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Find video protocols related to scientific articles indexed in Pubmed.
Human induced pluripotent stem cell-derived hepatocytes for toxicology testing.
Expert Opin Drug Metab Toxicol
PUBLISHED: 11-12-2014
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The need for more predictive in vitro toxicity models is a critical deficit in current preclinical pipeline safety evaluations. Current models employing tumor-derived cancer cell lines and isolated primary human hepatocytes (PHHs) afford an approximation of overt cytotoxicity but do not provide hepatotoxicity prediction owing to liabilities in metabolic activity along with phenotypic variability and instability in culture. Induced pluripotent stem cell-derived hepatocytes (iPSC-HCs) offer a long-term solution to accessing liver tissue from representative diverse as well as idiosyncratic patient populations and can be sourced indefinitely. iPSC-HCs are currently being evaluated as potential replacements for the existing cell models, but they have yet to prove superiority. It is acknowledged that iPSC-HCs are not functionally equivalent to PHHs and are somewhat mixed in terms of their gene expression profile, simultaneously displaying mature and immature markers in vitro. Combining iPSC-HCs with organotypic culture systems affords an opportunity to maximize the potential of both technologies where the cells benefit from more complex culture conditions while unlocking the potential of the culture systems by affording stability and reproducibility to provide the future of predictive in vitro toxicity models.
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Syntheses of polypyridyl metal complexes and studies of their interaction with quadruplex DNA.
Dalton Trans
PUBLISHED: 11-01-2014
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A series of mono- and bi-metallic metal complexes (with Cu(II), Pt(II) and Zn(II)) with substituted polypyridyl ligands have been prepared and their binding affinities towards quadruplex (c-Myc and human telomeric) and duplex DNA (ds26 and calf thymus) determined using fluorescent indicator displacement (FID) assays and UV/vis spectroscopic titrations. These studies have shown that the number of aromatic rings and number/position of cyclic amine substituents on the ligands, play an important role in defining the DNA binding abilities of the resulting metal complexes. We also show that bi-metallic complexes prepared using a novel terpyridine-cyclen ligand have higher affinity towards G-quadruplex DNA as compared to their mono-metallic counterparts. Cytotoxicity assays were carried out for all the new complexes against an osteosarcoma cancer cell line (U2OS) as well as a normal fibroblast cell line (GM05757). Several of these compounds displayed cytotoxicity similar to that of cisplatin.
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Human Vascular Tissue Models Formed from Human Induced Pluripotent Stem Cell Derived Endothelial Cells.
Stem Cell Rev
PUBLISHED: 09-05-2014
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Here we describe a strategy to model blood vessel development using a well-defined induced pluripotent stem cell-derived endothelial cell type (iPSC-EC) cultured within engineered platforms that mimic the 3D microenvironment. The iPSC-ECs used here were first characterized by expression of endothelial markers and functional properties that included VEGF responsiveness, TNF-?-induced upregulation of cell adhesion molecules (MCAM/CD146; ICAM1/CD54), thrombin-dependent barrier function, shear stress-induced alignment, and 2D and 3D capillary-like network formation in Matrigel. The iPSC-ECs also formed 3D vascular networks in a variety of engineering contexts, yielded perfusable, interconnected lumen when co-cultured with primary human fibroblasts, and aligned with flow in microfluidics devices. iPSC-EC function during tubule network formation, barrier formation, and sprouting was consistent with that of primary ECs, and the results suggest a VEGF-independent mechanism for sprouting, which is relevant to therapeutic anti-angiogenesis strategies. Our combined results demonstrate the feasibility of using a well-defined, stable source of iPSC-ECs to model blood vessel formation within a variety of contexts using standard in vitro formats.
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Accumulation of dipeptide repeat proteins predates that of TDP-43 in Frontotemporal Lobar Degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.
Neuropathol. Appl. Neurobiol.
PUBLISHED: 09-03-2014
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Frontotemporal lobar degeneration (FTLD) and Motor Neuron Disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene.
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A UBQLN2 variant of unknown significance in frontotemporal lobar degeneration.
Neurobiol. Aging
PUBLISHED: 08-06-2014
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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD.
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TREM2 analysis and increased risk of Alzheimer's disease.
Neurobiol. Aging
PUBLISHED: 07-28-2014
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Important insights into the pathogenic mechanism of Alzheimer's disease (AD) have arisen from the identification of genetic risk factors. Recently, a variant in the TREM2 gene (rs75932628), causing a C-to-T base-pair change that results in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein, has been associated with an increased risk of AD. We, therefore, genotyped samples from a cohort of 474 AD patients and 608 healthy controls, from the northwest region of the UK, using allelic discrimination assays, to replicate the results of the previous studies. We show a significant association of the T allele of the rs75932628 variant of TREM2 with AD (allelic odds ratio 11.08, 95% confidence interval 2.55-48.09, and Yates' corrected p value = 0.000146). TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management.
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Identification and overexpression of gibberellin 2-oxidase (GA2ox) in switchgrass (Panicum virgatum L.) for improved plant architecture and reduced biomass recalcitrance.
Plant Biotechnol. J.
PUBLISHED: 07-08-2014
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Gibberellin 2-oxidases (GA2oxs) are a group of 2-oxoglutarate-dependent dioxygenases that catalyse the deactivation of bioactive GA or its precursors through 2?-hydroxylation reaction. In this study, putatively novel switchgrass C20 GA2ox genes were identified with the aim of genetically engineering switchgrass for improved architecture and reduced biomass recalcitrance for biofuel. Three C20 GA2ox genes showed differential regulation patterns among tissues including roots, seedlings and reproductive parts. Using a transgenic approach, we showed that overexpression of two C20 GA2ox genes, that is PvGA2ox5 and PvGA2ox9, resulted in characteristic GA-deficient phenotypes with dark-green leaves and modified plant architecture. The changes in plant morphology appeared to be associated with GA2ox transcript abundance. Exogenous application of GA rescued the GA-deficient phenotypes in transgenic lines. Transgenic semi-dwarf lines displayed increased tillering and reduced lignin content, and the syringyl/guaiacyl lignin monomer ratio accompanied by the reduced expression of lignin biosynthetic genes compared to nontransgenic plants. A moderate increase in the level of glucose release in these transgenic lines might be attributed to reduced biomass recalcitrance as a result of reduced lignin content and lignin composition. Our results suggest that overexpression of GA2ox genes in switchgrass is a feasible strategy to improve plant architecture and reduce biomass recalcitrance for biofuel.
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Action preferences and the anticipation of action outcomes.
