1,308 research outputs found
The Predicted Binding Site and Dynamics of Peptide Inhibitors to the Methuselah GPCR from Drosophila melanogaster
Peptide inhibitors of Methuselah (Mth), a G protein-coupled receptor (GPCR), were reported that can extend the life span of Drosophila melanogaster. Mth is a class B GPCR, which is characterized by a large, N-terminal ectodomain that is often involved with ligand recognition. The crystal structure of the Mth ectodomain, which binds to the peptide inhibitors with high affinity, was previously determined. Here we report the predicted structures for RWR motif peptides in complex with the Mth ectodomain. We studied representatives of both Pro-class and Arg-class RWR motif peptides and identified ectodomain residues Asp139, Phe130, Asp127, and Asp78 as critical in ligand binding. To validate these structures, we predicted the effects of various ligand mutations on the structure and binding to Mth. The binding of five mutant peptides to Mth was characterized experimentally by surface plasmon resonance, revealing measured affinities that are consistent with predictions. The electron density map calculated from our MD structure compares well with the experimental map of a previously determined peptide/Mth crystal structure and could be useful in refining the current low-resolution data. The elucidation of the ligand binding site may be useful in analyzing likely binding sites in other class B GPCRs
An inhomogeneous toy-model of the quantum gravity with explicitly evolvable observables
An inhomogeneous (1+1)-dimensional model of the quantum gravity is
considered. It is found, that this model corresponds to a string propagating
against some curved background space. The quantization scheme including the
Wheeler-DeWitt equation and the "particle on a sphere" type of the gauge
condition is suggested. In the quantization scheme considered, the "problem of
time" is solved by building of the quasi-Heisenberg operators acting in a space
of solutions of the Wheeler-DeWitt equation and the normalization of the wave
function corresponds to the Klein-Gordon type. To analyze the physical
consequences of the scheme, a (1+1)-dimensional background space is considered
for which a classical solution is found and quantized. The obtained estimations
show the way to solution of the cosmological constant problem, which consists
in compensation of the zero-point oscillations of the matter fields by the
quantum oscillations of the scale factor. Along with such a compensation, a
slow global evolution of a background corresponding to an universe expansion
exists.Comment: 18 page
Supersymmetric Extension of GCA in 2d
We derive the infinite dimensional Supersymmetric Galilean Conformal Algebra
(SGCA) in the case of two spacetime dimensions by performing group contraction
on 2d superconformal algebra. We also obtain the representations of the
generators in terms of superspace coordinates. Here we find realisations of the
SGCA by considering scaling limits of certain 2d SCFTs which are non-unitary
and have their left and right central charges become large in magnitude and
opposite in sign. We focus on the Neveu-Schwarz sector of the parent SCFTs and
develop, in parallel to the GCA studies recently in (arXiv:0912.1090), the
representation theory based on SGCA primaries, Ward identities for their
correlation functions and their descendants which are null states.Comment: La TeX file, 32 pages; v2: typos corrected, journal versio
Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high CTC counts
Purpose: The purpose of this study was to directly compare mutation profiles in multiple single CTCs and cfDNA isolated from the same blood samples taken from patients with metastaic breast cancer (MBC). We aimed to determine whether cell-free DNA would reflect the heterogeneity observed in 40 single CTCs. Experimental design: CTCs were enumerated by Cellsearch. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with metastatic breast cancer. In 5 patients with {greater than or equal to}100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumour tissue by targeted next generation sequencing (NGS) of ~2200 mutations in 50 cancer genes. Results: In the whole cohort, total cfDNA levels and cell counts ({greater than or equal to}5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAM-positive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1 and KRAS genes between individual CTCs. In all 5 patients cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumour tissue and therefore likely reflect either a minor sub-clonal mutation or were acquired with disease progression. Conclusion: Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making. Experimental Design: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85â0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. Conclusions: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity
