Identification of human-to-human transmissibility factors in PB2 proteins of influenza A by large-scale mutual information analysis

<p>Abstract</p> <p>Background</p> <p>The identification of mutations that confer unique properties to a pathogen, such as host range, is of fundamental importance in the fight against disease. This paper describes a novel method for identifying amino acid sites that distinguish specific sets of protein sequences, by comparative analysis of matched alignments. The use of mutual information to identify distinctive residues responsible for functional variants makes this approach highly suitable for analyzing large sets of sequences. To support mutual information analysis, we developed the AVANA software, which utilizes sequence annotations to select sets for comparison, according to user-specified criteria. The method presented was applied to an analysis of influenza A PB2 protein sequences, with the objective of identifying the components of adaptation to human-to-human transmission, and reconstructing the mutation history of these components.</p> <p>Results</p> <p>We compared over 3,000 PB2 protein sequences of human-transmissible and avian isolates, to produce a catalogue of sites involved in adaptation to human-to-human transmission. This analysis identified 17 characteristic sites, five of which have been present in human-transmissible strains since the 1918 Spanish flu pandemic. Sixteen of these sites are located in functional domains, suggesting they may play functional roles in host-range specificity. The catalogue of characteristic sites was used to derive sequence signatures from historical isolates. These signatures, arranged in chronological order, reveal an evolutionary timeline for the adaptation of the PB2 protein to human hosts.</p> <p>Conclusion</p> <p>By providing the most complete elucidation to date of the functional components participating in PB2 protein adaptation to humans, this study demonstrates that mutual information is a powerful tool for comparative characterization of sequence sets. In addition to confirming previously reported findings, several novel characteristic sites within PB2 are reported. Sequence signatures generated using the characteristic sites catalogue characterize concisely the adaptation characteristics of individual isolates. Evolutionary timelines derived from signatures of early human influenza isolates suggest that characteristic variants emerged rapidly, and remained remarkably stable through subsequent pandemics. In addition, the signatures of human-infecting H5N1 isolates suggest that this avian subtype has low pandemic potential at present, although it presents more human adaptation components than most avian subtypes.</p

The Splicing Factor Proline-Glutamine Rich (SFPQ/PSF) Is Involved in Influenza Virus Transcription

The influenza A virus RNA polymerase is a heterotrimeric complex responsible for viral genome transcription and replication in the nucleus of infected cells. We recently carried out a proteomic analysis of purified polymerase expressed in human cells and identified a number of polymerase-associated cellular proteins. Here we characterise the role of one such host factors, SFPQ/PSF, during virus infection. Down-regulation of SFPQ/PSF by silencing with two independent siRNAs reduced the virus yield by 2–5 log in low-multiplicity infections, while the replication of unrelated viruses as VSV or Adenovirus was almost unaffected. As the SFPQ/PSF protein is frequently associated to NonO/p54, we tested the potential implication of the latter in influenza virus replication. However, down-regulation of NonO/p54 by silencing with two independent siRNAs did not affect virus yields. Down-regulation of SFPQ/PSF by siRNA silencing led to a reduction and delay of influenza virus gene expression. Immunofluorescence analyses showed a good correlation between SFPQ/PSF and NP levels in infected cells. Analysis of virus RNA accumulation in silenced cells showed that production of mRNA, cRNA and vRNA is reduced by more than 5-fold but splicing is not affected. Likewise, the accumulation of viral mRNA in cicloheximide-treated cells was reduced by 3-fold. In contrast, down-regulation of SFPQ/PSF in a recombinant virus replicon system indicated that, while the accumulation of viral mRNA is reduced by 5-fold, vRNA levels are slightly increased. In vitro transcription of recombinant RNPs generated in SFPQ/PSF-silenced cells indicated a 4–5-fold reduction in polyadenylation but no alteration in cap snatching. These results indicate that SFPQ/PSF is a host factor essential for influenza virus transcription that increases the efficiency of viral mRNA polyadenylation and open the possibility to develop new antivirals targeting the accumulation of primary transcripts, a very early step during infection

Donor safety: the role of the WMDA in ensuring the safety of volunteer unrelated donors: clinical and ethical considerations

