrowth of developing axons is guided by growth cones, dynamic actin-based structures that sense and respond to extracellular guidance cues that drive the forward motion of the axon(TESSIER-LAVIGNE AND GOODMAN 1996). The growth are the dynamic structures which are present at the growing tip of an axon and made up of dynamic filopodial and lamellipodial protrusions, which are involved in axon outgrowth and guidance (GOLDBERG AND BURMEISTER 1986). The lamellipodium is an actin-based, membrane sheet-like structure at the leading edge of the growth cone consisting of a meshwork of actin filaments, which provide the forward motive force of the developing neurite(GALLO AND LETOURNEAU 2004). Filopodia, are the dominate structures of a growth cone that emanate from the growth cone lamellipodial body, consist of bundled filamentous actin (F-actin). Filopodia are thought to be involved in the sensation of directional cues and subsequent changes in directional locomotion as it contains receptors for various guidance cues. Netrins were the first family of guidance cues to be found in both invertebrate and vertebrate nervous systems. In C. elegans, a genetic screen for mutants that affects axon guidance identified UNC-6 which is involved in controlling both dorsally and ventrally guided projecting axons (MERZ AND CULOTTI 2000). UNC-6 is a laminin-related protein secreted by ventral cells in C. elegans and by floor-plate cells in vertebrates (HEDGECOCK et al. 1990; ISHII et al. 1992). UNC-6/Netrin is a bi-functional guidance cue which mediates its functions through two classes of single-pass transmembrane receptors, UNC-40 ad UNC-5. Much work has been done to identify role of UNC-6/ Netrins and its receptors in regulating end point axon guidance by studying the developed nervous system in vivo and by studying developing growth cones in vitro. However, very little is known about how UNC-6/ Netrin regulates in vivo growth cone morphology and dynamics to regulate proper navigation o axons to their targets. The work here attempts to do that by utilizing the free-living nematode Caenorhabditis elegans. C. elegans is a useful system to study axon pathfinding and growth cone development in vivo due to its simple, well-characterized nervous system, transparency and fully sequenced genome. In this work we focus on D-type GABAergic neurons 13 VD and 6 DD, which are motor neurons required for locomotion of C. elegans. VD/DD motor neurons resides in the ventral nerve cord their axons first migrate anteriorly before turning 90 degrees and forming commissures until reaching the dorsal nerve cord, at which point they spread both anteriorly and posteriorly and establish their synaptic targets. Previous work from lab using VD growth cone analysis display a polarity/protrusion model of growth cone repulsion from UNC-6/Netrin, UNC-6 first polarizes the growth cone of VD neuron via the UNC-5 receptor, and then regulates protrusion asymmetrically across the growth cone based on this polarity. Through the UNC-40/DCC receptor, UNC-6 stimulates protrusion dorsally, and through UNC-5 inhibits protrusion ventrally and laterally, resulting in net dorsal growth (GUJAR et al. 2018). The work presented here is focused on how UNC-6/Netrin utilizes the receptor UNC-5 with the help of other signaling molecules and mediate inhibition of growth cone protrusions. In chapter III, we identify the role of MAX-1 in inhibiting growth cone protrusion by possibly affecting the trafficking or stability UNC-5. We show that max-1 acts independently of other pathways that regulate growth cone protrusion, including unc-40/DCC, unc-6/Netrin, unc-33/CRMP, and unc-34/Enabled. Our findings involving MAX-1 in the growth cone are in the contrast with endpoint axon guidance analysis which display synergistic interactions between max-1, unc-5, unc-6, unc-40, suggesting that we are still missing a link that translates how morphological changes in the growth cone affects axon guidance. In chapter IV, we show how regulation of vesicle exocytosis is exclusively used by receptor UNC-5 to inhibit growth cone protrusions. We identify tom-1 genetically interacts downstream of receptor unc-5 to inhibit the lateral and ventral protrusions in dorsally migrating VD growth cone. We also uncover the isoform specific role of TOM-1 in inhibiting UNC-5 signaling, where the short isoforms perform the canonical function inhibition and long isoform is pro-protrusive in nature. Further extension of this work is explained in chapter V, where we have shown that the TOM-1mediates inhibition of growth cone protrusions by inhibition AEX-3, which has pro-protrusive role in vesicle exocytosis. In chapter VI, we show that the long and short isoform of UNC-5 differentially regulates VD growth cone morphology. The long isoform of UNC-5 displays a conserved canonical role of inhibition of protrusions, but the short isoform has a pro-protrusive role. Lastly in chapter VII, we identify role of SRC-1 tyrosine kinase in mediation UNC-5 signaling by possible activation of UNC-5 through phosphorylation. In summary, the results contained here provide novel insights into the mechanisms by which receptor UNC-5 of UNC-6/Netrin utilizes the novel genes in repulsion, growth cone inhibition and regulates several aspects of growth cone protrusion during the process of axon guidance. The studies performed here also emphasis on the benefits of analyzing growth cones during outgrowth in addition to post-developmental end point analysis of axon guidance
REMPI SPECTROSCOPY OF NO COMPLEXES WITH , CO AND VIA THE STATE
No full textAuthor Institution: Department of Physics, School of Chemistry, Physics and Environmental Science, University of Sussex; Spectroscopy of Complexes and Radicals (SOCAR) Group, School of Chemistry, Physics and Environmental Science, University of SussexThe spectra of the transition of the molecular complexes, where , CO and , have been recorded using one-color REMPI spectroscopy. The spectra exhibit vibronic features, which are interpreted as hindered internal rotation and the underlying end-over-end rotational structure. Some insights into the structure of the spectra are gleaned from ab inition calculations
Overview of Serological Techniques for Influenza Vaccine Evaluation: Past, Present and Future
No full textSerological techniques commonly used to quantify influenza-specific antibodies include the Haemagglutination Inhibition (HI), Single Radial Haemolysis (SRH) and Virus Neutralization (VN) assays. HI and SRH are established and reproducible techniques, whereas VN is more demanding. Every new influenza vaccine needs to fulfil the strict criteria issued by the European Medicines Agency (EMA) in order to be licensed. These criteria currently apply exclusively to SRH and HI assays and refer to two different target groups—healthy adults and the elderly, but other vaccine recipient age groups have not been considered (i.e., children). The purpose of this timely review is to highlight the current scenario on correlates of protection concerning influenza vaccines and underline the need to revise the criteria and assays currently in use. In addition to SRH and HI assays, the technical advantages provided by other techniques such as the VN assay, pseudotype-based neutralization assay, neuraminidase and cell-mediated immunity assays need to be considered and regulated via EMA criteria, considering the many significant advantages that they could offer for the development of effective vaccines
A study of the BrO and BrO₂ radicals with vacuum ultraviolet photoelectron spectroscopy
No full textAuthor name used in this publication: J. M. DykeAuthor name used in this publication: E. P. F. LeeAuthor name used in this publication: D. K. W. MokAuthor name used in this publication: F. T. ChauVersion of RecordPublishedVoR allowe
