The envelope gene of transmitted HIV-1 resists a late interferon gamma-induced block

Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFNγ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFNγ stimulation can induce an antiviral state that can be both distinct from that of type I interferon, and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFNγ- sensitive/resistant viruses indicates that interferon-resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from those previously described to be resisted by env, and is therefore mediated by unknown IFNγ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission

Electrochromic properties of a poly(dithienylfuran) derivative featuring a redox-active dithiin unit

A teraryl monomer containing a 1,4-dithiin-furan central unit has been synthesised and characterised by single crystal X-ray crystallography. The di(thienyl)furan monomer 11 was successfully polymerised electrochemically and shown to possess a lower electrochemical band gap than its terthiophene analogue (1.97 eV cf. 2.11 eV). The electrochromic properties of this polymer proved to be superior to PEDOT, with fast switching and reversible colour transformation at high colour contrast (CE = 212 cm(2) C-1 cf. 183 cm(2) C-1 for PEDOT at 95% optical switch)

Designing and evaluating complex interventions to improve health care

Complex interventions are “built up from a number of components, which may act both independently and interdependently.”1 2 Many health service activities should be considered as complex. Evaluating complex interventions can pose a considerable challenge and requires a substantial investment of time. Unless the trials illuminate processes and mechanisms they often fail to provide useful information. If the result is negative, we are left wondering whether the intervention is inherently ineffective (either because the intervention was inadequately developed or because all similar interventions are ineffective), whether it was inadequately applied or applied in an inappropriate context, or whether the trial used an inappropriate design, comparison groups or outcomes. If there is a positive effect, it can be hard to judge how the results of the trial might be applied to a different context (box 1)

Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers

The Murmur of the Sleeping Black Hole: Detection of Nuclear Ultraviolet Variability in LINER Galaxies

LINER nuclei, which are present in many nearby galactic bulges, may be the manifestation of low-rate or low-radiative-efficiency accretion onto supermassive central black holes. However, it has been unclear whether the compact UV nuclear sources present in many LINERs are clusters of massive stars, rather than being directly related to the accretion process. We have used HST to monitor the UV variability of a sample of 17 galaxies with LINER nuclei and compact nuclear UV sources. Fifteen of the 17 galaxies were observed more than once, with two to five epochs per galaxy, spanning up to a year. We detect significant variability in most of the sample, with peak-to-peak amplitudes from a few percent to 50%. In most cases, correlated variations are seen in two independent bands (F250W and F330W). Comparison to previous UV measurements indicates, for many objects, long-term variations by factors of a few over decade timescales. Variability is detected in LINERs with and without detected compact radio cores, in LINERs that have broad H-alpha wings detected in their optical spectra (``LINER 1's''), and in those that do not (``LINER 2s''). This variability demonstrates the existence of a non-stellar component in the UV continuum of all types, and sets a lower limit to the luminosity of this component. We note a trend in the UV color (F250W/F330W) with spectral type - LINER 1s tend to be bluer than LINER 2s. This trend may indicate a link between the shape of the nonstellar continuum and the presence or the visibility of a broad-line region. In one target, the post-starburst galaxy NGC 4736, we detect variability in a previously noted UV source that is offset by 2.5" (60 pc in projection) from the nucleus. This may be the nearest example of a binary active nucleus, and of the process leading to black hole merging.Comment: accepted to Ap