Since the beginning of hematopoietic stem cell harvesting from volunteer unrelated donors, ensuring donor safety has been a necessary goal of all parties involved in the process. As donation of BM or PBSCs is not in the interest of the donor's own physical health, donor registries and transplantation centers must take into account both medical and ethical aspects involved in the donation procedure. One of the principal goals leading to the formation of the World Marrow Donor Association (WMDA) was to establish internationally acceptable standards for all aspects of unrelated donor care. Bone Marrow Transplantation (2010) 45, 832-838; doi:10.1038/bmt.2010.2; published online 22 February 201

Beyond the looking glass? ‘Aidland’ reconsidered

This paper engages with an emerging genre in anthropology’s engagement with international development – writing about ‘Aidland’ which focus attention on the lives, motivations and personalities of ‘development professionals’. It suggests that there are two possible problems with the growing popularity of work on Aidland: first, that it rests on a reified and dated view of the worlds of aid and development; second, that an ethnographic focus on development professionals may serve to divert attention to the significance of both the politics and the material effects of development intervention and the relations of power within which they are embedded

Urinary heavy metals, phthalates, perchlorate, nitrate, thiocyanate, hydrocarbons, and polyfluorinated compounds are associated with adult hearing disturbance: USA NHANES, 2011–2012

Background Links between environmental chemicals and human health have emerged, but the effects on hearing were less studied. Therefore, the aim of the present study was to investigate the relationships of different sets of environmental chemicals and the hearing conditions in a national and population-based setting. Methods Data was retrieved from the US National Health and Nutrition Examination Surveys, 2011–2012 including demographics, serum measurements, lifestyle factors, self-reported hearing conditions, and urinary environmental chemical concentrations. Chi-square test, t test, and survey-weighted logistic regression models were performed. Results Among the American adults aged 20–69 (n=5560), 462 (8.3 %) people reported their hearing condition as moderate trouble to deaf. They had higher levels of urinary hydrocarbons and polyfluorinated compounds but not heavy metals, phthalates, arsenic, pesticides, phenols, parabens, perchlorate, nitrate, and thiocyanate concentrations. Also, 466 (10.0 %) people had hearing difficulties during conversation. They had higher levels of urinary cobalt (odds ratio (OR) 1.27, 95 % confidence interval (95%CI) 1.00–1.63), molybdenum (OR 1.45, 95%CI 1.04–2.02), strontium (OR 1.56, 95%CI 1.10–2.21), phthalates, perchlorate (OR 1.27, 95%CI 1.05– 1.54), nitrate (OR 1.60, 1.03–2.49) and thiocyanate (OR 1.22, 95%CI 1.01–1.48) concentrations but not arsenic, pesticides, phenols, parabens, hydrocarbons, and polyfluorinated compounds. Moreover, people who reported difficulties in following conversation with background noise had higher levels of urinary tin concentrations (OR 1.17, 1.00–1.36). Conclusions Urinary heavy metals, phthalates, perchlorate, nitrate, thiocyanate, hydrocarbons, and polyfluorinated compounds were associated with the adult hearing disturbance, although the causality cannot be established. Elimination of these environmental chemicals might need to be considered in future environmental health policy and health intervention programs

Linguistic capital and inequality in aid relations

Globalisation processes and the spread of English as a Lingua Franca are closely related. I consider language skills as symbolic capital and focus on the hegemony of English as Lingua Franca in international aid organisations. I argue that more attention must be paid to the role of language and linguistic capital when analysing global inequality and post-colonial power relations. Humanitarian and development organisations have so far received less sociological attention than other aspects of globalisation processes, whereas in the context of development studies, attention to language usually focuses on the ‘discourse of development’ rather than on the role of linguistic capital in multi-lingual settings. Aid work, which includes the transfer of skills and resources, simultaneously addresses and perpetuates global inequalities. Language structures power relations and inequality within aid organisations, in particular between national and international staff. My article is based on qualitative interviews with multi-lingual and mono-lingual aid workers from a wide variety of aid organisations. My article is innovative by demonstrating how linguistic capital intersects with other aspects of inequality in the global context of aid organisations. It makes an important contribution to the understanding of globalisation processes and to post-colonial sociology