424 research outputs found
Staphylococcus aureus extracellular adherence protein triggers TNF alpha release, promoting attachment to endothelial cells via protein A
Staphylococcus aureus is a leading cause of bacteraemia, which frequently results in complications such as infective endocarditis, osteomyelitis and exit from the bloodstream to cause metastatic abscesses. Interaction with endothelial cells is critical to these complications and several bacterial proteins have been shown to be involved. The S. aureus extracellular adhesion protein (Eap) has many functions, it binds several host glyco-proteins and has both pro- and anti-inflammatory activity. Unfortunately its role in vivo has not been robustly tested to date, due to difficulties in complementing its activity in mutant strains. We previously found Eap to have pro-inflammatory activity, and here show that purified native Eap triggered TNFα release in whole human blood in a dose-dependent manner. This level of TNFα increased adhesion of S. aureus to endothelial cells 4-fold via a mechanism involving protein A on the bacterial surface and gC1qR/p33 on the endothelial cell surface. The contribution this and other Eap activities play in disease severity during bacteraemia was tested by constructing an isogenic set of strains in which the eap gene was inactivated and complemented by inserting an intact copy elsewhere on the bacterial chromosome. Using a murine bacteraemia model we found that Eap expressing strains cause a more severe infection, demonstrating its role in invasive disease
Detection of Lyman-alpha Emitting Galaxies at Redshift z=4.55
Studies of the formation and early history of galaxies have been hampered by
the difficulties inherent in detecting faint galaxy populations at high
redshift. As a consequence, observations at the highest redshifts (3.5 < z < 5)
have been restricted to objects that are intrinsically bright. These include
quasars, radio galaxies, and some Ly alpha-emitting objects that are very close
to (within ~10 kpc) -- and appear to be physically associated with -- quasars.
But the extremely energetic processes which make these objects easy to detect
also make them unrepresentative of normal (field) galaxies. Here we report the
discovery using Keck spectroscopic observations of two Ly alpha-emitting
galaxies at redshift z = 4.55, which are sufficiently far from the nearest
quasar (~700 kpc) that radiation from the quasar is unlikely to provide the
excitation source of the Ly alpha emission. Instead, these galaxies appear to
be undergoing their first burst of star formation, at a time when the Universe
was less than one billion years old.Comment: 8 pages, 1 landscape table, and 3 PostScript figures. Uses
aaspp4.sty, flushrt.sty, aj_pt4.sty, overcite.sty (style macros available
from xxx.lanl.gov) Figure 1 is bitmapped to 100 dpi. The original PostScript
version of Fig. 1 is available via anonymous ftp to
ftp://hubble.ifa.hawaii.edu/pub/preprints To appear in Natur
Laimaphelenchus suberensis sp. nov. associated with Quercus suber in Portugal
Laimaphelenchus suberensis sp. nov. obtained
from declining Quercus suber trees of Herdade da
Gouveia de Baixo, Alentejo, Portugal, is described and
illustrated based on morphological, biometrical and molecular
characters. The diagnosis of Laimaphelenchus
species has been commonly based on the presence or
absence of a vulval flap and on the shape structure of the
tail tip. The species described here has been included in
the Laimaphelenchus group without vulval flap, and can
be distinguished from morphologically similar species
by its tail tip shape structure that has a stalk-like terminus
and three diffuse tubercles with 4–6 finger-like
protrusions. For the molecular analyses, the mitochondrial
DNA region from the cytochrome oxidase subunit
I (mtCOI), the D2-D3 expansion segments of the large
subunit (LSU) and small subunit (SSU) of rRNA gene
were amplified and sequenced. Sequences of
L. suberensis sp. nov. clustered separately from all
Laimaphelenchus spp. with available sequences in
Genbank, confirming its identification as a new species.