Acta Psychol (Amst)
PUBLISHED: 07-08-2014
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Skilled performers of time-constrained motor actions acquire information about the action preferences of their opponents in an effort to better anticipate the outcome of that opponent's actions. However, there is reason to doubt that knowledge of an opponent's action preferences would unequivocally influence anticipatory responses in a positive way. It is possible that overt information about an opponent's actions could distract skilled performers from using the advance kinematic information they would usually rely on to anticipate actions, particularly when the opponent performs an 'unexpected' action that is not in accordance with his or her previous behaviour. The aim of this study was to examine how the ability to anticipate the outcome of an opponent's actions can be influenced by exposure to the action preferences of that opponent. Two groups of skilled handball goalkeepers anticipated the direction of penalty throws performed by opponents before and after a training intervention that provided situational probability information in the form of action preferences (AP). During the training phase participants in an AP-training group anticipated the action outcomes of two throwers who had a strong preference to throw in one particular direction, whilst participants in a NP-training group viewed players who threw equally to all directions. Exposure to opponents who did have an action preference during the training phase resulted in improved anticipatory performance if the opponent continued to bias their throws towards their preferred direction, but decreased performance if the opponent did not. These findings highlight that skilled observers use information about action preferences to enhance their anticipatory ability, but that doing so can be disadvantageous when the outcomes are no longer consistent with their generated expectations.
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Survival of salmonella on dried fruits and in aqueous dried fruit homogenates as affected by temperature.
J. Food Prot.
PUBLISHED: 07-03-2014
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A study was done to determine the ability of Salmonella to survive on dried cranberries, raisins, and strawberries and in date paste, as affected by storage temperature. Acid-adapted Salmonella, initially at 6.57 to 7.01 log CFU/g, was recovered from mist-inoculated cranberries (water activity [aw] 0.47) and raisins (aw 0.46) stored at 25°C for 21 days but not 42 days, strawberries (aw 0.21) for 42 days but not 84 days, and date paste (aw 0.69) for 84 days but not 126 days. In contrast, the pathogen was detected in strawberries stored at 4°C for 182 days (6 months) but not 242 days (8 months) and in cranberries, date paste, and raisins stored for 242 days. Surface-grown cells survived longer than broth-grown cells in date paste. The order of rate of inactivation at 4°C was cranberry > strawberry > raisin > date paste. Initially at 2.18 to 3.35 log CFU/g, inactivation of Salmonella on dry (sand)&ndash inoculated fruits followed trends similar to those for mist-inoculated fruits. Survival of Salmonella in aqueous homogenates of dried fruits as affected by fruit concentration and temperature was also studied. Growth was not observed in 10% (aw 0.995 to 0.999) and 50% (aw 0.955 to 0.962) homogenates of the four fruits held at 4°C, 50% homogenates at 25°C, and 10% cranberry and strawberry homogenates at 25°C. Growth of the pathogen in 10% date paste and raisin homogenates stored at 25°C was followed by rapid inactivation. Results of these studies suggest the need to subject dried fruits that may be contaminated with Salmonella to a lethal process and prevent postprocess contamination before they are eaten out-of-hand or used as ingredients in ready-to-eat foods. Observations showing that Salmonella can grow in aqueous homogenates of date paste and raisins emphasize the importance of minimizing contact of these fruits with high-moisture environments during handling and storage.
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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
Hum. Mol. Genet.
PUBLISHED: 06-27-2014
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Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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Predatory fish sounds can alter crab foraging behaviour and influence bivalve abundance.
Proc. Biol. Sci.
PUBLISHED: 06-20-2014
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The risk of predation can have large effects on ecological communities via changes in prey behaviour, morphology and reproduction. Although prey can use a variety of sensory signals to detect predation risk, relatively little is known regarding the effects of predator acoustic cues on prey foraging behaviour. Here we show that an ecologically important marine crab species can detect sound across a range of frequencies, probably in response to particle acceleration. Further, crabs suppress their resource consumption in the presence of experimental acoustic stimuli from multiple predatory fish species, and the sign and strength of this response is similar to that elicited by water-borne chemical cues. When acoustic and chemical cues were combined, consumption differed from expectations based on independent cue effects, suggesting redundancies among cue types. These results highlight that predator acoustic cues may influence prey behaviour across a range of vertebrate and invertebrate taxa, with the potential for cascading effects on resource abundance.
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Frontotemporal dementia and its subtypes: a genome-wide association study.
Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustin Ruíz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R A Mackenzie, Ging-Yuek R Hsiung, David M A Mann, Jordan Grafman, Christopher M Morris, Johannes Attems, Timothy D Griffiths, Ian G McKeith, Alan J Thomas, P Pietrini, Edward D Huey, Eric M Wassermann, Atik Baborie, Evelyn Jaros, Michael C Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B Rowe, Johannes C M Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M Van Deerlin, Murray Grossman, John Q Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise G P Dopper, Harro Seelaar, Yolande A L Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni.
Lancet Neurol
PUBLISHED: 06-20-2014
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Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
Acta Neuropathol Commun
PUBLISHED: 06-05-2014
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A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. 'Inappropriate' formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD?+?MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD?+?MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease.
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Histone deacetylases (HDACs) in Frontotemporal Lobar Degeneration.
Neuropathol. Appl. Neurobiol.
PUBLISHED: 04-15-2014
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Frontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other non-genetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process.
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Do NIA-AA criteria distinguish Alzheimer's disease from frontotemporal dementia?
Alzheimers Dement
PUBLISHED: 03-27-2014
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Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies.
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Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.
Neurobiol. Aging
PUBLISHED: 03-16-2014
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Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).
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Two-year field analysis of reduced recalcitrance transgenic switchgrass.
Plant Biotechnol. J.
PUBLISHED: 03-13-2014
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Switchgrass (Panicum virgatum L.) is a leading candidate for a dedicated lignocellulosic biofuel feedstock owing to its high biomass production, wide adaptation and low agronomic input requirements. Lignin in cell walls of switchgrass, and other lignocellulosic feedstocks, severely limits the accessibility of cell wall carbohydrates to enzymatic breakdown into fermentable sugars and subsequently biofuels. Low-lignin transgenic switchgrass plants produced by the down-regulation of caffeic acid O-methyltransferase (COMT), a lignin biosynthetic enzyme, were analysed in the field for two growing seasons. COMT transcript abundance, lignin content and the syringyl/guaiacyl lignin monomer ratio were consistently lower in the COMT-down-regulated plants throughout the duration of the field trial. In general, analyses with fully established plants harvested during the second growing season produced results that were similar to those observed in previous greenhouse studies with these plants. Sugar release was improved by up to 34% and ethanol yield by up to 28% in the transgenic lines relative to controls. Additionally, these results were obtained using senesced plant material harvested at the end of the growing season, compared with the young, green tissue that was used in the greenhouse experiments. Another important finding was that transgenic plants were not more susceptible to rust (Puccinia emaculata). The results of this study suggest that lignin down-regulation in switchgrass can confer real-world improvements in biofuel yield without negative consequences to biomass yield or disease susceptibility.
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Whistle source levels of free-ranging bottlenose dolphins and Atlantic spotted dolphins in the Gulf of Mexico.
J. Acoust. Soc. Am.
PUBLISHED: 03-11-2014
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Whistles of bottlenose dolphins (Tursiops truncatus) and Atlantic spotted dolphins (Stenella frontalis) in the eastern Gulf of Mexico were recorded and measured with a calibrated towed hydrophone array. Surveys encountered groups of both bottlenose (N?=?10) and spotted dolphins (N?=?5). Analysis of those data produced 1695 bottlenose dolphin whistles and 1273 spotted dolphin whistles with a high signal-to-noise ratio. Whistle frequency metrics were lower in bottlenose than spotted dolphins, while whistle duration was longer in spotted dolphins, data that may help inform automatic classification algorithms. Source levels were estimated by determining the range and bearing of an individual dolphin from the array and then adding the predicted transmission loss to the calculated received level. The median bottlenose dolphin source level was 138?dB re 1?Pa at 1?m with a range of 114-163?dB re 1?Pa at 1?m. The median spotted dolphin source level was 138?dB re 1?Pa at 1?m with a range of 115-163?dB re 1?Pa at 1?m. These source level measurements, in conjunction with estimates of vocalization rates and transmission loss models, can be used to improve passive acoustically determined dolphin abundance estimates in the Gulf of Mexico.
