495 research outputs found
Making the longest sugars: a chemical synthesis of heparin-related [4](n) oligosaccharides from 16-mer to 40-mer
The chemical synthesis of long oligosaccharides remains a major challenge. In particular, the synthesis of glycosaminoglycan (GAG) oligosaccharides belonging to the heparin and heparan sulfate (H/HS) family has been a high profile target, particularly with respect to the longer heparanome. Herein we describe a synthesis of the longest heparin-related oligosaccharide to date and concurrently provide an entry to the longest synthetic oligosaccharides of any type yet reported. Specifically, the iterative construction of a series of [4]n-mer heparin-backbone oligosaccharides ranging from 16-mer through to the 40-mer in length is described. This demonstrates for the first time the viability of generating long sequence heparanoids by chemical synthesis, via practical solution-phase synthesis. Pure-Shift HSQC NMR provides a dramatic improvement in anomeric signal resolution, allowing full resolution of all 12 anomeric protons and extrapolation to support anomeric integrity of the longer species. A chemically pure 6-O-desfulfated GlcNS-IdoAS icosasaccharide (20-mer) represents the longest pure synthetic heparin-like oligosaccharide
How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) progresses. The natural history of ME/CFS
We propose a framework for understanding and interpreting the pathophysiology
of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers
wider determinants of health and long-term temporal variation in pathophysiological
features and disease phenotype throughout the natural history of the disease. As in
other chronic diseases, ME/CFS evolves through different stages, from asymptomatic
predisposition, progressing to a prodromal stage, and then to symptomatic disease.
Disease incidence depends on genetic makeup and environment factors, the exposure
to singular or repeated insults, and the nature of the host response. In people
who develop ME/CFS, normal homeostatic processes in response to adverse insults
may be replaced by aberrant responses leading to dysfunctional states. Thus, the
predominantly neuro-immune manifestations, underlined by a hyper-metabolic state,
that characterize early disease, may be followed by various processes leading to
multi-systemic abnormalities and related symptoms. This abnormal state and the effects
of a range of mediators such as products of oxidative and nitrosamine stress, may
lead to progressive cell and metabolic dysfunction culminating in a hypometabolic
state with low energy production. These processes do not seem to happen uniformly;
although a spiraling of progressive inter-related and self-sustaining abnormalities may
ensue, reversion to states of milder abnormalities is possible if the host is able to
restate responses to improve homeostatic equilibrium. With time variation in disease
presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular
feature is currently representative of all patients at different disease stages. While
acknowledging its limitations due to the incomplete research evidence, we suggest the
proposed framework may support future research design and health care interventions
for people with ME/CFS
Structural effects of the highly protective V127 polymorphism on human prion protein
Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP ÎČ-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the ÎČ2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease
ÂčH, Âčâ”N, ÂčÂłC backbone resonance assignments of human phosphoglycerate kinase in a transition state analogue complex with ADP, 3-phosphoglycerate and magnesium trifluoride
Human phosphoglycerate kinase (PGK) is an energy generating glycolytic enzyme that catalyses the transfer of a phosphoryl group from 1,3-bisphosphoglycerate (BPG) to ADP producing 3-phosphoglycerate (3PG) and ATP. PGK is composed of two α/ÎČ Rossmann-fold domains linked by a central α-helix and the active site is located in the cleft formed between the N-domain which binds BPG or 3PG, and the C-domain which binds the nucleotides ADP or ATP. Domain closure is required to bring the two substrates into close proximity for phosphoryl transfer to occur, however previous structural studies involving a range of native substrates and substrate analogues only yielded open or partly closed PGK complexes. X-ray crystallography using magnesium trifluoride (MgF3(-)) as a isoelectronic and near-isosteric mimic of the transferring phosphoryl group (PO3(-)), together with 3PG and ADP has been successful in trapping human PGK in a fully closed transition state analogue (TSA) complex. In this work we report the (1)H, (15)N and (13)C backbone resonance assignments of human PGK in the solution conformation of the fully closed PGK:3PG:MgF3:ADP TSA complex. Assignments were obtained by heteronuclear multidimensional NMR spectroscopy. In total, 97% of all backbone resonances were assigned in the complex, with 385 out of a possible 399 residues assigned in the (1)H-(15)N TROSY spectrum. Prediction of solution secondary structure from a chemical shift analysis using the TALOS-N webserver is in good agreement with the published X-ray crystal structure of this complex