Accuracy of breeding values of 'unrelated' individuals predicted by dense SNP genotyping
<p>Abstract</p> <p>Background</p> <p>Recent developments in SNP discovery and high throughput genotyping technology have made the use of high-density SNP markers to predict breeding values feasible. This involves estimation of the SNP effects in a training data set, and use of these estimates to evaluate the breeding values of other 'evaluation' individuals. Simulation studies have shown that these predictions of breeding values can be accurate, when training and evaluation individuals are (closely) related. However, many general applications of genomic selection require the prediction of breeding values of 'unrelated' individuals, i.e. individuals from the same population, but not particularly closely related to the training individuals.</p> <p>Methods</p> <p>Accuracy of selection was investigated by computer simulation of small populations. Using scaling arguments, the results were extended to different populations, training data sets and genome sizes, and different trait heritabilities.</p> <p>Results</p> <p>Prediction of breeding values of unrelated individuals required a substantially higher marker density and number of training records than when prediction individuals were offspring of training individuals. However, when the number of records was 2*N<sub>e</sub>*L and the number of markers was 10*N<sub>e</sub>*L, the breeding values of unrelated individuals could be predicted with accuracies of 0.88 â 0.93, where N<sub>e </sub>is the effective population size and L the genome size in Morgan. Reducing this requirement to 1*N<sub>e</sub>*L individuals, reduced prediction accuracies to 0.73â0.83.</p> <p>Conclusion</p> <p>For livestock populations, 1N<sub>e</sub>L requires about ~30,000 training records, but this may be reduced if training and evaluation animals are related. A prediction equation is presented, that predicts accuracy when training and evaluation individuals are related. For humans, 1N<sub>e</sub>L requires ~350,000 individuals, which means that human disease risk prediction is possible only for diseases that are determined by a limited number of genes. Otherwise, genotyping and phenotypic recording need to become very common in the future.</p
Argyres-Douglas theories and S-duality
This article is distributed under the terms of the Creative Commons
Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are creditedM.B. and T.N. are partly supported by the U.S. Department of Energy under grants DOE-SC0010008, DOE-ARRA-SC0003883, and DOE-DE-SC0007897.
This research was supported in part by the National Science Foundation under Grant No.
NSF PHY11-25915. S.G. is partially supported by the ERC Advanced Grant âSyDuGraMâ,
by FNRS-Belgium (convention FRFC PDR T.1025.14 and convention IISN 4.4514.08) and by the âCommunaut´e Francaise de Belgiqueâ through the ARC progra
Amygdaloid Kindling and the GABA System
The effect of increased brain GABA levels on fully kindled amygdala seizures was investigated in Long-Evans rats. The newly synthesized GABA-transaminase inhibitor, -Î-acetylenic GABA (GAG) administered on four consecutive days (100 mg/kg, followed by 50 mg/kg, i.p.) was found to either significantly reduce, or eliminate entirely, the behavioral seizures normally produced by amygdala stimulation. The effect is seen after the first injection of GAG although its magnitude was greater on subsequent days. Behavioral seizures reappeared 2 to 3 days after termination of GAG treatment. The duration of electrographic seizures (self-sustained amygdala after-discharge) was either unchanged or greater on the first day of GAG treatment, but was briefer on subsequent days. The duration of afterdischarges returned to normal levels 1 to 2 days earlier than the behavioral seizures after the termination of GAG. Picrotoxin (1.5-2 mg/kg, i.p.) did not antagonize either electrographic or behavioral effects of inhibition produced with GAG. Electrical stimulation of amygdala delivered during the initial sedation stage induced by picrotoxin resulted in further regression of kindled seizures in the majority of animals. Although in doses employed, GAG alleviates amygdaloid-kindled seizures its use requires caution in view of its ability to reduce arousal level. RĂSUMĂ L'effet de l'ĂlĂvation des taux cĂrĂbraux de GABA sur les crises amygdaliennes par effet d'embrasement complet a ĂtĂĂtudiĂ chez des rats Long-Evans. l'injection pendant 4 jours consĂcutifs de 100 mg/kg