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When is sampling complete? The effects of geographical range and marker choice on perceived diversity in Nitzschia palea (Bacillariophyta).
Protist
PUBLISHED: 03-10-2014
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DNA barcoding, being developed for biomonitoring, requires a database of reference sequences and knowledge of how much sequences can deviate before they are assigned to separate species. The molecular hunt for hidden species also raises the question of species definitions. We examined whether there are objective criteria for sequence-based species delimitation in diatoms, using Nitzschia palea, an important monophyletic indicator species already known to contain cryptic diversity. Strains from a wide geographical range were sequenced for 28S rRNA, COI and rbcL. Homogeneity indices and the Chao index failed to objectively select a precise number of species existing in N. palea as well as an evolutionary method based on coalescence theory. COI always gave higher diversity estimations than 28S rRNA or rbcL. Mating data did not provide a precise calibration of molecular species thresholds. Rarefaction curves indicated that further MOTUs would be detected with more isolates than we sampled (81 clones, 42 localities). Although some genotypes had intercontinental distributions, there was a positive relationship between genetic and geographical distance, suggesting even higher richness than we assessed, given that many regions were not sampled. Overall, no objective criteria were found for species separation; instead barcoding will need a consensual approach to molecular species limits.
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Global profiling of co- and post-translationally N-myristoylated proteomes in human cells.
Nat Commun
PUBLISHED: 03-05-2014
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Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in the development and progression of a range of human diseases. Here, we report the global N-myristoylated proteome in human cells determined using quantitative chemical proteomics combined with potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of N-myristoylation during normal growth or apoptosis allowed the identification of >100 N-myristoylated proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.
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Working with communities to achieve health equity in Maryland's five Health Enterprise Zones.
J Health Care Poor Underserved
PUBLISHED: 03-04-2014
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This report introduces Maryland's Health Enterprise Zones (HEZ) Initiative, describes the efforts to establish the first HEZs, describes the principles fundamental to the HEZ intervention, provides an overview of their intervention strategies, and summarizes efforts to assess the impact of the program.
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Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion.
Acta Neuropathol.
PUBLISHED: 01-24-2014
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Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent.
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Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach.
Nat Chem
PUBLISHED: 01-24-2014
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Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.
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Hearing threshold measurements of five stranded short-finned pilot whales (Globicephala macrorhynchus).
J. Acoust. Soc. Am.
PUBLISHED: 01-21-2014
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On May 5, 2011, 23 short-finned pilot whales, Globicephala macrorhynchus, were stranded along the coastline near Cudjoe Key, FL. Five animals (two adult females, two juvenile females, and an adult male) were transported to a rehabilitation facility in Key Largo, FL. Auditory evoked potentials (AEPs) were recorded in response to amplitude modulated tone pips modulated at 1000?Hz. AEP thresholds were determined at 10, 20, 40, 80, and 120?kHz for the four females. However, the adult male was euthanized prior to testing. Short-finned pilot whales had peak sensitivity at lower frequencies than other odontocetes such as bottlenose dolphins. Greatest sensitivity was around 40?kHz for all whales, while thresholds for the two adult females were 25-61?dB higher at 80?kHz than the juveniles. Click evoked potentials were similar between the four whales and comparable to other echolocating odontocetes. Click evoked potential data from a fifth short-finned pilot whale that had stranded in Curacao showed no response. These findings add to the limited database of pilot whale (short- and long-finned) hearing studies, of which there are only two others [Schlundt et al. (2011). J. Acoust. Soc. Am. 129, 1111-1116 and Pacini et al. (2010). J. Exp. Biol. 213, 3138-3143].
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A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension.
Am. J. Pathol.
PUBLISHED: 01-06-2014
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A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.
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Phosphorylation status of thymidine kinase 1 following antiproliferative drug treatment mediates 3'-deoxy-3'-[18F]-fluorothymidine cellular retention.
PLoS ONE
PUBLISHED: 01-01-2014
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3'-Deoxy-3'-[18F]-fluorothymidine ([18F]FLT) is being investigated as a Positron Emission Tomography (PET) proliferation biomarker. The mechanism of cellular [18F]FLT retention has been assigned primarily to alteration of the strict transcriptionally regulated S-phase expression of thymidine kinase 1 (TK1). This, however, does not explain how anticancer agents acting primarily through G2/M arrest affect [18F]FLT uptake. We investigated alternative mechanisms of [18F]FLT cellular retention involving post-translational modification of TK1 during mitosis.
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Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue.
Am J Neurodegener Dis
PUBLISHED: 01-01-2014
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In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ?4 was confirmed. However APOE ?2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA.
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Classification and pathology of primary progressive aphasia.
Neurology
PUBLISHED: 10-18-2013
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We aimed to determine the extent to which patients with progressive language impairment conform to 2011 primary progressive aphasia (PPA) classification and to examine clinicopathologic correlations within PPA variants.
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High-throughput analysis of meiotic crossover frequency and interference via flow cytometry of fluorescent pollen in Arabidopsis thaliana.
Nat Protoc
PUBLISHED: 10-10-2013
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During meiosis, reciprocal exchange between homologous chromosomes occurs as a result of crossovers (COs). CO frequency varies within genomes and is subject to genetic, epigenetic and environmental control. As robust measurement of COs is limited by their low numbers, typically 1-2 per chromosome, we adapted flow cytometry for use with Arabidopsis transgenic fluorescent protein-tagged lines (FTLs) that express eCFP, dsRed or eYFP fluorescent proteins in pollen. Segregation of genetically linked transgenes encoding fluorescent proteins of distinct colors can be used to detect COs. The fluorescence of up to 80,000 pollen grains per individual plant can be measured in 10-15 min using this protocol. A key element of CO control is interference, which inhibits closely spaced COs. We describe a three-color assay for the measurement of CO frequency in adjacent intervals and calculation of CO interference. We show that this protocol can be used to detect changes in CO frequency and interference in the fancm zip4 double mutant. By enabling high-throughput measurement of CO frequency and interference, these methods will facilitate genetic dissection of meiotic recombination control.
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Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
Acta Neuropathol Commun
PUBLISHED: 09-23-2013
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Cases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus.
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Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimers disease brain.
Acta Neuropathol Commun
PUBLISHED: 08-17-2013
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Intracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains.
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Guiding attention aids the acquisition of anticipatory skill in novice soccer goalkeepers.
Res Q Exerc Sport
PUBLISHED: 08-13-2013
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The ability to anticipate the actions of opponents can be enhanced through perceptual-skill training, though there is doubt regarding the most effective form of doing so. We sought to evaluate whether perceptual-skill learning would be enhanced when supplemented with guiding visual information.