This is the second report of the genus Laimaphelenchus
in Portugal, associated with Q. suber: L. heidelbergi and
L. suberensis sp. nov.This research was supported by CFE,
CIEPQPF and FEDER funds through the ‘Programa Operacional
Factores de Competitividade – COMPETE’ and by national funds
through FCT–Fundação para a Ciência e a Tecnologia under the
projects UID/BIA/04004/2013, PEst-C/EQB/UI0102/2013 and
FCOMP-01-0124-008937 (Ref. PTDC/BIA–BEC/102834/2008)
and by Instituto do Ambiente, Tecnologia e Vida (IATV). Carla
Maleita (SFRH/BPD/85736/2012) and Sofia Costa (SFRH/BPD/
102438/2014) were financed by MEC National funding and The
European Social Fund through POCH (Programa Operacional
Capital Humano).info:eu-repo/semantics/publishedVersio
Estimating the malaria risk of African mosquito movement by air travel
BACKGROUND: The expansion of global travel has resulted in the importation of African Anopheles mosquitoes, giving rise to cases of local malaria transmission. Here, cases of 'airport malaria' are used to quantify, using a combination of global climate and air traffic volume, where and when are the greatest risks of a Plasmodium falciparum-carrying mosquito being importated by air. This prioritises areas at risk of further airport malaria and possible importation or reemergence of the disease. METHODS: Monthly data on climate at the World's major airports were combined with air traffic information and African malaria seasonality maps to identify, month-by-month, those existing and future air routes at greatest risk of African malaria-carrying mosquito importation and temporary establishment. RESULTS: The location and timing of recorded airport malaria cases proved predictable using a combination of climate and air traffic data. Extending the analysis beyond the current air network architecture enabled identification of the airports and months with greatest climatic similarity to P. falciparum endemic regions of Africa within their principal transmission seasons, and therefore at risk should new aviation routes become operational. CONCLUSION: With the growth of long haul air travel from Africa, the identification of the seasonality and routes of mosquito importation is important in guiding effective aircraft disinsection and vector control. The recent and continued addition of air routes from Africa to more climatically similar regions than Europe will increase movement risks. The approach outlined here is capable of identifying when and where these risks are greatest
Global Burden of Sickle Cell Anaemia in Children under Five, 2010-2050: Modelling Based on Demographics, Excess Mortality, and Interventions
The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400-398,800) in 2010 to 404,200 (CI: 242,500-657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900-106,100]; 2050: 140,800 [CI: 95,500-200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600-48,800]; 2050: 44,700 [CI: 27,100-70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700-59,100]; 2050: 33,900 [CI: 15,900-64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800-6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800-14,232,700) newborns with SCA globally, 85% (CI: 81%-88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India
The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes
Many cases of non-standard genetic codes are known in mitochondrial genomes.
We carry out analysis of phylogeny and codon usage of organisms for which the
complete mitochondrial genome is available, and we determine the most likely
mechanism for codon reassignment in each case. Reassignment events can be
classified according to the gain-loss framework. The gain represents the
appearance of a new tRNA for the reassigned codon or the change of an existing
tRNA such that it gains the ability to pair with the codon. The loss represents
the deletion of a tRNA or the change in a tRNA so that it no longer translates
the codon. One possible mechanism is Codon Disappearance, where the codon
disappears from the genome prior to the gain and loss events. In the
alternative mechanisms the codon does not disappear. In the Unassigned Codon
mechanism, the loss occurs first, whereas in the Ambiguous Intermediate
mechanism, the gain occurs first. Codon usage analysis gives clear evidence of
cases where the codon disappeared at the point of the reassignment and also
cases where it did not disappear. Codon disappearance is the probable
explanation for stop to sense reassignments and a small number of reassignments
of sense codons. However, the majority of sense to sense reassignments cannot
be explained by codon disappearance. In the latter cases, by analysis of the
presence or absence of tRNAs in the genome and of the changes in tRNA
sequences, it is sometimes possible to distinguish between the Unassigned Codon
and Ambiguous Intermediate mechanisms. We emphasize that not all reassignments
follow the same scenario and that it is necessary to consider the details of
each case carefully.Comment: 53 pages (45 pages, including 4 figures + 8 pages of supplementary
information). To appear in J.Mol.Evo