Measles on the Edge: Coastal Heterogeneities and Infection Dynamics
Mathematical models can help elucidate the spatio-temporal dynamics of epidemics as well as the impact of control measures. The gravity model for directly transmitted diseases is currently one of the most parsimonious models for spatial epidemic spread. This model uses distance-weighted, population size-dependent coupling to estimate host movement and disease incidence in metapopulations. The model captures overall measles dynamics in terms of underlying human movement in pre-vaccination England and Wales (previously established). In spatial models, edges often present a special challenge. Therefore, to test the model's robustness, we analyzed gravity model incidence predictions for coastal cities in England and Wales. Results show that, although predictions are accurate for inland towns, they significantly underestimate coastal persistence. We examine incidence, outbreak seasonality, and public transportation records, to show that the model's inaccuracies stem from an underestimation of total contacts per individual along the coast. We rescue this predicted âedge effectâ by increasing coastal contacts to approximate the number of per capita inland contacts. These results illustrate the impact of âedge effectsâ on epidemic metapopulations in general and illustrate directions for the refinement of spatiotemporal epidemic models
A Small Conductance Calcium-Activated K<sup>+</sup> Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying
In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al
Search for CP violation in D+âÏÏ+ and D+sâK0SÏ+ decays
A search for CP violation in D + â ÏÏ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fbâ1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (â0.04 ± 0.14 ± 0.14)% for candidates with K â K + mass within 20 MeV/c 2 of the Ï meson mass. A search for a CP -violating asymmetry that varies across the Ï mass region of the D + â K â K + Ï + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+sâK0SÏ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%
Study of decays to the final state and evidence for the decay
A study of decays is performed for the first time
using data corresponding to an integrated luminosity of 3.0
collected by the LHCb experiment in collisions at centre-of-mass energies
of and TeV. Evidence for the decay
is reported with a significance of 4.0 standard deviations, resulting in the
measurement of
to
be .
Here denotes a branching fraction while and
are the production cross-sections for and mesons.
An indication of weak annihilation is found for the region
, with a significance of
2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html,
link to supplemental material inserted in the reference
Differential branching fraction and angular analysis of decays
The differential branching fraction of the rare decay is measured as a function of , the
square of the dimuon invariant mass. The analysis is performed using
proton-proton collision data, corresponding to an integrated luminosity of 3.0
\mbox{ fb}^{-1}, collected by the LHCb experiment. Evidence of signal is
observed in the region below the square of the mass. Integrating
over 15 < q^{2} < 20 \mbox{ GeV}^2/c^4 the branching fraction is measured as
d\mathcal{B}(\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-)/dq^2 = (1.18 ^{+
0.09} _{-0.08} \pm 0.03 \pm 0.27) \times 10^{-7} ( \mbox{GeV}^{2}/c^{4})^{-1},
where the uncertainties are statistical, systematic and due to the
normalisation mode, , respectively.
In the intervals where the signal is observed, angular distributions are
studied and the forward-backward asymmetries in the dimuon ()
and hadron () systems are measured for the first time. In the
range 15 < q^2 < 20 \mbox{ GeV}^2/c^4 they are found to be A^{l}_{\rm FB} =
-0.05 \pm 0.09 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)} and A^{h}_{\rm FB} =
-0.29 \pm 0.07 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)}.Comment: 27 pages, 10 figures, Erratum adde
GIS and spatial data analysis: Converging perspectives
We take as our starting point the state of geographic information systems (GIS) and spatial data analysis 50 years ago when regional science emerged as a new field of enquiry. In the late 1950s and 1960s advances in computing technology were making possible forms of automated cartography that in due course would lead to th
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