A robust broadband fat suppressing phaser T2 preparation module for cardiac magnetic resonance imaging at 3T

Purpose: Designing a new T2 preparation (T2-Prep) module in order to simultaneously provide robust fat suppression and efficient T2 preparation without requiring an additional fat suppression module for T2-weighted imaging at 3T. Methods: The tip-down RF pulse of an adiabatic T2 preparation (T2-Prep) module was replaced by a custom-designed RF excitation pulse that induces a phase difference between water and fat, resulting in a simultaneous T2 preparation of water signals and the suppression of fat signals at the end of the module (now called a phaser adiabatic T2-Prep). Using numerical simulations, in vitro and in vivo ECG-triggered navigator gated acquisitions of the human heart, the blood, myocardium and fat signal-to-noise ratio and right coronary artery (RCA) vessel sharpness using this approach were compared against previously published conventional adiabatic T2-Prep approaches Results: Numerical simulations predicted an increased fat suppression bandwidth and decreased sensitivity against transmit magnetic field inhomogeneities using the proposed approach, while preserving the water T2 preparation capabilities. This was confirmed by the tissue signals acquired on the phantom and the in vivo MRA, which show similar blood and myocardium SNR and CNR and significantly reduced fat SNR compared to the other methods tested. As a result, the RCA conspicuity was significantly increased and the motion artifacts were visually decreased. Conclusion: A novel fat-suppressing T2-preparation method was developed and implemented that demonstrated robust fat suppression and increased vessel sharpness compared with conventional techniques, while preserving its T2 preparation capabilities.Comment: 23 pages, 5 figures, submitted to Magnetic Resonance in Medicin

Linking functional traits to multiscale statistics of leaf venation networks

Funding Information UK Natural Environment Research Council. Grant Number: NE/M019160/1 US National Science Foundation. Grant Number: DEB‐2025282 NERC Human‐modified Tropical Forest Programme. Grant Number: NE/M017508/1 Biodiversity And Land‐use Impacts on Tropical Ecosystem Function (BALI). Grant Numbers: NE/K016253/1, NE/K016253/1 Sime Darby Foundation Stability of Altered Forest Ecosystems (SAFE) Project Sabah Biodiversity Council Institute for Tropical Biology and Conservation (ITBC) at the University of Malaysia, Sabah (UMS) Sabah Forest Research Centre (FRC) at Sepilok Sabah Forestry Department SEARRP, Yayasan Sabah (Maliau Basin Conservation Area) Maliau Basin and Danum Valley Management Committees Acknowledgements Fieldwork was supported by Unding Jami, Matheus Henrique Nuñes, Rudi Saul Cruz Chino, Milenka Ximena Montoya, and South East Asia Rainforest Research Program (SEARRP) staff. Research was facilitated by Rob Ewers, Laura Kruitbos, Reuben Nilus, Glen Reynolds, and Charles Vairappan. Species identifications were made by Bernadus Bala Ola, Bill McDonald, Alexander Karolus, and MinSheng Khoo. This work also was supported by the UK Natural Environment Research Council (NERC; no. NE/M019160/1, to BB) and the US National Science Foundation (no. DEB‐2025282, to BB). This publication is a contribution from the NERC Human‐modified Tropical Forest Programme (no. NE/M017508/1, to YAT) and Biodiversity And Land‐use Impacts on Tropical Ecosystem Function (BALI) consortium (no. NE/K016253/1, to YM and no. NE/K016253/1, to YAT). The SAFE Project was funded by the Sime Darby Foundation and the UK NERC. The study areas are part of the Global Ecosystems Monitoring Network (GEM) via an ERC Advanced Investigator Award to YM (no. 321131). The project also was supported by the Stability of Altered Forest Ecosystems (SAFE) Project, the Sabah Biodiversity Council (SaBC, permits JKM/MBS.1000‐2/2 JLD.3‐126 and ‐154), the Institute for Tropical Biology and Conservation (ITBC) at the University of Malaysia, Sabah (UMS), the Sabah Forest Research Centre (FRC) at Sepilok, the Sabah Forestry Department, the SEARRP, Yayasan Sabah (Maliau Basin Conservation Area), and the Maliau Basin and Danum Valley Management Committees. Sean Gleason and several anonymous reviewers provided constructive feedback on the manuscript.Peer reviewedPublisher PD

Tropical forests post-logging are a persistent net carbon source to the atmosphere

