835 research outputs found
Association of Trypanosoma vivax in extracellular sites with central nervous system lesions and changes in cerebrospinal fluid in experimentally infected goats
Changes in cerebrospinal fluid (CSF) and anatomical and histopathological central nervous system (CNS) lesions were evaluated, and the presence of Trypanosoma vivax in CNS tissues was investigated through PCR. Twelve adult male goats were divided into three groups (G): G1, infected with T. vivax and evaluated during the acute phase; G2, infected goats evaluated during the chronic phase; and G3, consisting of non-infected goats. Each goat from G1 and G2 was infected with 1.25 Ă 105 trypomastigotes. Cerebrospinal fluid (CSF) analysis and investigation of T. vivax was performed at the 15th day post-infection (dpi) in G1 goats and on the fifth day after the manifestation of nervous system infection signs in G2 goats. All goats were necropsied, and CNS fragments from G1 and G2 goats were evaluated by PCR for the determination of T. vivax. Hyperthermia, anemia and parasitemia were observed from the fifth dpi for G1 and G2, with the highest parasitemia peak between the seventh and 21st dpi. Nervous system infection signs were observed in three G2 goats between the 30th and 35th dpi. CSF analysis revealed the presence of T. vivax for G2. Meningitis and meningoencephalitis were diagnosed in G2. PCR were positive for T. vivax in all the samples tested. In conclusion, T. vivax may reach the nervous tissue resulting in immune response from the host, which is the cause of progressive clinical and pathological manifestations of the CNS in experimentally infected goats
Association of creatine kinase and skin toxicity in phase I trials of anticancer agents.
BACKGROUND: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. METHODS: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. RESULTS: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 Uâl(-1)) compared with G1 (median 81 Uâl(-1)) and no rash (median 55 Uâl(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. CONCLUSION: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials
Kahler Moduli Inflation Revisited
We perform a detailed numerical analysis of inflationary solutions in Kahler
moduli of type IIB flux compactifications. We show that there are inflationary
solutions even when all the fields play an important role in the overall shape
of the scalar potential. Moreover, there exists a direction of attraction for
the inflationary trajectories that correspond to the constant volume direction.
This basin of attraction enables the system to have an island of stability in
the set of initial conditions. We provide explicit examples of these
trajectories, compute the corresponding tilt of the density perturbations power
spectrum and show that they provide a robust prediction of n_s approximately
0.96 for 60 e-folds of inflation.Comment: 27 pages, 9 figure
Smooth tensionful higher-codimensional brane worlds with bulk and brane form fields
Completely regular tensionful codimension-n brane world solutions are
discussed, where the core of the brane is chosen to be a thin codimension-(n-1)
shell in an infinite volume flat bulk, and an Einstein-Hilbert term localized
on the brane is included (Dvali-Gabadadze-Porrati models). In order to support
such localized sources we enrich the vacuum structure of the brane by the
inclusion of localized form fields. We find that phenomenological constraints
on the size of the internal core seem to impose an upper bound to the brane
tension. Finite transverse-volume smooth solutions are also discussed.Comment: 1+14 pages, 2 figures; section 2.3 improved, typos corrected and
references added. Published versio
Antibiotics Threaten Wildlife: Circulating Quinolone Residues and Disease in Avian Scavengers
Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in the plasma of many nestling cinereous (57%) and Egyptian (40%) vultures. Enrofloxacin and ciprofloxacin were also found in liver samples of all dead cinereous vultures. This is the first report of antibiotic residues in wildlife. We also provide evidence of a direct association between antibiotic residues, primarily quinolones, and severe disease due to bacterial and fungal pathogens. Our results indicate that, by damaging the liver and kidney and through the acquisition and proliferation of pathogens associated with the depletion of lymphoid organs, continuous exposure to antibiotics could increase mortality rates, at least in cinereous vultures. If antibiotics ingested with livestock carrion are clearly implicated in the decline of the vultures in central Spain then it should be considered a primary concern for conservation of their populations
Rebooting the human mitochondrial phylogeny: an automated and scalable methodology with expert knowledge
<p>Abstract</p> <p>Background</p> <p>Mitochondrial DNA is an ideal source of information to conduct evolutionary and phylogenetic studies due to its extraordinary properties and abundance. Many insights can be gained from these, including but not limited to screening genetic variation to identify potentially deleterious mutations. However, such advances require efficient solutions to very difficult computational problems, a need that is hampered by the very plenty of data that confers strength to the analysis.</p> <p>Results</p> <p>We develop a systematic, automated methodology to overcome these difficulties, building from readily available, public sequence databases to high-quality alignments and phylogenetic trees. Within each stage in an autonomous workflow, outputs are carefully evaluated and outlier detection rules defined to integrate expert knowledge and automated curation, hence avoiding the manual bottleneck found in past approaches to the problem. Using these techniques, we have performed exhaustive updates to the human mitochondrial phylogeny, illustrating the power and computational scalability of our approach, and we have conducted some initial analyses on the resulting phylogenies.</p> <p>Conclusions</p> <p>The problem at hand demands careful definition of inputs and adequate algorithmic treatment for its solutions to be realistic and useful. It is possible to define formal rules to address the former requirement by refining inputs directly and through their combination as outputs, and the latter are also of help to ascertain the performance of chosen algorithms. Rules can exploit known or inferred properties of datasets to simplify inputs through partitioning, therefore cutting computational costs and affording work on rapidly growing, otherwise intractable datasets. Although expert guidance may be necessary to assist the learning process, low-risk results can be fully automated and have proved themselves convenient and valuable.</p
