Pyrin is a cytosolic pattern‐recognition receptor that normally functions as a guard to trigger capase‐1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The ...MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD‐PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA‐PRK‐pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector‐triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.
Summary Novel influenza viruses continue to emerge, posing zoonotic and potentially pandemic threats, such as with avian influenza A H7N9. Although closure of live poultry markets (LPMs) in mainland ...China stopped H7N9 outbreaks temporarily, closures are difficult to sustain, in view of poultry production and marketing systems in China. In this Personal View, we summarise interventions taken in mainland China, and provide evidence for other more sustainable but effective interventions in the live poultry market systems that reduce risk of zoonotic influenza including rest days, and banning live poultry in markets overnight. Separation of live ducks and geese from land-based (ie, non-aquatic) poultry in LPM systems can reduce the risk of emergence of zoonotic and epizootic viruses at source. In view of evidence that H7N9 is now endemic in over half of the provinces in mainland China and will continue to cause recurrent zoonotic disease in the winter months, such interventions should receive high priority in China and other Asian countries at risk of H7N9 through cross-border poultry movements. Such generic measures are likely to reduce known and future threats of zoonotic influenza.
We experimentally investigate the spontaneous emission (SE) rates of single InAs quantum dots embedded in GaAs photonic nanowires. For a diameter leading to the optimal confinement of the fundamental ...guided mode HE11, the coupling to HE11 dominates the SE process and an increase of the SE rate by a factor of 1.5 is achieved. When the diameter is decreased, the coupling to this mode vanishes rapidly, thus allowing the coupling to the other radiation modes to be probed. In these conditions, a SE inhibition factor of 16, equivalent to the one obtained in state-of-the-art photonic crystals, is measured. These results, which are supported by fully vectorial calculations, confirm the potential of photonic nanowires for a nearly perfect, broadband SE control.
...at a very minimum, each of the more than 31 families of endogenous retrovirus found in the human genome 1 must have arisen from one or more separate paleoviruses that infected the ancestors of ...modern humans. Since reinfections of the germline with members of the same families occurred frequently 2, retroviral infections that impacted the genome had to have happened repeatedly during primate evolution with the most recent episode in humans between 100,000 and 1 million years ago 3 (Figure 1). ...the selective changes that these antiviral genes incurred during these periods of evolutionary pressure might make them less competent to fight modern viral challenges (Figure 2; Box 1).
Background: Epidemiologic evidence for the relation between carbohydrate quality and risk of type 2 diabetes (T2D) has been mixed.Objective: We prospectively examined the association of dietary ...glycemic index (GI) and glycemic load (GL) with T2D risk.Design: We prospectively followed 74,248 women from the Nurses’ Health Study (1984–2008), 90,411 women from the Nurses’ Health Study II (1991–2009), and 40,498 men from the Health Professionals Follow-Up Study (1986–2008) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by using a validated questionnaire and updated every 4 y. We also conducted an updated meta-analysis, including results from our 3 cohorts and other studies.Results: During 3,800,618 person-years of follow-up, we documented 15,027 cases of incident T2D. In pooled multivariable analyses, those in the highest quintile of energy-adjusted GI had a 33% higher risk (95% CI: 26%, 41%) of T2D than those in the lowest quintile. Participants in the highest quintile of energy-adjusted GL had a 10% higher risk (95% CI: 2%, 18%) of T2D. Participants who consumed a combination diet that was high in GI or GL and low in cereal fiber had an ∼50% higher risk of T2D. In the updated meta-analysis, the summary RRs (95% CIs) comparing the highest with the lowest categories of GI and GL were 1.19 (1.14, 1.24) and 1.13 (1.08, 1.17), respectively.Conclusion: The updated analyses from our 3 cohorts and meta-analyses provide further evidence that higher dietary GI and GL are associated with increased risk of T2D.
Management of cervical cancer has undergone refinement in the past two decades; concurrent chemo-radiation (CCRT) (with cisplatin alone or in combination) is currently the standard treatment approach ...for patients with locally advanced disease (FIGO stage IIB-IVA). About 30%-40% of such patients fail to achieve complete response; alternative approaches are needed to improve outcome for them. Treatment with bevacizumab (an inhibitor of vascular endothelial growth factor) along with chemotherapy is associated with improved survival in patients with recurrent or metastatic cervical cancer. Weekly paclitaxel and carboplatin for 4-6 weeks as dose dense chemotherapy prior to CCRT is currently under study in a phase III, multicentric trial. Role of adjuvant chemotherapy after CCRT in patients with positive lymph nodes, larger tumor volume and those with stage III-IVA disease needs further exploration. Novel agents targeting molecular pathways are currently being studied. Recent development of immune check point inhibitors is exciting, results of ongoing studies are awaited with interest.