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Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.
Breast Cancer Res.
PUBLISHED: 08-08-2013
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Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
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Rare coding variants in the phospholipase D3 gene confer risk for Alzheimers disease.
Nature
PUBLISHED: 08-07-2013
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Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimers disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimers disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimers disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimers disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-? precursor protein (APP) and extracellular A?42 and A?40 (the 42- and 40-residue isoforms of the amyloid-? peptide), and knockdown of PLD3 leads to a significant increase in extracellular A?42 and A?40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.
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Pathological assessments for the presence of hexanucleotide repeat expansions in C9ORF72 in Alzheimers disease.
Acta Neuropathol Commun
PUBLISHED: 08-05-2013
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We have sought histological evidence, using TDP-43 and p62 immunohistochemistry, for the presence of expansions in C9ORF72 among 200 patients with pathologically confirmed AD.
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A longitudinal study on ?-synuclein in blood plasma as a biomarker for Parkinsons disease.
Sci Rep
PUBLISHED: 07-02-2013
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There have been no longitudinal studies on ?-synuclein as a potential biomarker for the progression of Parkinsons disease (PD). Here, blood plasma total ?-synuclein and Ser-129 phosphorylated ?-synuclein were assayed at 4-6 monthly intervals from a cohort of 189 newly-diagnosed patients with PD. For log-transformed data, plasma total ?-synuclein levels increased with time for up to 20?yrs after the appearance of initial symptoms (p = 0.012), whereas phosphorylated ?-synuclein remained constant over this same period. The mean level of phosphorylated ?-synuclein, but not of total ?-synuclein, was higher in the PD plasma samples taken at first visit than in single samples taken from a group of 91 healthy controls (p = 0.012). Overall, we conclude that the plasma level of phosphorylated ?-synuclein has potential value as a diagnostic tool, whereas the level of total ?-synuclein could act as a surrogate marker for the progression of PD.
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Vascular histomolecular analysis by sequential endoarterial biopsy in a shunt model of pulmonary hypertension.
Pulm Circ
PUBLISHED: 05-11-2013
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The molecular mechanisms of pulmonary arterial hypertension (PAH) remain ill-defined. The aims of this study were to obtain sequential endoarterial biopsy samples in a surgical porcine model of PAH and assess changes in histology and mRNA expression during the disease progression. Differentially expressed genes were then analyzed as potential pharmacological targets. Four Yucatan micro-pigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Endovascular samples were obtained with a biopsy catheter at baseline (before surgery) and from the left lung 7, 60, and 180 days after surgery. RNA was isolated from biopsy samples, amplified and analyzed. Dysregulated genes were linked to drugs with potential to treat or prevent PAH. With the development of PAH in our model, we identified changes in histology and in the expression of several genes with known or investigational inhibitors and several novel genes for PAH. Gene dysregulation displayed time-related variations during disease progression. Endoarterial biopsy provides a new method of assessing pulmonary vascular histology and gene expression in PAH. This analysis could identify novel applications for existing and new PAH drugs. The detection of stage- and disease-specific variation in gene expression could lead to individualized therapies.
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Efficacy of sanitizers in reducing Salmonella on pecan nutmeats during cracking and shelling.
J. Food Prot.
PUBLISHED: 05-07-2013
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Studies were done to evaluate the efficacy of chlorine (200 to 1,000 ?g/ml), lactic acid (0.5 to 2%), levulinic acid (0.5 to 2%), sodium dodecyl sulfate (SDS, 0.05%), lactic acid plus SDS, levulinic acid plus SDS, and a mixed peroxyacid sanitizer (Tsunami 200, 40 and 80 ?g/ml) in killing Salmonella on or in immersion- and on surface-inoculated pecan nutmeats (U.S. Department of Agriculture medium pieces and mammoth halves). The addition of SDS to treatment solutions containing lactic acid or levulinic acid resulted in generally higher reductions of Salmonella, but differences in these reductions were not always significant. Lactic and levulinic acids (2%) containing SDS (0.05%) were equivalent in killing Salmonella on immersion-inoculated nutmeats. Tsunami 200 (40 ?g/ml) was less lethal or equivalent to 1 or 2% lactic and levulinic acids, with or without 0.05% SDS. Reductions did not exceed 1.1 log CFU/g of immersion-inoculated pieces and halves, regardless of sanitizer concentration or treatment time (up to 20 min). Reductions on surface-inoculated pieces and halves were 0.7 to 2.6 log CFU/g and 1.2 to 3.0 log CFU/g, respectively. Treatment with 2% lactic acid plus SDS (0.05%) and Tsunami (80 ?g/ml) was most effective in killing Salmonella on surface-inoculated pieces; treatment of halves with chlorine (1,000 ?g/ml) or lactic acid (1 or 2%), with or without SDS, was most efficacious. Exposure of immersion-inoculated pecan pieces to chlorine (200 ?g/ml), lactic acid (2%) and levulinic acid (2%) with or without SDS, and Tsunami (80 ?g/ml) during intermittent vacuum (18 ± 2 mbar) and ambient atmospheric pressure treatments for up to 20 min reduced Salmonella by only 0.1 to 1.0 log CFU/g. These studies emphasize the importance of preventing contamination of pecan nutmeats with Salmonella. Once nuts are contaminated, the lethality of sanitizers tested in this study is minimal.
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Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia.
Neurology
PUBLISHED: 04-17-2013
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We aimed to assess sensitivity and specificity of the updated criteria for behavioral variant frontotemporal dementia (bvFTD) based on a large autopsy-confirmed cohort of patients with dementia.
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Detection of hydrodynamic stimuli by the Florida manatee (Trichechus manatus latirostris).
J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol.
PUBLISHED: 04-16-2013
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Florida manatees inhabit the coastal and inland waters of the peninsular state. They have little difficulty navigating the turbid waterways, which often contain obstacles that they must circumnavigate. Anatomical and behavioral research suggests that the vibrissae and associated follicle-sinus complexes that manatees possess over their entire body form a sensory array system for detecting hydrodynamic stimuli analogous to the lateral line system of fish. This is consistent with data highlighting that manatees are tactile specialists, evidenced by their specialized facial morphology and use of their vibrissae during feeding and active investigation/manipulation of objects. Two Florida manatees were tested in a go/no-go procedure using a staircase method to assess their ability to detect low-frequency water movement. Hydrodynamic vibrations were created by a sinusoidally oscillating sphere that generated a dipole field at frequencies from 5 to 150 Hz, which are below the apparent functional hearing limit of the manatee. The manatees detected particle displacement of less than 1??m for frequencies of 15-150 Hz and of less than a nanometer at 150 Hz. Restricting the facial vibrissae with various size mesh openings indicated that the specialized sensory hairs played an important role in the manatees exquisite tactile sensitivity.
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A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin.
