234 research outputs found
Cloning, in silico structural characterization and expression analysis of MfAtr4, an ABC transporter from the banana pathogen Mycosphaerella fijiensis
ABC transporters are membrane proteins that use the energy released from the hydrolysis of ATP to drive the transport of compounds across biological membranes. In some plants, pathogenic fungi ABC transporters play a role as virulence factors by mediating the export of plant defense compounds or fungal virulence factors. Mycosphaerella fijiensis, the causal agent of black Sigatoka disease in banana, is the main constraint for the banana industry worldwide. So far, little is known about molecular mechanism that it uses to infect the host. In this study, degenerated primers designed from fungal ABC transporters known to be involved in virulence were used to isolate homologs from M. fijiensis. Here, we reported the full cloning of MfAtr4 a putative ortholog of MgAtr4, an ABC transporter of the related Mycosphaerella graminicola with a function in virulence. Similarities and differences with its presumed ortholog MgAtr4 are described, and the putative function of MfAtr4 are discussed. Analysis of MfAtr4 gene expression in field banana samples exhibiting visible symptoms of black Sigatoka disease indicated a higher expression of MfAtr4 during the first symptomatic stages in comparison to the late necrotrophic phases, suggesting a role for MfAtr4 in the early stages of pathogenic development of M. fijiensis.Key words: ABC transporters, virulence factors, MgAtr4 ortholog, Mycosphaerella fijiensis, black Sigatoka, Musa sp
P-P Total Cross Sections at VHE from Accelerator Data
Comparison of P-P total cross-sections estimations at very high energies -
from accelerators and cosmic rays - shows a disagreement amounting to more than
10 %, a discrepancy which is beyond statistical errors. Here we use a
phenomenological model based on the Multiple-Diffraction approach to
successfully describe data at accelerator energies. The predictions of the
model are compared with data On the basis of regression analysis we determine
confident error bands, analyzing the sensitivity of our predictions to the
employed data for extrapolation. : using data at 546 and 1.8 TeV, our
extrapolations for p-p total cross-sections are only compatible with the Akeno
cosmic ray data, predicting a slower rise with energy than other cosmic ray
results and other extrapolation methods. We discuss our results within the
context of constraints in the light of future accelerator and cosmic ray
experimental results.Comment: 26 pages aqnd 11 figure
Systematic identification of signaling pathways with potential to confer anticancer drug resistance
Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)–mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF[superscript V600E] melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.National Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant AI07389
Resolvin D2 Attenuates Cardiovascular Damage in Angiotensin II-Induced Hypertension.
Background:
Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension.
Methods:
Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion.
Results:
Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype.
Conclusions:
There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.pre-print362 K
Kepler Flares II: The Temporal Morphology of White-Light Flares on GJ 1243
We present the largest sample of flares ever compiled for a single M dwarf,
the active M4 star GJ 1243. Over 6100 individual flare events, with energies
ranging from to erg, are found in 11 months of 1-minute
cadence data from Kepler. This sample is unique for its completeness and
dynamic range. We have developed automated tools for finding flares in
short-cadence Kepler light curves, and performed extensive validation and
classification of the sample by eye. From this pristine sample of flares we
generate a median flare template. This template shows that two exponential
cooling phases are present during the white-light flare decay, providing
fundamental constraints for models of flare physics. The template is also used
as a basis function to decompose complex multi-peaked flares, allowing us to
study the energy distribution of these events. Only a small number of flare
events are not well fit by our template. We find that complex, multi-peaked
flares occur in over 80% of flares with a duration of 50 minutes or greater.
