442 research outputs found
XMM-Newton discovery of O VII emission from warm gas in clusters of galaxies
XMM-Newton recently discovered O VII line emission from ~2 million K gas near
the outer parts of several clusters of galaxies. This emission is attributed to
the Warm-Hot Intergalactic Medium. The original sample of clusters studied for
this purpose has been extended and two more clusters with a soft X-ray excess
have been found. We discuss the physical properties of the warm gas, in
particular the density, spatial extent, abundances and temperature.Comment: 8 pages, 3 figures, conference "Soft X-ray emission from clusters of
galaxies and related phenomena", ed. R. Lieu, Kluwer, in pres
Vaccinia Virus Protein C6 Inhibits Type I IFN Signalling in the Nucleus and Binds to the Transactivation Domain of STAT2.
The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells. Ectopic expression of C6 inhibits the induction of interferon stimulated genes (ISGs) in response to IFNα treatment at both the mRNA and protein level. C6 inhibits the IFNα-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway at a late stage, downstream of STAT1 and STAT2 phosphorylation, nuclear translocation and binding of the interferon stimulated gene factor 3 (ISGF3) complex to the interferon stimulated response element (ISRE). Mechanistically, C6 associates with the transactivation domain of STAT2 and this might explain how C6 inhibits the type I IFN signalling very late in the pathway. During virus infection C6 reduces ISRE-dependent gene expression despite the presence of the viral protein phosphatase VH1 that dephosphorylates STAT1 and STAT2. The ability of a cytoplasmic replicating virus to dampen the immune response within the nucleus, and the ability of viral immunomodulators such as C6 to inhibit multiple stages of the innate immune response by distinct mechanisms, emphasizes the intricacies of host-pathogen interactions and viral immune evasion.Wellcome-Trust, Lister Institute of Preventive Medicine U
The structure of an infectious human polyomavirus and its interactions with cellular receptors
BK polyomavirus (BKV) causes polyomavirus-associated nephropathy and hemorrhagic cystitis in immunosuppressed patients. These are diseases for which we currently have limited treatment options, but potential therapies could include pre-transplant vaccination with a multivalent BKV vaccine or therapeutics which inhibit capsid assembly or block attachment and entry into target cells. A useful tool in such efforts would be a high-resolution structure of the infectious BKV virion and how this interacts with its full repertoire of cellular receptors. We present
the 3.4-AË cryoelectron microscopy structure of native, infectious BKV in complex with the receptor fragment of GT1b ganglioside. We also present
structural evidence that BKV can utilize glycosaminoglycans as attachment receptors. This work highlights features that underpin capsid stability and provides a platform for rational design and development
of urgently needed pharmacological interventions for BKV-associated diseases
Functional advantages of triplication of the 3B coding region of the FMDV genome
For gene duplication to be maintained, particularly in the small genomes of RNA viruses, this should offer some advantages. We have investigated the functions of a small protein termed VPg or 3B, which acts as a primer in the replication of footâandâmouth disease virus (FMDV). Many related picornaviruses encode a single copy but uniquely the FMDV genome includes three (nonidentical) copies of the 3B coding region. Using subâgenomic replicons incorporating nonfunctional 3Bs and 3B fusion products in competition and complementation assays, we investigated the contributions of individual 3Bs to replication and the structural requirements for functionality. We showed that a free Nâterminus is required for 3B to function as a primer and although a single 3B can support genome replication, additional copies provide a competitive advantage. However, a fourth copy confers no further advantage. Furthermore, we find that a minimum of two 3Bs is necessary for trans replication of FMDV replicons, which is unlike other picornaviruses where a single 3B can be used for both cis and trans replication. Our data are consistent with a model in which 3B copy number expansion within the FMDV genome has allowed evolution of separate cis and trans acting functions, providing selective pressure to maintain multiple copies of 3B
Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial
Background
Young male cancer survivors have lower testosterone levels, higher fat mass, and worse quality of life (QoL) than age-matched healthy controls. Low testosterone in cancer survivors can be due to orchidectomy or effects of chemotherapy and radiotherapy. We have undertaken a double-blind, placebo-controlled, 6-month trial of testosterone replacement in young male cancer survivors with borderline low testosterone (7â12 nmol/l).
Methods and findings
This was a multicentre United Kingdom study conducted in secondary care hospital outpatients. Male survivors of testicular cancer, lymphoma, and leukaemia aged 25â50 years with morning total serum testosterone 7â12 nmol/l were recruited. A total of 136 men were randomised between July 2012 and February 2015 (42.6% aged 25â37 years, 57.4% 38â50 years, 88% testicular cancer, 10% lymphoma, matched for body mass index [BMI]). Participants were randomised 1:1 to receive testosterone (Tostran 2% gel) or placebo for 26 weeks. A dose titration was performed after 2 weeks. The coprimary end points were trunk fat mass and SF36 Physical Functioning score (SF36-PF) at 26 weeks by intention to treat. At 26 weeks, testosterone treatment compared with placebo was associated with decreased trunk fat mass (â0.9 kg, 95% CI â1.6 to â0.3, p = 0.0073), decreased whole-body fat mass (â1.8 kg, 95% CI â2.9 to â0.7, p = 0.0016), and increased lean body mass (1.5 kg, 95% CI 0.9â2.1, p < 0.001). Decrease in fat mass was greatest in those with a high truncal fat mass at baseline. There was no treatment effect on SF36-PF or any other QoL scores. Testosterone treatment was well tolerated. The limitations of our study were as follows: a relatively short duration of treatment, only three cancer groups included, and no hard end point data such as cardiovascular events.
Conclusions
In young male cancer survivors with low-normal morning total serum testosterone, replacement with testosterone is associated with an improvement in body composition.
Trial registration
ISRCTN: 70274195, EudraCT: 2011-000677-31
Structural insight into Pichia pastoris fatty acid synthase
Type I fatty acid synthases (FASs) are critical metabolic enzymes which are common targets for bioengineering in the production of biofuels and other products. Serendipitously, we identified FAS as a contaminant in a cryoEM dataset of virus-like particles (VLPs) purified from P. pastoris, an important model organism and common expression system used in protein production. From these data, we determined the structure of P. pastoris FAS to 3.1 Ă
resolution. While the overall organisation of the complex was typical of type I FASs, we identified several differences in both structural and enzymatic domains through comparison with the prototypical yeast FAS from S. cerevisiae. Using focussed classification, we were also able to resolve and model the mobile acyl-carrier protein (ACP) domain, which is key for function. Ultimately, the structure reported here will be a useful resource for further efforts to engineer yeast FAS for synthesis of alternate products
The Imprint of Galaxy Formation on X-ray Clusters
It is widely believed that structure in the Universe evolves hierarchically,
as primordial density fluctuations, amplified by gravity, collapse and merge to
form progressively larger systems. The structure and evolution of X-ray
clusters, however, seems at odds with this hierarchical scenario for structure
formation. Poor clusters and groups, as well as most distant clusters detected
to date, are substantially fainter than expected from the tight relations
between luminosity, temperature and redshift predicted by these models. Here we
show that these discrepancies arise because, near the centre, the entropy of
the hot, diffuse intracluster medium (ICM) is higher tha possible if the ICM
is heated at modest redshift (z \ltsim 2) but prior to cluster collapse,
indicating that the formation of galaxies precedes that of clusters and that
most clusters have been assembled very recently.Comment: 5 pages, plus 2 postscript figures (one in colour), accepted for
publication in Natur
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