Metallomics
PUBLISHED: 03-13-2013
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Cisplatin and some of its derivatives have been shown to be very successful anticancer agents. Their main mode of action has been proposed to be via covalent binding to DNA. However, one of the limitations of these drugs is their poor activity against some tumours due to intrinsic or acquired resistance. Therefore, there is interest in developing complexes with different binding modes and mode of action. Herein we present a novel platinum(ii)-terpyridine complex (1) which interacts non-covalently with DNA and induces cell death via a different mechanism than cisplatin. The interaction of this complex with DNA was studied by UV/Vis spectroscopic titrations, fluorescent indicator displacement (FID) assays and circular dichroism (CD) titrations. In addition, computational docking studies were carried out with the aim of establishing the complexs binding mode. These experimental and computational studies showed the complex to have an affinity constant for DNA of ?10(4) M(-1), a theoretical free energy of binding of -10.83 kcal mol(-1) and selectivity for the minor groove of DNA. Long-term studies indicated that 1 did not covalently bind (or nick) DNA. The cancer cell antiproliferative properties of this platinum(ii) complex were probed in vitro against human and murine cell lines. Encouragingly the platinum(ii) complex displayed selective toxicity for the cancerous (U2OS and SH-SY5Y) and proliferating NIH 3T3 cell lines. Further cell based studies were carried out to establish the mode of action. Cellular uptake studies demonstrated that the complex is able to penetrate the cell membrane and localize to the nucleus, implying that genomic DNA could be a cellular target. Detailed immunoblotting studies in combination with DNA-flow cytometry showed that the platinum(ii) complex induced cell death in a manner consistent with necrosis.
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Prion-like properties of pathological TDP-43 aggregates from diseased brains.
Cell Rep
PUBLISHED: 03-12-2013
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TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.
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Prion-like spreading of pathological ?-synuclein in brain.
Brain
PUBLISHED: 03-06-2013
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?-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative ?-synucleinopathies. However, the molecular mechanisms underlying ?-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble ?-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated ?-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse ?-synuclein efficiently induced similar ?-synuclein pathologies in wild-type mice. C57BL/6J mice injected with ?-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble ?-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse ?-synuclein started to accumulate 3 months after inoculation, while injected human ?-synuclein fibrils disappeared in about a week. These results indicate that ?-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces ?-synuclein pathology in vivo. This is a new mouse model of sporadic ?-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.
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An inordinate fondness? The number, distributions, and origins of diatom species.
J. Eukaryot. Microbiol.
PUBLISHED: 03-01-2013
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The number of extant species of diatoms is estimated here to be at least 30,000 and probably ca. 100,000, by extrapolation from an eclectic sample of genera and species complexes. Available data, although few, indicate that the pseudocryptic species being discovered in many genera are not functionally equivalent. Molecular sequence data show that some diatom species are ubiquitously dispersed. A good case can be made that at least some diatom species and even a few genera are endemics, but many such claims are still weak. The combination of very large species numbers and relatively rapid dispersal in diatoms is inconsistent with some versions of the "ubiquity hypothesis" of protist biogeography, and appears paradoxical. However, population genetic data indicate geographical structure in all the (few) marine and freshwater species that have been examined in detail, sometimes over distances of a few tens of kilometres. The mode of speciation may often be parapatric, in the context of a constantly shifting mosaic of temporarily isolated (meta) populations, but if our "intermediate dispersal hypothesis" is true (that long-distance dispersal is rare, but not extremely rare), allopatric speciation could also be maximized.
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Frontotemporal dementia with amyotrophic lateral sclerosis: a clinical comparison of patients with and without repeat expansions in C9orf72.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 02-19-2013
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Repeat expansions in C9orf72 are a major cause of frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Not all FTD-ALS patients show expansions. The study examined whether there are clinical differences between FTD-ALS patients with and without expansions in C9orf72. We examined case notes from consecutive FTD-ALS patients, screened for C9orf72 expansions, and documented demographic, neurological, behavioural and cognitive characteristics. Sixty patients met the selection criteria, of whom 11 showed expanded repeats (C9-positive) and 49 did not (C9-negative). A strong male bias was present in the C9-negative group only. A family history of FTD or ALS was recorded in both groups, but was significantly more common in C9-positive cases. Psychotic and irrational behaviours, apathy, disinhibition and loss of empathy were significantly more common in C9-positive cases, with a trend towards more frequent bulbar signs. No differences were found in onset age, presentation (ALS or FTD first), or cognitive changes (language and executive impairments). In conclusion, FTD-ALS is not clinically uniform. Phenotypic differences exist between patients with and without C9orf72 expansions, suggesting that FTD-ALS may be underpinned by distinct neurobiological substrates. The presence of psychiatric symptoms in the context of FTD-ALS should alert clinicians to the possibility of C9orf72 expansions.
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Histone deacetylase class II and acetylated core histone immunohistochemistry in human brains with Huntingtons disease.
Brain Res.
PUBLISHED: 02-08-2013
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Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG/polyglutamine repeat expansion, which is associated with a dysregulation of histone function and an impairment of protein transcription. Histone deacetylase (HDAC) inhibitors, such as vorinostat (SAHA), have shown promise as therapeutic agents. However, there have been few studies on the expression of HDACs and acetylated core histones (AcHs) in either normal animals or humans, or in HD patients or HD animal models. Therefore, we investigated the expression of HDACs and AcHs in HD brain by immunohistochemistry, and have compared findings with elderly control subjects and patients with frontotemporal lobar degeneration (FTLD) to determine whether any observed changes were specific for HD. Results and conclusion: we show specific and significant losses of AcH2A, AcH2B, AcH3 and AcH4 expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD compared to patients with FTLD and control subjects, while the level of HDAC 5 was increased in these cells.
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Correlation of A? oligomer levels in matched cerebrospinal fluid and serum samples.
Neurosci. Lett.
PUBLISHED: 02-02-2013
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We recently reported a newly developed enzyme-linked immunosorbent assay (ELISA) for high molecular weight amyloid-? (A?) oligomers in which the same A? monoclonal antibody, BAN50, was used for both capture and detection in a single antibody sandwich enzyme linked immunosorbent assay (ELISA) system. Although our previous data have suggested that this assay will be useful for the early diagnosis of Alzheimer disease (AD) in cerebrospinal fluid (CSF) samples, the invasive CSF sampling procedure, with associated potential complications, limits use of these samples in routine clinical practice. In this study, we have demonstrated that our ELISA can detect signals in 60% of serum samples and in 80% of CSF samples obtained from non-demented subjects. Heterophilic antibodies that are reported to be a primary confounding factor in this type of ELISA system did not affect the signals obtained. Although the levels of serum A? oligomers were unexpectedly high, suggesting the possible detection of non-pathological A? complexes associated with serum carrier proteins, they did show a significant positive correlation with the levels obtained from matched CSF samples. This correlation between CSF and serum A? oligomer levels implies that the levels of serum A? oligomers measured with our ELISA might be useful as a marker for AD that reflects an intact system of A? transport across the blood brain barrier.
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The head tracks and gaze predicts: how the worlds best batters hit a ball.