Antiferromagnetic-ferromagnetic phase domain development in nanopatterned FeRh islands
The antiferromagnetic-to-ferromagnetic phase transition in B2-ordered FeRh is imaged in laterally confined nanopatterned islands using photoemission electron microscopy with x-ray magnetic circular dichroism contrast. The resulting magnetic images directly detail the progression in the shape and size of the FM phase domains during heating and cooling through the transition. In 5-μm-square islands this domain development during heating is shown to proceed in three distinct modes—nucleation, growth, and merging—each with subsequently greater energy costs. In 0.5-μm islands, which are smaller than the typical final domain size, the growth mode is stunted and the transition temperature is found to be reduced by 20 K. The modification to the transition temperature is found by high-resolution scanning transmission electron microscopy to be due to a 100-nm chemically disordered edge grain present as a result of ion implantation damage during the patterning. FeRh has unique possibilities for magnetic memory applications; the inevitable changes to its magnetic properties due to subtractive nanofabrication will need to be addressed in future work in order to progress from sheet films to suitable patterned devices
Strongyloides stercoralis age-1: A Potential Regulator of Infective Larval Development in a Parasitic Nematode
Infective third-stage larvae (L3i) of the human parasite Strongyloides stercoralis share many morphological, developmental, and behavioral attributes with Caenorhabditis elegans dauer larvae. The ‘dauer hypothesis’ predicts that the same molecular genetic mechanisms control both dauer larval development in C. elegans and L3i morphogenesis in S. stercoralis. In C. elegans, the phosphatidylinositol-3 (PI3) kinase catalytic subunit AGE-1 functions in the insulin/IGF-1 signaling (IIS) pathway to regulate formation of dauer larvae. Here we identify and characterize Ss-age-1, the S. stercoralis homolog of the gene encoding C. elegans AGE-1. Our analysis of the Ss-age-1 genomic region revealed three exons encoding a predicted protein of 1,209 amino acids, which clustered with C. elegans AGE-1 in phylogenetic analysis. We examined temporal patterns of expression in the S. stercoralis life cycle by reverse transcription quantitative PCR and observed low levels of Ss-age-1 transcripts in all stages. To compare anatomical patterns of expression between the two species, we used Ss-age-1 or Ce-age-1 promoter::enhanced green fluorescent protein reporter constructs expressed in transgenic animals for each species. We observed conservation of expression in amphidial neurons, which play a critical role in developmental regulation of both dauer larvae and L3i. Application of the PI3 kinase inhibitor LY294002 suppressed L3i in vitro activation in a dose-dependent fashion, with 100 µM resulting in a 90% decrease (odds ratio: 0.10, 95% confidence interval: 0.08–0.13) in the odds of resumption of feeding for treated L3i in comparison to the control. Together, these data support the hypothesis that Ss-age-1 regulates the development of S. stercoralis L3i via an IIS pathway in a manner similar to that observed in C. elegans dauer larvae. Understanding the mechanisms by which infective larvae are formed and activated may lead to novel control measures and treatments for strongyloidiasis and other soil-transmitted helminthiases
Cheating on the Edge
We present the results of an individual agent-based model of antibiotic resistance in bacteria. Our model examines antibiotic resistance when two strategies exist: “producers”–who secrete a substance that breaks down antibiotics–and nonproducers (“cheats”) who do not secrete, or carry the machinery associated with secretion. The model allows for populations of up to 10,000, in which bacteria are affected by their nearest neighbors, and we assume cheaters die when there are no producers in their neighborhood. Each of 10,000 slots on our grid (a torus) could be occupied by a producer or a nonproducer, or could (temporarily) be unoccupied. The most surprising and dramatic result we uncovered is that when producers and nonproducers coexist at equilibrium, nonproducers are almost always found on the edges of clusters of producers
Thiothymidine combined with UVA as a potential novel therapy for bladder cancer
BACKGROUND: Thiothymidine (S4TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S4TdR and UVA could be an effective treatmentfor bladder cancer.
METHODS: Uptake and incorporation of S4TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S4TdR and UVA was investigated in an orthotopic model of bladder cancer in rats.
RESULTS: Thiothymidine (200 uM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S4TdR (10–200 uM) and UVA (1–5 kJm-2) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S4TdR into DNA (up to 20-fold at IC5) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S4TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated.
CONCLUSION: These data indicate that the combination of S4TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components
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