Hsp90β inhibition modulates nitric oxide production and nitric oxide-induced apoptosis in human chondrocytes
<p>Abstract</p> <p>Background</p> <p>Hsp90β is a member of the Hsp90 family of protein chaperones. This family plays essential roles in the folding, maturation and activity of many proteins that are involved in signal transduction and transcriptional regulation. The role of this protein in chondrocytes is not well understood, although its increase in osteoarthritic cells has been reported. The present study aimed to explore the role of Hsp90β in key aspects of OA pathogenesis.</p> <p>Methods</p> <p>Human OA chondrocytes were isolated from cartilage obtained from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with proinflammatory cytokines (IL-1β or TNF-ι) and nitric oxide donors (NOC-12 or SNP). For Hsp90β inhibition, two different chemical inhibitors (Geldanamycin and Novobiocin) were employed, or siRNA transfection procedures were carried out. Gene expression was determined by real-time PCR, apoptosis was quantified by flow cytometry and ELISA, and nitric oxide (NO) production was evaluated by the Griess method. Indirect immunofluorescence assays were performed to evaluate the presence of Hsp90β in stimulated cells.</p> <p>Results</p> <p>Hsp90β was found to be increased by proinflammatory cytokines. Inhibition of Hsp90β by the chemicals Geldanamycin (GA) and Novobiocin (NB) caused a dose-dependent decrease of the NO production induced by IL-1β in chondrocytes, up to basal levels. Immunofluorescence analyses demonstrate that the NO donors NOC-12 and SNP also increased Hsp90β. Chemical inhibition or specific gene silencing of this chaperone reduced the DNA condensation and fragmentation, typical of death by apoptosis, that is induced by NO donors in chondrocytes.</p> <p>Conclusions</p> <p>The present results show how Hsp90β modulates NO production and NO-mediated cellular death in human OA chondrocytes.</p
Assisted evolution enables HIV-1 to overcome a high trim5Îą-imposed genetic barrier to rhesus macaque tropism
Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5Îą protein (rhTRIM5Îą). Initially, we attempted to derive rhTRIM5Îą-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5Îą. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5Îą sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5Îą sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5Îą recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5Îą were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5Îą sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5Îą-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5Îą. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5Îą on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5Îą is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection
Wheat-barley hybridization â the last forty years
Abstract Several useful alien gene transfers have
been reported from related species into wheat (Triticum
aestivum), but very few publications have dealt
with the development of wheat/barley (Hordeum
vulgare) introgression lines. An overview is given
here of wheat 9 barley hybridization over the last
forty years, including the development of
wheat 9 barley hybrids, and of addition and translocation
lines with various barley cultivars. A short
summary is also given of the wheat 9 barley hybrids
produced with other Hordeum species. The meiotic
pairing behaviour of wheat 9 barley hybrids is presented,
with special regard to the detection of wheatâ
barley homoeologous pairing using the molecular
cytogenetic technique GISH. The effect of in vitro
multiplication on the genome composition of intergeneric
hybrids is discussed, and the production and
characterization of the latest wheat/barley translocation
lines are presented. An overview of the agronomical
traits (b-glucan content, earliness, salt tolerance,
sprouting resistance, etc.) of the newly developed
introgression lines is given. The exploitation and
possible use of wheat/barley introgression lines for
the most up-to-date molecular genetic studies
(transcriptome analysis, sequencing of flow-sorted
chromosomes) are also discussed
Brane-World Gravity
The observable universe could be a 1+3-surface (the "brane") embedded in a
1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model
particles and fields trapped on the brane while gravity is free to access the
bulk. At least one of the \textit{d} extra spatial dimensions could be very
large relative to the Planck scale, which lowers the fundamental gravity scale,
possibly even down to the electroweak ( TeV) level. This revolutionary
picture arises in the framework of recent developments in M theory. The
1+10-dimensional M theory encompasses the known 1+9-dimensional superstring
theories, and is widely considered to be a promising potential route to quantum
gravity. At low energies, gravity is localized at the brane and general
relativity is recovered, but at high energies gravity "leaks" into the bulk,
behaving in a truly higher-dimensional way. This introduces significant changes
to gravitational dynamics and perturbations, with interesting and potentially
testable implications for high-energy astrophysics, black holes, and cosmology.
Brane-world models offer a phenomenological way to test some of the novel
predictions and corrections to general relativity that are implied by M theory.
This review analyzes the geometry, dynamics and perturbations of simple
brane-world models for cosmology and astrophysics, mainly focusing on warped
5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover
the simplest brane-world models in which 4-dimensional gravity on the brane is
modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati
models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004)
"Brane-World Gravity", 119 pages, 28 figures, the update contains new
material on RS perturbations, including full numerical solutions of
gravitational waves and scalar perturbations, on DGP models, and also on 6D
models. A published version in Living Reviews in Relativit
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