PLoS ONE
PUBLISHED: 02-01-2013
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Hitters in fast ball-sports do not align their gaze with the ball throughout ball-flight; rather, they use predictive eye movement strategies that contribute towards their level of interceptive skill. Existing studies claim that (i) baseball and cricket batters cannot track the ball because it moves too quickly to be tracked by the eyes, and that consequently (ii) batters do not - and possibly cannot - watch the ball at the moment they hit it. However, to date no studies have examined the gaze of truly elite batters. We examined the eye and head movements of two of the worlds best cricket batters and found both claims do not apply to these batters. Remarkably, the batters coupled the rotation of their head to the movement of the ball, ensuring the ball remained in a consistent direction relative to their head. To this end, the ball could be followed if the batters simply moved their head and kept their eyes still. Instead of doing so, we show the elite batters used distinctive eye movement strategies, usually relying on two predictive saccades to anticipate (i) the location of ball-bounce, and (ii) the location of bat-ball contact, ensuring they could direct their gaze towards the ball as they hit it. These specific head and eye movement strategies play important functional roles in contributing towards interceptive expertise.
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Comparative analysis of detection methods for congenital cytomegalovirus infection in a Guinea pig model.
JAMA Otolaryngol Head Neck Surg
PUBLISHED: 01-19-2013
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To assess the validity of the guinea pig as a model for congenital cytomegalovirus (CMV) infection by comparing the effectiveness of detecting the virus by real-time polymerase chain reaction (PCR) in blood, urine, and saliva.
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Effect of angle on flow-induced vibrations of pinniped vibrissae.
PLoS ONE
PUBLISHED: 01-01-2013
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Two types of vibrissal surface structures, undulated and smooth, exist among pinnipeds. Most Phocidae have vibrissae with undulated surfaces, while Otariidae, Odobenidae, and a few phocid species possess vibrissae with smooth surfaces. Variations in cross-sectional profile and orientation of the vibrissae also exist between pinniped species. These factors may influence the way that the vibrissae behave when exposed to water flow. This study investigated the effect that vibrissal surface structure and orientation have on flow-induced vibrations of pinniped vibrissae. Laser vibrometry was used to record vibrations along the whisker shaft from the undulated vibrissae of harbor seals (Phoca vitulina) and northern elephant seals (Mirounga angustirostris) and the smooth vibrissae of California sea lions (Zalophus californianus). Vibrations along the whisker shaft were measured in a flume tank, at three orientations (0°, 45°, 90°) to the water flow. The results show that vibration frequency and velocity ranges were similar for both undulated and smooth vibrissae. Angle of orientation, rather than surface structure, had the greatest effect on flow-induced vibrations. Vibration velocity was up to 60 times higher when the wide, flat aspect of the whisker faced into the flow (90°), compared to when the thin edge faced into the flow (0°). Vibration frequency was also dependent on angle of orientation. Peak frequencies were measured up to 270 Hz and were highest at the 0° orientation for all whiskers. Furthermore, CT scanning was used to quantify the three-dimensional structure of pinniped vibrissae that may influence flow interactions. The CT data provide evidence that all vibrissae are flattened in cross-section to some extent and that differences exist in the orientation of this profile with respect to the major curvature of the hair shaft. These data support the hypothesis that a compressed cross-sectional profile may play a key role in reducing self-noise of the vibrissae.
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Neurophysiological studies may provide a misleading picture of how perceptual-motor interactions are coordinated.
Iperception
PUBLISHED: 01-01-2013
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Neurophysiological measurement techniques like fMRI and TMS are increasingly being used to examine the perceptual-motor processes underpinning the ability to anticipate the actions of others. Crucially, these techniques invariably restrict the experimental task that can be used and consequently limit the degree to which the findings can be generalised. These limitations are discussed based on a recent paper by Tomeo et al. (2012) who sought to examine responses to fooling actions by using TMS on participants who passively observed spliced video clips where bodily information was, and was not, linked to the action outcome. We outline two particular concerns with this approach. First, spliced video clips that show physically impossible actions are unlikely to simulate a "fooling" action. Second, it is difficult to make meaningful inferences about perceptual-motor expertise from experiments where participants cannot move. Taken together, we argue that wider generalisations based on these findings may provide a misunderstanding of the phenomenon such a study is designed to explore.
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Low frequency narrow-band calls in bottlenose dolphins (Tursiops truncatus): signal properties, function, and conservation implications.
J. Acoust. Soc. Am.
PUBLISHED: 11-18-2011
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Dolphins routinely use sound for social purposes, foraging and navigating. These sounds are most commonly classified as whistles (tonal, frequency modulated, typical frequencies 5-10 kHz) or clicks (impulsed and mostly ultrasonic). However, some low frequency sounds have been documented in several species of dolphins. Low frequency sounds produced by bottlenose dolphins (Tursiops truncatus) were recorded in three locations along the Gulf of Mexico. Sounds were characterized as being tonal with low peak frequencies (mean?=?990 Hz), short duration (mean?=?0.069 s), highly harmonic, and being produced in trains. Sound duration, peak frequency and number of sounds in trains were not significantly different between Mississippi and the two West Florida sites, however, the time interval between sounds within trains in West Florida was significantly shorter than in Mississippi (t?=?-3.001, p?=?0.011). The sounds were significantly correlated with groups engaging in social activity (F=8.323, p=0.005). The peak frequencies of these sounds were below what is normally thought of as the range of good hearing in bottlenose dolphins, and are likely subject to masking by boat noise.
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Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-08-2011
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TAR DNA-binding protein of 43 kDa (TDP-43) is the major component of the intracellular inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we show that both monoclonal (60019-2-Ig) and polyclonal (10782-2-AP) anti-TDP-43 antibodies recognize amino acids 203-209 of human TDP-43. The monoclonal antibody labeled human TDP-43 by recognizing Glu204, Asp205 and Arg208, but failed to react with mouse TDP-43. The antibodies stained the abnormally phosphorylated C-terminal fragments of 24-26 kDa in addition to normal TDP-43 in ALS and FTLD brains. Immunoblot analysis after protease treatment demonstrated that the epitope of the antibodies (residues 203-209) constitutes part of the protease-resistant domain of TDP-43 aggregates which determine a common characteristic of the pathological TDP-43 in both ALS and FTLD-TDP. The antibodies and methods used in this study will be useful for the characterization of abnormal TDP-43 in human materials, as well as in vitro and animal models for TDP-43 proteinopathies.
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Functional characterization of the switchgrass (Panicum virgatum) R2R3-MYB transcription factor PvMYB4 for improvement of lignocellulosic feedstocks.
New Phytol.
PUBLISHED: 10-11-2011
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• The major obstacle for bioenergy production from switchgrass biomass is the low saccharification efficiency caused by cell wall recalcitrance. Saccharification efficiency is negatively correlated with both lignin content and cell wall ester-linked p-coumarate: ferulate (p-CA : FA) ratio. In this study, we cloned and functionally characterized an R2R3-MYB transcription factor from switchgrass and evaluated its potential for developing lignocellulosic feedstocks. • The switchgrass PvMYB4 cDNAs were cloned and expressed in Escherichia coli, yeast, tobacco and switchgrass for functional characterization. Analyses included determination of phylogenetic relations, in situ hybridization, electrophoretic mobility shift assays to determine binding sites in target promoters, and protoplast transactivation assays to demonstrate domains active on target promoters. • PvMYB4 binds to the AC-I, AC-II and AC-III elements of monolignol pathway genes and down-regulates these genes in vivo. Ectopic overexpression of PvMYB4 in transgenic switchgrass resulted in reduced lignin content and ester-linked p-CA : FA ratio, reduced plant stature, increased tillering and an approx. threefold increase in sugar release efficiency from cell wall residues. • We describe an alternative strategy for reducing recalcitrance in switchgrass by manipulating the expression of a key transcription factor instead of a lignin biosynthetic gene. PvMYB4-OX transgenic switchgrass lines can be used as potential germplasm for improvement of lignocellulosic feedstocks and provide a platform for further understanding gene regulatory networks underlying switchgrass cell wall recalcitrance.