Acknowledgments This study was part of the SAFE Project, the Global Ecosystems Monitoring network (gem.tropicalforests.ox.ac.uk) and Imperial College's Grand Challenges in Ecosystems and the Environment Initiative. We acknowledge funding from the Sime Darby Foundation, the Biodiversity And Land-use Impacts on tropical ecosystem function (BALI) Project (NE/K016377/1) within the Natural Environment Research Council Human-Modified Tropical Forests Programme, the Malaysian Palm Oil Board (MPOB), and Centre for Tropical Forest Science (CTFS) in collaboration with HSBC Climate Partnership. The 52-ha Long-Term Ecological Research Project in Lambir is a collaborative project of the Forest Department of Sarawak, Malaysia, the Center for Tropical Forest Science of the Smithsonian Tropical Research Institute, USA (NSF awards DEB- 9107247 and DEB- 9629601), and Osaka City, Ehime & Kyoto Universities, Japan (Monbusho grants 06041094, 08NP0901 and 09NP0901). M.B.M. was supported by NERC studentship awarded through the Central England NERC Training Alliance (CENTA; grant referenceNE/S007350/1) and the University of Leicester, Y.M. was supported by the Jackson Foundation and European Research Council Advanced Investigator Grant, GEM-TRAIT (321131), Y.M., RME, and T.R. by NERC grant NE/P002218/1, and R.M.E. is supported by the NOMIS Foundation. TR also acknowledges support from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 865403). Maliau Basin and Danum Valley Management Committees, Royal Society South East Asia Rainforest Research Partnership (SEARRP), Sabah Foundation, Benta Wawasan, the State Secretary, Sabah Chief Minister’s Departments, Sabah Forestry Department, Sabah Biodiversity Council, and the Economic Planning Unit are acknowledged for their support and access to the sites in Sabah. Rostin Jantan, Rohid Kailoh, Suhaini Patik, Ampat Siliwong, Yehezekiel Jahuri, Robecca Siwaring, Jeffry Amin, Sarah Watson, Ryan Gray, Johnny Larenus, Unding Jami, Toby Marthews, Alexander Karolus, the Danum 50 ha plot team, Sylvester Tan, Xyxtus Tan, Nasir Muhi and Abilano Deres helped with the data collection. We thank Susan Page, Juan Carlos Berrio, Jörg Kaduk and Katie O’Brien for their constructive comments.Peer reviewedPublisher PD

Genomewide identification of \u3ci\u3ePseudomonas syringae\u3c/i\u3e pv.\u3ci\u3etomato\u3c/i\u3e DC3000 promoters controlled by the HrpL alternative sigma factor

The ability of Pseudomonas syringae pv. tomato DC3000 to parasitize tomato and Arabidopsis thaliana depends on genes activated by the HrpL alternative sigma factor. To support various functional genomic analyses of DC3000, and specifically, to identify genes involved in pathogenesis, we developed a draft sequence of DC3000 and used an iterative process involving computational and gene expression techniques to identify virulence-implicated genes downstream of HrpLresponsive promoters. Hypersensitive response and pathogenicity (Hrp) promoters are known to control genes encoding the Hrp (type III protein secretion) machinery and a few type III effector proteins in DC3000. This process involved (i) identification of 9 new virulenceimplicated genes in the Hrp regulon by miniTn5gus mutagenesis, (ii) development of a hidden Markov model (HMM) trained with known and transposon-identified Hrp promoter sequences, (iii) HMM identification of promoters upstream of 12 additional virulence-implicated genes, and (iv) microarray and RNA blot analyses of the HrpLdependent expression of a representative subset of these DC3000 genes. We found that the Hrp regulon encodes candidates for 4 additional type III secretion machinery accessory factors, homologs of the effector proteins HopPsyA, AvrPpiB1 (2 copies), AvrPpiC2, AvrPphD (2 copies), AvrPphE, AvrPphF, and AvrXv3, and genes associated with the production or metabolism of virulence factors unrelated to the Hrp type III secretion system, including syringomycin synthetase (SyrE), N-(indole-3-acetyl)-L-lysine synthetase (IaaL), and a subsidiary regulon controlling coronatine production. Additional candidate effector genes, hopPtoA2, hopPtoB2, and an avrRps4 homolog, were preceded by Hrp promoter-like sequences, but these had HMM expectation values of relatively low significance and were not detectably activated by HrpL

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms

Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology

Cross-Attraction between an Exotic and a Native Pine Bark Beetle: A Novel Invasion Mechanism?

Aside from the ecological impacts, invasive species fascinate ecologists because of the unique opportunities that invasives offer in the study of community ecology. Some hypotheses have been proposed to illustrate the mechanisms that allow exotics to become invasive. However, positive interactions between exotic and native insects are rarely utilized to explain invasiveness of pests.Here, we present information on a recently formed association between a native and an exotic bark beetle on their shared host, Pinus tabuliformis, in China. In field examinations, we found that 35-40% of P. tabuliformis attacked by an exotic bark beetle, Dendroctonus valens, were also attacked by a native pine bark beetle, Hylastes parallelus. In the laboratory, we found that the antennal and walking responses of H. parallelus to host- and beetle-produced compounds were similar to those of the exotic D. valens in China. In addition, D. valens was attracted to volatiles produced by the native H. parallelus.We report, for the first time, facilitation between an exotic and a native bark beetle seems to involve overlap in the use of host attractants and pheromones, which is cross-attraction. The concept of this interspecific facilitation could be explored as a novel invasive mechanism which helps explain invasiveness of not only exotic bark beetles but also other introduced pests in principle. The results reported here also have particularly important implications for risk assessments and management strategies for invasive species

The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of Familial Hemiplegic Migraine type 1 (FHM-1)

A knock-in (KI) mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the \u3b11 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT) neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining) migraine attacks, such as TNF\u3b1, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNF\u3b1 potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNF\u3b1 receptor TNFR2. However, sustained TNF\u3b1 neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNF\u3b1 does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNF\u3b1 enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP. \ua9 2013 Hullugundi et al