suivis de 50 mg/kg i.p. d'un inhibiteur de la GABA. Transaminase nouvellement synthĂtisĂ (Î-acetylenic GABA ou GAG) a significativement rĂduit ou mĂme supprimĂ les crises normalement provoquĂes par la stimulation amygdalienne. l'effet est observĂ aprĂs la premiere injection de GAG, mais son importance s'accroit les jours suivants. Les crises rĂapparaissent 2 ou 3 jours aprĂs la fin du traitement au GAG. Du point de vue Ălectrographique, la durĂe de la postdĂcharge amygdalienne autoentretenue est inchingĂe ou accrue le premier jour du traitement, mais elle diminue les jours suivants pour retourner Ă la normale un ou deux jours avant que les crises ne rĂapparaissent aprĂs la fin de ('administration du GAG. l'injection de picrotoxine (1.5-2 mg/kg i.p.) ne s'oppose pas aux effets inhibiteurs du GAG sur les crises ou leur accompagnement EEG. La stimulation Ălectrique de l'amygdala pendant l'Ătape sĂdative initiate induite par la picrotoxine provoque une rĂgression supplĂmentaire des crises d'embrasement chez la majoritĂ des animaux. Bien que, aux doses utilisĂes, le GAG attĂnue les crises amyg-daliennes d'embrasement, son utilisation nĂcessite des prĂcautions compte tenu de sa tendance Ă rĂduire le niveau d'Ăveil. RESUMEN En ratas Long-Evans se ha investigado el efecto del aumento de los niveles cerebrales de GABA, sobre los ataques originados en la amĂgdala totalmente condicionada, (Kindling). El recientemente sintetizado in-hibidor de la GABA transaminasa, Î-acetilĂnico GABA (GAG), redujo significativamente o eliminĂ totalmente las crisis de comportamiento que habitualmente se producen con la estimulaciĂn de la amĂgdala. El efecto se observa despuĂs de la primera in-yecciĂn de GAG pero su magnitud aumentĂ en dias subsiguientes. Las crisis de comportamiento reaparecieron a los 2â3 dĂas de la interrupciĂn del tratamiento con GAG. La duraciĂn de los ataques electrogrĂficos (perservaciĂn de la post-descarga de la amigdala) no se modificĂ, o incluso aumentĂ, en el primer dia de la administraciĂn de GAG pero se redujo en los dias siguientes. La duraciĂn de las post-descargas volviĂ a sus niveles normales 1 o 2 dias antes que la reapariciĂn de las crisis de comportamiento una vez terminado el tratamiento con GAG. La picrotoxina (1.5-2 mg/kg, i.p.) no antagonizĂ los efectos inhibitorios producidos por el GAG sobre el electroencefalograma o las crisis de comportamiento. La estimulaciĂn elĂctrica sobre la amĂgdala, aplicada durante la fase de sedaciĂn inicial inducida por la picrotoxina, condujo a una regresiĂn aĂn mĂs intensa de las crisis condicionadas, en la mayorĂa de los animales. A pesar de que, con las dosis utilizadas, el GAG alivia las crisis de la amĂgdala previamente condicionada, se requiere gran precauciĂn en su utilizaciĂn en vista de su propiedad de reducir el nivel del despertar. ZUSAMMENFASSUNG Die Wirkung erhĂhter GABA-Spiegel des Gehirns auf AmygdalonkrĂmpfe nach Kindling wurden bei Long-Evans-Ratten untersucht. Der neuerdings synthetisierte GABA-TYansaminasen-Inhibitor, Gamma-Acetylen-GABA (GAG) wurde an 4 aufeinander-folgenden Tagen in einer Dosis von 100 mg/kg und anschlieliend 50 mg/kg i.p. verabfolgt. Er reduzierte entweder signifikant oder eliminierte vĂllig die anfalls-weisen VerhaltensĂnderungen, die normalerweise durch Stimulation des Amygdalon produziert wurden. Die Wirkung ist nach der Erstinjektion des GAG zu beobachten, obgleich ihr AusmaĂ an folgenden Tagen grĂĂer war. Die VerhaltensanfĂlle kamen 2 bis 3 Tagen nach Beendigung der GAG-Behandlung wieder. Die Dauer der elektrographischen AnfĂlle (sich selbst un-terhaltende Amydalonnachentladungen) blieben entweder gleich oder sie wurden grĂĂer am 1. Tag der GAG-Behandlung, wurden aber kĂrzer an folgenden Tagen. Die Dauer der Nachentladungen nor-malisierte sich 1 bis 2 Tage frĂher als die VerhaltensanfĂlle nach Beendigung des GAG verschwanden. Picrotoxin (1.5 bis 2 mg/kg i.p.) wirken nicht als Antagonist gegenĂber der durch GAG produzierten Hemmung der elektrographischen-oder Verhalten-seffekte. Die elektrische Stimulierung des Amygdalon wĂhrend der initialen Sedierung nach Picrotoxin ver-ursachte bei der Mehrzahl der Tiere einen weiteren RĂckgang der durch Kindling entstandenen AnfĂlle. Obgleich das GAG in den verwandten Dosen, die durch Kindling des Amygdalon erzeugten KrĂmpfe leichter ablaufen lUĂt, erfordert seine Anwendung Vorsicht hinsichtlich seiner FĂhigkeit, das Erreg-barkeitsniveau zu senken.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66112/1/j.1528-1157.1980.tb04058.x.pd
Quantifying variation in the ability of yeasts to attract Drosophila melanogaster