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Localization and source level estimates of black drum (Pogonias cromis) calls.
J. Acoust. Soc. Am.
PUBLISHED: 10-07-2011
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A four hydrophone linear array was used to localize calling black drum and estimate source levels and signal propagation. A total of 1025 source level estimates averaged 165 dB(RMS) relative (re:) 1 ?Pa (standard deviation (SD)=1.0). The authors suggest that the diverticulated morphology of the black drum swimbladder increase the bladders surface area, thus contributing to sound amplitude. Call energy was greatest in the fundamental frequency (94 Hz) followed by the second (188 Hz) and third harmonics (282 Hz). A square root model best described propagation of the entire call, and separately the fundamental frequency and second harmonic. A logarithmic model best described propagation of the third harmonic which was the only component to satisfy the cut-off frequency equation. Peak auditory sensitivity was 300 Hz at a 94 dB re: 1 ?Pa threshold based on auditory evoked potential measurements of a single black drum. Based on mean RMS source level, signal propagation, background levels, and hearing sensitivity, the communication range of black drum was estimated at 33-108 m and was limited by background levels not auditory sensitivity. This estimate assumed the source and receiver were at approximately 0.5 m above the bottom. Consecutive calls of an individual fish localized over 59 min demonstrated a mean calling period of 3.6 s (SD=0.48), mean swimming speed of 0.5 body lengths/s, and a total distance swam of 1035 m.
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Gateway-compatible vectors for high-throughput gene functional analysis in switchgrass (Panicum virgatum L.) and other monocot species.
Plant Biotechnol. J.
PUBLISHED: 09-28-2011
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Switchgrass (Panicum virgatum L.) is a C4 perennial grass and has been identified as a potential bioenergy crop for cellulosic ethanol because of its rapid growth rate, nutrient use efficiency and widespread distribution throughout North America. The improvement of bioenergy feedstocks is needed to make cellulosic ethanol economically feasible, and genetic engineering of switchgrass is a promising approach towards this goal. A crucial component of creating transgenic switchgrass is having the capability of transforming the explants with DNA sequences of interest using vector constructs. However, there are limited options with the monocot plant vectors currently available. With this in mind, a versatile set of Gateway-compatible destination vectors (termed pANIC) was constructed to be used in monocot plants for transgenic crop improvement. The pANIC vectors can be used for transgene overexpression or RNAi-mediated gene suppression. The pANIC vector set includes vectors that can be utilized for particle bombardment or Agrobacterium-mediated transformation. All the vectors contain (i) a Gateway cassette for overexpression or silencing of the target sequence, (ii) a plant selection cassette and (iii) a visual reporter cassette. The pANIC vector set was functionally validated in switchgrass and rice and allows for high-throughput screening of sequences of interest in other monocot species as well.
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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.
Neuron
PUBLISHED: 09-14-2011
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The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
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Inactivation of Salmonella on pecan nutmeats by hot air treatment and oil roasting.
J. Food Prot.
PUBLISHED: 09-10-2011
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Studies were done to determine the effectiveness of hot air drying, dry roasting, and oil roasting in killing Salmonella on pecan nutmeats. Pecan halves and pieces were inoculated by immersion in a five-serotype suspension of Salmonella or by surface application of powdered chalk containing the pathogen. Hot air treatment of low-moisture (2.8 to 4.1%) and high-moisture (10.5 to 11.2%) immersion-inoculated nutmeats (initial population, 6.18 to 7.16 log CFU/g) at 120°C for 20 min reduced the number of Salmonella by 1.18 to 1.26 and 1.89 to 2.04 log CFU/g, respectively. However, regardless of the moisture content, hot air treatment of pecan halves containing 0.77 log CFU/g at 120°C for 20 min failed to eliminate Salmonella. Reductions were >7 log CFU/g when dry pieces were dry roasted at 160°C for 15 min. Treatment of halves at 140°C for 20 min, 150°C for 15 min, or 170°C for 10 min reduced Salmonella by 5 log CFU/g. The pathogen was slightly more heat resistant in immersion-inoculated nutmeats than on surface-inoculated nutmeats. Exposure of immersion-inoculated pieces to peanut oil at 127°C for 1.5 min or 132°C for 1.0 min reduced the number of Salmonella by 5 log CFU/g. Treatment of halves at 138°C for 2.0 min reduced Salmonella by 5 log CFU/g; treatment at 132°C for 2.5 to 4.0 min did not always achieve this reduction. Hot air treatment cannot be relied upon to reduce Salmonella by 5 log CFU/g of raw pecan nutmeats without changing sensory qualities. Treatment temperatures and times typically used to oil roast nutmeats appear to be sufficient to reduce Salmonella by 5 log CFU/g.
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Phosphorylated ?-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinsons disease.
FASEB J.
PUBLISHED: 08-24-2011
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Parkinsons disease (PD) is characterized by the presence of Lewy bodies containing phosphorylated and aggregated ?-synuclein (?-syn). ?-Syn is present in human body fluids, including blood plasma, and is a potential biomarker for PD. Immunoassays for total and oligomeric forms of both normal and phosphorylated (at Ser-129) ?-syn have been used to assay plasma samples from a longitudinal cohort of 32 patients with PD (sampled at mo 0, 1, 2, 3), as well as single plasma samples from a group of 30 healthy control participants. The levels of ?-syn in plasma varied greatly between individuals, but were remarkably consistent over time within the same individual with PD. The mean level of phospho-?-syn was found to be higher (P=0.053) in the PD samples than the controls, whereas this was not the case for total ?-syn (P=0.244), oligo-?-syn (P=0.221), or oligo-phospho-?-syn (P=0.181). Immunoblots of plasma revealed bands (at 21, 24, and 50-60 kDa) corresponding to phosphorylated ?-syn. Thus, phosphorylated ?-syn can be detected in blood plasma and shows more promise as a diagnostic marker than the nonphosphorylated protein. Longitudinal studies undertaken over a more extended time period will be required to determine whether ?-syn can act as a marker of disease progression.
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Novel sex cells and evidence for sex pheromones in diatoms.
PLoS ONE
PUBLISHED: 08-16-2011
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Diatoms belong to the stramenopiles, one of the largest groups of eukaryotes, which are primarily characterized by a presence of an anterior flagellum with tubular mastigonemes and usually a second, smooth flagellum. Based on cell wall morphology, diatoms have historically been divided into centrics and pennates, of which only the former have flagella and only on the sperm. Molecular phylogenies show the pennates to have evolved from among the centrics. However, the timing of flagellum loss--whether before the evolution of the pennate lineage or after--is unknown, because sexual reproduction has been so little studied in the araphid basal pennate lineages, to which Pseudostaurosira belongs.
