Emergence and development of H7N9 influenza viruses in China

The occurrence of human infections with avian H7N9 viruses since 2013 demonstrates the continuing pandemic threat posed by the current influenza ecosystem in China. Influenza surveillance and phylogenetic analyses showed that these viruses were generated by multiple interspecies transmissions and reassortments among the viruses resident in domestic ducks and the H9N2 viruses enzootic in chickens. A large population of domestic ducks hosting diverse influenza viruses provided the precondition for these events to occur, while acquiring internal genes from enzootic H9N2 influenza viruses in chickens promoted the spread of these viruses. Human infections effectively act as sentinels, reflecting the intensity of the activity of these viruses in poultry.postprin

Comparison of Mutation Patterns in Full-Genome A/H3N2 Influenza Sequences Obtained Directly from Clinical Samples and the Same Samples after a Single MDCK Passage

Human influenza viruses can be isolated efficiently from clinical samples using Madin-Darby canine kidney (MDCK) cells. However, this process is known to induce mutations in the virus as it adapts to this non-human cell-line. We performed a systematic study to record the pattern of MDCK-induced mutations observed across the whole influenza A/H3N2 genome. Seventy-seven clinical samples collected from 2009-2011 were included in the study. Two full influenza genomes were obtained for each sample: one from virus obtained directly from the clinical sample and one from the matching isolate cultured in MDCK cells. Comparison of the full-genome sequences obtained from each of these sources showed that 42% of the 77 isolates had acquired at least one MDCK-induced mutation. The presence or absence of these mutations was independent of viral load or sample origin (in-patients versus out-patients). Notably, all the five hemagglutinin missense mutations were observed at the hemaggutinin 1 domain only, particularly within or proximal to the receptor binding sites and antigenic site of the virus. Furthermore, 23% of the 77 isolates had undergone a MDCK-induced missense mutation, D151G/N, in the neuraminidase segment. This mutation has been found to be associated with reduced drug sensitivity towards the neuraminidase inhibitors and increased viral receptor binding efficiency to host cells. In contrast, none of the neuraminidase sequences obtained directly from the clinical samples contained the D151G/N mutation, suggesting that this mutation may be an indicator of MDCK culture-induced changes. These D151 mutations can confound the interpretation of the hemagglutination inhibition assay and neuraminidase inhibitor resistance results when these are based on MDCK isolates. Such isolates are currently in routine use in the WHO influenza vaccine and drug-resistance surveillance programs. Potential data interpretation miscalls can therefore be avoided by careful exclusion of such D151 mutants after further sequence analysis.published_or_final_versio

Fast measurement of SEP for monitoring spinal cord during scoliosis

Recently there has been considerable interest in the use of somatosensory evoked potential (SEP) for monitoring the functional integrity of the spinal cord during surgery such as scoliosis. This paper describes a monitoring system and signal processing algorithms, which consist of an artificial neural network filter and a wavelet signal enhancer developed to enhance the signal-to-noise ratio (SNR) of surface recorded SEP. Our system allows fast detection of change in SEP's peak latency, amplitude and signal waveform, which are the main parameters of interest during intra-operative procedures.published_or_final_versionThe 20th IEEE Engineering in Medicine and Biology Society Conference Proceedings, Hong Kong, China, 29 October - 1 November 1998, v. 4, p. 2239-224

Changes in BMI before and during economic development and subsequent risk of cardiovascular disease and total mortality: A 35-year follow-up study in China

postprin

Rifampin- or Capreomycin-Induced Remodeling of the Mycobacterium smegmatis Mycolic Acid Layer Is Mitigated in Synergistic Combinations with Cationic Antimicrobial Peptides

The mycobacterial cell wall affords natural resistance to antibiotics. Antimicrobial peptides (AMPs) modify the surface properties of mycobacteria and can act synergistically with antibiotics from differing classes. Here, we investigate the response of Mycobacterium smegmatis to the presence of rifampin or capreomycin, either alone or in combination with two synthetic, cationic, α-helical AMPs that are distinguished by the presence (D-LAK120-HP13) or absence (D-LAK120-A) of a kink-inducing proline. Using a combination of high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) metabolomics, diphenylhexatriene (DPH) fluorescence anisotropy measurements, and laurdan emission spectroscopy, we show that M. smegmatis responds to challenge with rifampin or capreomycin by substantially altering its metabolism and, in particular, by remodeling the cell envelope. Overall, the changes are consistent with a reduction of trehalose dimycolate and an increase of trehalose monomycolate and are associated with increased rigidity of the mycolic acid layer observed following challenge by capreomycin but not rifampin. Challenge with D-LAK120-A or D-LAK120-HP13 induced no or modest changes, respectively, in mycomembrane metabolites and did not induce a significant increase in the rigidity of the mycolic acid layer. Furthermore, the response to rifampin or capreomycin was significantly reduced when these were combined with D-LAK120-HP13 and D-LAK120-A, respectively, suggesting a possible mechanism for the synergy of these combinations. The remodeling of the mycomembrane in M. smegmatis is therefore identified as an important countermeasure deployed against rifampin or capreomycin, but this can be mitigated and the efficacy of rifampin or capreomycin potentiated by combining the drug with AMPs

Abundance measurements of H₂O and carbon-bearing species in the atmosphere of WASP-127b confirm its super-solar metallicity