Yeasts that invade and colonise fruit significantly enhance the volatile chemical diversity of this ecosystem. These modified bouquets are thought to be more attractive to Drosophila flies than the fruit alone, but the variance of attraction in natural yeast populations is uncharacterised. Here we investigate how a range of yeast isolates affect the attraction of female D. melanogaster to fruit in a simple two choice assay comparing yeast to sterile fruit. Of the 43 yeast isolates examined, 33 were attractive and seven repellent to the flies. The results of isolate-versus-isolate comparisons provided the same relative rankings. Attractiveness varied significantly by yeast, with the strongly fermenting Saccharomyces species generally being more attractive than the mostly respiring non-Saccharomyces species (P = 0.0035). Overall the habitat (fruit or other) from which the isolates were directly sampled did not explain attraction (P = 0.2352). However, yeasts isolated from fruit associated niches were more attractive than those from non-fruit associated niches (P = 0.0188) regardless of taxonomic positioning. These data suggest that while attractiveness is primarily correlated with phylogenetic status, the ability to attract Drosophila is a labile trait among yeasts that is potentially associated with those inhabiting fruit ecosystems. Preliminary analysis of the volatiles emitted by four yeast isolates in grape juice show the presence/absence of ethanol and acetic acid were not likely explanations for the observed variation in attraction. These data demonstrate variation among yeasts for their ability to attract Drosophila in a pattern that is consistent with the hypothesis that certain yeasts are manipulating fruit odours to mediate interactions with their Drosophila dispersal agent. ĂŠ 2013 Palanca et al
Advances in understanding of air-sea exchange and cycling of greenhouse gases in the upper ocean
\ua9 2024 University of California Press. All rights reserved. The airâsea exchange and oceanic cycling of greenhouse gases (GHG), including carbon dioxide (CO2), nitrous oxide (N2O), methane (CH4), carbon monoxide (CO), and nitrogen oxides (NOx \ubc NO \ufe NO2), are fundamental in controlling the evolution of the Earthâs atmospheric chemistry and climate. Significant advances have been made over the last 10 years in understanding, instrumentation and methods, as well as deciphering the production and consumption pathways of GHG in the upper ocean (including the surface and subsurface ocean down to approximately 1000 m). The global ocean under current conditions is now well established as a major sink for CO2, a major source for N2O and a minor source for both CH4 and CO. The importance of the ocean as a sink or source of NOx is largely unknown so far. There are still considerable uncertainties about the processes and their major drivers controlling the distributions of N2O, CH4, CO, and NOx in the upper ocean. Without having a fundamental understanding of oceanic GHG production and consumption pathways, our knowledge about the effects of ongoing major oceanic changesâwarming, acidification, deoxygenation, and eutrophicationâon the oceanic cycling and airâsea exchange of GHG remains rudimentary at best. We suggest that only through a comprehensive, coordinated, and interdisciplinary approach that includes data collection by global observation networks as well as joint process studies can the necessary data be generated to (1) identify the relevant microbial and phytoplankton communities, (2) quantify the rates of ocean GHG production and consumption pathways, (3) comprehend their major drivers, and (4) decipher economic and cultural implications of mitigation solutions
Data regarding transplant induced germinal center humoral autoimmunity
This data is related to the research article entitled âGerminal center humoral autoimmunity independently mediates progression of allograft vasculopathyâ (Harper et al., 2016) [2]. The data presented here focuses on the humoral autoimmune response triggered by transferred allogeneic CD4 T cells and includes details on: (a) the recipient splenic germinal center (GC) response; (b) augmentation of humoral autoimmunity and accelerated heart allograft rejection following transplantation from donors primed against recipient; (c) flow cytometric analysis of donor and recipient CD4 T cells for signature markers of T follicular helper cell differentiation; (d) in vitro donor endothelial cell migration in response to column purified autoantibody from recipient sera; (e) analysis of development of humoral responses in recipients following adoptive transfer of donor CD4 T cells and; (f) the development of humoral autoimmunity in mixed haematopoietic chimeric mice
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