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Biomechanics and visual-motor control: how it has, is, and will be used to reveal the secrets of hitting a cricket ball.
Sports Biomech
PUBLISHED: 08-11-2011
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Cricket batting is an incredibly complex task which requires the coordination of full-body movements to successfully hit a fast moving ball. Biomechanical studies on batting have helped to shed light on how this intricate skill may be performed, yet the many different techniques exhibited by batters make the systematic examination of batting difficult. This review seeks to critically evaluate the existing literature examining cricket batting, but doing so by exploring the strong but often neglected relationship between biomechanics and visual-motor control. In three separate sections, the paper seeks to address (i) the different theories of motor control which may help to explain how skilled batters can hit a ball, (ii) strategies used by batters to overcome the (at times excessive) temporal constraints, and (iii) an interpretation from a visual-motor perspective of the prevailing biomechanical data on batting.
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The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships.
Brain
PUBLISHED: 08-11-2011
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Accuracy of clinical diagnosis of dementia is increasingly important for therapeutic and scientific investigations. In this study, we examine diagnostic accuracy in a consecutive series of 228 patients referred to a specialist early-onset dementia clinic, whose brains were subsequently examined at post-mortem. Diagnosis was based on structured history, neurological examination and neuropsychological assessment, with emphasis on qualitative as well as quantitative aspects of performance. Neuroimaging provided support for but did not alter the clinical diagnosis. We set out the principles that guided diagnosis: (i) time course of illness; (ii) weighting of physical, behavioural and cognitive symptoms and signs; (iii) anterior versus posterior hemisphere character of cognitive change; and (iv) specificity of deficit, paying attention to the differentiation between syndromes of frontotemporal lobar degeneration and focal forms of Alzheimers disease. Forty-two per cent of the patients had clinical diagnoses of one of the syndromes of frontotemporal lobar degeneration, the high proportion reflecting the research interests of the group. Forty-six per cent were diagnosed with Alzheimers disease and the remaining patients, dementia with Lewy bodies, Creutzfeldt-Jakob disease, vascular or unclassified dementia. Frontotemporal lobar degeneration was identified with 100% sensitivity and 97% specificity and Alzheimers disease with 97% sensitivity and 100% specificity. Patients with other pathologies were accurately identified on clinical grounds. Examination of subsyndromes of frontotemporal lobar degeneration showed a relatively predictable relationship between clinical diagnosis and pathological subtype. Whereas the behavioural disorder of frontotemporal dementia was associated with tau, transactive response DNA binding protein 43 and fused-in-sarcoma pathology, cases of frontotemporal dementia with motoneuron disease, semantic dementia and, with one exception, progressive non-fluent aphasia were associated with transactive response DNA binding protein 43 pathology, distinguished by ubiquitin subtyping (types B, C and A, respectively). Clinical diagnoses of progressive apraxia, corticobasal degeneration and progressive supranuclear palsy were, with one exception, associated with Pick, corticobasal and progressive supranuclear palsy subtypes of tau pathology, respectively. Unanticipated findings included Alzheimer pathology in two patients presenting with the behavioural syndrome of frontotemporal dementia and corticobasal pathology in four others with clinical frontotemporal dementia. Notwithstanding such anomalies, which serve as a reminder that there is not an absolute concordance between clinical phenotype and underlying pathology, the findings show that dementias can be distinguished in life with a high level of accuracy. Moreover, careful clinical phenotyping allows prediction of histopathological subtype of frontotemporal lobar degeneration. The principles guiding diagnosis provide the foundation for future prospective studies.
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Hemodynamic and histologic characterization of a swine (Sus scrofa domestica) model of chronic pulmonary arterial hypertension.
Comp. Med.
PUBLISHED: 08-09-2011
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The purpose of this work was to develop and characterize an aortopulmonary shunt model of chronic pulmonary hypertension in swine and provide sequential hemodynamic, angiographic, and histologic data by using an experimental endoarterial biopsy catheter. Nine Yucatan female microswine (Sus scrofa domestica) underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Sequential hemodynamic, angiographic, and pulmonary vascular samples were obtained. Six pigs (mean weight, 22.4±5.3 kg; mean age, 7.3±2.7 mo at surgery) survived long-term (6 mo) and consistently developed marked pulmonary arterial hypertension. Angiography showed characteristic central pulmonary arterial enlargement and peripheral tortuosity and pruning. The biopsy catheter was safe and effective in obtaining pulmonary endoarterial samples for histologic studies, which showed neointimal and medial changes. Autopsy confirmed severe pulmonary vascular changes, including concentric obstructive neointimal and plexiform-like lesions. This swine model showed hemodynamic, angiographic, and histologic characteristics of chronic pulmonary arterial hypertension that mimicked the arterial pulmonary hypertension of systemic-to-pulmonary arterial shunts in humans. Experimental data obtained using this and other models and application of an in vivo endoarterial biopsy technique may aid in understanding mechanisms and developing therapies for experimental and human pulmonary arterial hypertension.
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TDP-43 pathological changes in early onset familial and sporadic Alzheimers disease, late onset Alzheimers disease and Downs syndrome: association with age, hippocampal sclerosis and clinical phenotype.
Acta Neuropathol.
PUBLISHED: 08-08-2011
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TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimers disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Downs Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.
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Hearing and morphological specializations of the mojarra (Eucinostomus argenteus).
J. Exp. Biol.
PUBLISHED: 07-29-2011
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The air-filled swimbladder acts as an acoustic amplifier for some fish by converting sound pressure into particle motion, which is transmitted to the inner ear. Here, we describe in detail the specialized connection between the swimbladder and ear in the mojarra, as well as a modified cone on the anal fin in which the posterior end of the swimbladder sits. Hearing tests show the mojarra has better hearing sensitivity than other species of fish without a connection. However, mojarras do not seem to use this adaptation for communication. Furthermore, the inclined position of the swimbladder may help the fish to catch their prey more easily, as the swimbladder will be horizontal when they are picking up benthic prey.
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Early treatment of scoliosis with growing rods in children with severe spinal muscular atrophy: a preliminary report.
J Pediatr Orthop
PUBLISHED: 05-17-2011
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Spinal muscle atrophy (SMA) is a progressive neuromuscular disease predominantly presenting in infancy and early childhood. Scoliosis is the most common spinal deformity in these patients and treatment in SMA patients is controversial. Treatment is usually definitive fusion. The purpose of this study is to evaluate a novel growing rod technique used to treat more involved children with SMA types I and II with scoliosis at an earlier age.
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Glucocerebrosidase mutations in diffuse Lewy body disease.
Parkinsonism Relat. Disord.
PUBLISHED: 05-10-2011
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Clinicogenetic and pathological studies have shown that mutations of the glucocerebrosidase gene (GBA) are a risk factor for Parkinsons disease and Lewy body disorders. In the present study, we have identified GBA mutations in 6.8% (4/59) of cases with a pathological diagnosis of diffuse Lewy body disease. Taken with previous studies, it appears that GBA mutations are associated with a more diffuse pattern of Lewy body distribution involving the cerebral cortex than the brainstem/limbic distribution observed in typical Parkinsons disease.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.