The underlying distribution of flare durations for events 10 minutes and longer
appears to follow a broken power law. Our results support the idea that
sympathetic flaring may be responsible for some complex flare events.Comment: 12 pages, 9 figures, accepted for publication in Ap
Accounting for uncertainty when assessing association between copy number and disease: a latent class model
<p>Abstract</p> <p>Background</p> <p>Copy number variations (CNVs) may play an important role in disease risk by altering dosage of genes and other regulatory elements, which may have functional and, ultimately, phenotypic consequences. Therefore, determining whether a CNV is associated or not with a given disease might be relevant in understanding the genesis and progression of human diseases. Current stage technology give CNV probe signal from which copy number status is inferred. Incorporating uncertainty of CNV calling in the statistical analysis is therefore a highly important aspect. In this paper, we present a framework for assessing association between CNVs and disease in case-control studies where uncertainty is taken into account. We also indicate how to use the model to analyze continuous traits and adjust for confounding covariates.</p> <p>Results</p> <p>Through simulation studies, we show that our method outperforms other simple methods based on inferring the underlying CNV and assessing association using regular tests that do not propagate call uncertainty. We apply the method to a real data set in a controlled MLPA experiment showing good results. The methodology is also extended to illustrate how to analyze aCGH data.</p> <p>Conclusion</p> <p>We demonstrate that our method is robust and achieves maximal theoretical power since it accommodates uncertainty when copy number status are inferred. We have made <monospace>R</monospace> functions freely available.</p
Kochen-Specker Vectors
We give a constructive and exhaustive definition of Kochen-Specker (KS)
vectors in a Hilbert space of any dimension as well as of all the remaining
vectors of the space. KS vectors are elements of any set of orthonormal states,
i.e., vectors in n-dim Hilbert space, H^n, n>3 to which it is impossible to
assign 1s and 0s in such a way that no two mutually orthogonal vectors from the
set are both assigned 1 and that not all mutually orthogonal vectors are
assigned 0. Our constructive definition of such KS vectors is based on
algorithms that generate MMP diagrams corresponding to blocks of orthogonal
vectors in R^n, on algorithms that single out those diagrams on which algebraic
0-1 states cannot be defined, and on algorithms that solve nonlinear equations
describing the orthogonalities of the vectors by means of statistically
polynomially complex interval analysis and self-teaching programs. The
algorithms are limited neither by the number of dimensions nor by the number of
vectors. To demonstrate the power of the algorithms, all 4-dim KS vector
systems containing up to 24 vectors were generated and described, all 3-dim
vector systems containing up to 30 vectors were scanned, and several general
properties of KS vectors were found.Comment: 19 pages, 6 figures, title changed, introduction thoroughly
rewritten, n-dim rotation of KS vectors defined, original Kochen-Specker 192
(117) vector system translated into MMP diagram notation with a new graphical
representation, results on Tkadlec's dual diagrams added, several other new
results added, journal version: to be published in J. Phys. A, 38 (2005). Web
page: http://m3k.grad.hr/pavici
Functional and structural brain network correlates of visual hallucinations in Lewy body dementia
Visual hallucinations are a common feature of Lewy body dementia. Previous studies have shown that visual hallucinations are highly specific in differentiating Lewy body dementia from Alzheimer’s disease dementia and Alzheimer-Lewy body mixed pathology cases. Computational models propose that impairment of visual and attentional networks is aetiologically key to the manifestation of visual hallucinations symptomatology. However, there is still a lack of experimental evidence on functional and structural brain network abnormalities associated with visual hallucinations in Lewy body dementia. We used EEG source localisation and Network Based Statistics to assess differential topographical patterns in Lewy body dementia between 25 participants with visual hallucinations and 17 participants without hallucinations. Diffusion tensor imaging was used to assess structural connectivity between thalamus, basal forebrain and cortical regions belonging to the functionally affected network component in the hallucinating group, as assessed with Network Based Statistics. Number of white matter streamlines within the cortex and between subcortical and cortical regions was compared between hallucinating and not hallucinating groups and correlated with average EEG source connectivity of the affected subnetwork. Moreover, modular organisation of the EEG source network was obtained, compared between groups, and tested for correlation with structural connectivity. Network analysis showed that compared to non-hallucinating patients, those with hallucinations feature consistent weakened connectivity within the visual ventral network, and between this network and default mode and ventral attentional networks, but not between or within attentional networks. The occipital lobe was the most functionally disconnected region. Structural analysis yielded significantly affected white matter streamlines connecting the cortical regions to the nucleus basalis of Meynert and the thalamus in hallucinating compared to not hallucinating patients. The number of streamlines in the tract between the basal forebrain and the cortex correlated with cortical functional connectivity in non-hallucinating patients, whilst a correlation emerged for the white matter streamlines connecting the functionally affected cortical regions in the hallucinating group. This study proposes, for the first time, differential functional networks between hallucinating and not hallucinating Lewy body dementia patients, and provides an empirical evidence for existing models of visual hallucinations. Specifically, the outcome of the present study shows that the hallucinating condition is associated with functional network segregation in Lewy body dementia and supports the involvement of the cholinergic system as proposed in the current literature
Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models
Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression
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