Recent progress in nanotechnology has allowed the fabrication of new hybrid systems in which a single two-level system is coupled to a mechanical nanoresonator. In such systems the quantum nature of ...a macroscopic degree of freedom can be revealed and manipulated. This opens up appealing perspectives for quantum information technologies, and for the exploration of the quantum-classical boundary. Here we present the experimental realization of a monolithic solid-state hybrid system governed by material strain: a quantum dot is embedded within a nanowire that features discrete mechanical resonances corresponding to flexural vibration modes. Mechanical vibrations result in a time-varying strain field that modulates the quantum dot transition energy. This approach simultaneously offers a large light-extraction efficiency and a large exciton-phonon coupling strength g0. By means of optical and mechanical spectroscopy, we find that g0/2 π is nearly as large as the mechanical frequency, a criterion that defines the ultrastrong coupling regime.
Influenza virus binds to cell receptors via sialic acid (SA) linked glycoproteins. They recognize SA on host cells through their haemagglutinins (H). The distribution of SA on cell surfaces is one ...determinant of host tropism and understanding its expression on human cells and tissues is important for understanding influenza pathogenesis. The objective of this study therefore was to optimize the detection of alpha2,3-linked and alpha2,6-linked SA by lectin histochemistry by investigating the binding of Sambucus nigra agglutinin (SNA) for SAalpha2,6Gal and Maackia amurensis agglutinin (MAA) for SAalpha2,3Gal in the respiratory tract of normal adults and children.
We used fluorescent and biotinylated SNA and MAA from different suppliers on archived and prospectively collected biopsy and autopsy specimens from the nasopharynx, trachea, bronchus and lungs of fetuses, infants and adults. We compared different methods of unmasking for tissue sections to determine if these would affect lectin binding. Using serial sections we then compared the lectin binding of MAA from different suppliers.
We found that unmasking using microwave treatment in citrate buffer produced increased lectin binding to the ciliated and glandular epithelium of the respiratory tract. In addition we found that there were differences in tissue distribution of the alpha2,3 linked SA when 2 different isoforms of MAA (MAA1 and MAA2) lectin were used. MAA1 had widespread binding throughout the upper and lower respiratory tract and showed more binding to the respiratory epithelium of children than in adults. By comparison, MAA2 binding was mainly restricted to the alveolar epithelial cells of the lung with weak binding to goblet cells. SNA binding was detected in bronchial and alveolar epithelial cells and binding of this lectin was stronger to the paediatric epithelium compared to adult epithelium. Furthermore, the MAA lectins from 2 suppliers (Roche and EY Labs) tended to only bind in a pattern similar to MAA1 (Vector Labs) and produced a different binding pattern to MAA2 from Vector Labs.
The lectin binding pattern of MAA may vary depending on the supplier and the different isoforms of MAA show a different tissue distribution in the respiratory tract. This finding is important if conclusions about the potential binding sites of SAalpha2,3 binding viruses, such as influenza or human parainfluenza are to be made.
Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ...ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variants are conserved across all eukaryotes, whereas others are lineage-specific. Here, we performed detailed phylogenomic analyses of "short H2A histone" variants found in mammalian genomes. We discovered a previously undescribed typically-sized H2A variant in monotremes and marsupials,
, which may represent the common ancestor of the short H2As. We also discovered a novel class of short H2A histone variants in eutherian mammals,
We show that short H2A variants arose on the X Chromosome in the common ancestor of all eutherian mammals and diverged into four evolutionarily distinct clades:
,
,
, and
However, the repertoires of short histone H2A variants vary extensively among eutherian mammals due to lineage-specific gains and losses. Finally, we show that all four short H2As are subject to accelerated rates of protein evolution relative to both canonical and other variant H2A proteins including H2A.R. Our analyses reveal that short H2As are a unique class of testis-restricted histone variants displaying an unprecedented evolutionary dynamism. Based on their X-Chromosomal localization, genetic turnover, and testis-specific expression, we hypothesize that short H2A variants may participate in genetic conflicts involving sex chromosomes during reproduction.
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