The chemical abundances of exoplanet atmospheres may provide valuable information about the bulk compositions, formation pathways, and evolutionary histories of planets. Exoplanets with large, relatively cloud-free atmospheres, and which orbit bright stars provide the best opportunities for accurate abundance measurements. For this reason, we measured the transmission spectrum of the bright (V∼10.2), large (1.37 RJ), sub-Saturn mass (0.19 MJ) exoplanet WASP-127b across the near-UV to near-infrared wavelength range (0.3–5 μm), using the Hubble and Spitzer Space Telescopes. Our results show a feature-rich transmission spectrum, with absorption from Na, H2O, and CO2, and wavelength-dependent scattering from small-particle condensates. We ran two types of atmospheric retrieval models: one enforcing chemical equilibrium, and the other which fit the abundances freely. Our retrieved abundances at chemical equilibrium for Na, O and C are all super-solar, with abundances relative to solar values of 9+15−6⁠, 16+7−5⁠, and 26+12−9 respectively. Despite giving conflicting C/O ratios, both retrievals gave super-solar CO2 volume mixing ratios, which adds to the likelihood that WASP-127b’s bulk metallicity is super-solar, since CO2 abundance is highly sensitive to atmospheric metallicity. We detect water at a significance of 13.7 σ. Our detection of Na is in agreement with previous ground-based detections, though we find a much lower abundance, and we also do not find evidence for Li or K despite increased sensitivity. In the future, spectroscopy with JWST will be able to constrain WASP-127b’s C/O ratio, and may reveal the formation history of this metal-enriched, highly observable exoplanet

Bolaamphiphile analogues of 12-bis-THA Cl2 are potent antimicrobial therapeutics with distinct mechanisms of action against bacterial, mycobacterial, and fungal pathogens.

12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used

Effectiveness of Terbutaline Pump for the Prevention of Preterm Birth. A Systematic Review and Meta-Analysis

Subcutaneous terbutaline (SQ terbutaline) infusion by pump is used in pregnant women as a prolonged (beyond 48-72 h) maintenance tocolytic following acute treatment of preterm contractions. The effectiveness and safety of this maintenance tocolysis have not been clearly established. We aimed to systematically evaluate the effectiveness and safety of subcutaneous (SQ) terbutaline infusion by pump for maintenance tocolysis.MEDLINE, EMBASE, CINAHL, the Cochrane Library, the Centre for Reviews and Dissemination databases, post-marketing surveillance data and grey literature were searched up to April 2011 for relevant experimental and observational studies. Two randomized trials, one nonrandomized trial, and 11 observational studies met inclusion criteria. Non-comparative studies were considered only for pump-related harms. We excluded case-reports but sought FDA summaries of post-marketing surveillance data. Non-English records without an English abstract were excluded. Evidence of low strength from observational studies with risk of bias favored SQ terbutaline pump for the outcomes of delivery at <32 and <37 weeks, mean days of pregnancy prolongation, and neonatal death. Observational studies of medium to high risk of bias also demonstrated benefit for other surrogate outcomes, such as birthweight and neonatal intensive care unit (NICU) admission. Several cases of maternal deaths and maternal cardiovascular events have been reported in patients receiving terbutaline tocolysis.Although evidence suggests that pump therapy may be beneficial as maintenance tocolysis, our confidence in its validity and reproducibility is low, suggesting that its use should be limited to the research setting. Concerns regarding safety of therapy persist

The emergence of the 2013 H7N9 and related viruses in China

Promising Investigator ScholarshipPoster Session: News and Views from the H7N9 OutbreakBackground: The novel H7N9 influenza A virus first detected in March 2013 has caused more than 130 cases of human infection in China, resulting in 39 deaths. This virus is a reassortant of H7, N9 and H9N2 avian influenza viruses and carries some amino acids linked to mammalian receptor binding, raising concerns of a new pandemic. However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully understood. Materials and Methods: Following the initial reports of H7N9 influenza infection in humans, field surveillance was conducted during 4th-18th April in Zhejiang, Shandong and Guangdong provinces. Pairs of oropharyngeal and cloacal samples from chickens and other poultry, together with faecal and water samples from live poultry markets (LPMs), farms and wetlands were collected for virus isolation and whole genomic sequencing. H7, N9, N7 and H9N2 archived isolates, obtained during previous influenza surveillance between 2000-2013 in southern China, were also sequenced and phylogenetically analyzed to pinpoint the genesis of the H7N9 and a related H7N7 virus. The infectivity and pathology of H7N9 and H7N7 viruses were tested in a ferret model. Results: Through a combination of active surveillance, screening of virus archives, and evolutionary analyses, we found that H7 viruses have independently transferred from domestic ducks to chickens in China on at least two occasions. Subsequently they reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related but previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at LPMs that appear to be the immediate source of human infections. In ferrets this virus caused a productive infection and pneumonia. Virus was shed via the nasal route and transmitted to physical contact and some airborne-exposed animals. Like the H7N9 virus, the H7N7 virus was also mainly isolated from chickens at LPMs and it could efficiently infect ferrets, be shed via the nasal and rectal routes, and cause severe pneumonia. Conclusions: These findings provide a clear picture showing how the current H7N9 human viruses emerged. Domestic ducks act as primary vectors to acquire and maintain diversified viruses from migratory birds, and facilitate different subtype combinations between H7 and N9 or N7 viruses and interspecies transmissions to chickens. After being introduced, the H7N9 or H7N7 viruses reassorted with enzootic H9N2 viruses and formed the current reassortant H7N9 or H7N7 viruses seen in chickens. This likely led to outbreaks in chickens, resulting in the rapid spread of the novel reassortant H7N9 virus through LPMs, which then became the source of human infections. Whether the H7N9 outbreak lineage will, or has, become enzootic in China needs further investigation. Our results also indicate that H7 viruses pose a broader threat than the current H7N9 virus. Continued prevalence of this family of H7 viruses in poultry could lead to further sporadic human infections, with an ongoing risk that the virus might acquire efficient human-to-human transmissibility.published_or_final_versio

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514