bluuebunny/crossref_metadata_2025 huggingface dataset:
Trait to gene analysis reveals that allelic variation in three genes determines seed vigour
Authors: Morris Karl , Barker Guy C. , Walley Peter G. , Lynn James R. , Finch‐Savage William E.
Published: July 2016

Predictable seedling establishment is essential for resource‐efficient and cost‐effective crop production; it is widely accepted as a critically important trait determining yield and profitability. Seed vigour is essential to this, but its genetic basis is not understood.

We used natural variation and fine mapping in the cropBrassica oleraceato show that allelic variation at three loci influence the key vigour trait of rapid germination. Functional analysis in bothB. oleraceaand the modelArabidopsisidentified and demonstrated activity of genes at these loci.

Two candidate genes were identified at the principal Speed of GerminationQTL(SOG1) inB. oleracea. One geneBoLCVIG2is a homologue of the alternative‐splicing regulator (AtPTB1). The other geneBoLCVIG1was unknown, but different alleles had different splice forms that were coincident with altered abscisic acid (ABA) sensitivity. We identified a furtherQTL, ReducedABscisic Acid 1 (RABA1) that influencedABAcontent and provide evidence that this results from the activity of a homologue of theABAcatabolic geneAtCYP707A2at this locus.

Lines containing beneficial alleles of these three genes had greater seed vigour. We propose a mechanism in which both seedABAcontent and sensitivity to it determines speed of germination.
Creativity in gifted identification: increasing accuracy and diversity
Authors: Luria Sarah R. , O'Brien Rebecca L. , Kaufman James C.
Published: July 2016

Many federal definitions and popular theories of giftedness specify creativity as a core component. Nevertheless, states rely primarily on measures of intelligence for giftedness identification. As minority and culturally diverse students continue to be underrepresented in gifted programs, it is reasonable to ask if increasing the prominence of creativity in gifted identification may help increase balance and equity. In this paper, we explore both layperson and psychometric conceptions of bias and suggest that adding creativity measures to the identification process alleviates both perceptions and the presence of bias. We recognize, however, the logistic and measurement‐related challenges to including creativity assessments.
Multidisciplinary approaches to stimulate wound healing
Authors: Businaro Rita , Corsi Mariangela , Di Raimo Tania , Marasco Sergio , Laskin Debra L. , Salvati Bruno , Capoano Raffaele , Ricci Serafino , Siciliano Camilla , Frati Giacomo , De Falco Elena
Published: July 2016

New civil wars and waves of terrorism are causing crucial social changes, with consequences in all fields, including health care. In particular, skin injuries are evolving as an epidemic issue. From a physiological standpoint, although wound repair takes place more rapidly in the skin than in other tissues, it is still a complex organ to reconstruct. Genetic and clinical variables, such as diabetes, smoking, and inflammatory/immunological pathologies, are also important risk factors limiting the regenerative potential of many therapeutic applications. Therefore, optimization of current clinical strategies is critical. Here, we summarize the current state of the field by focusing on stem cell therapy applications in wound healing, with an emphasis on current clinical approaches being developed. These involve protocols for the ex vivo expansion of adipose tissue–derived mesenchymal stem cells by means of a patented Good Manufacturing Practice–compliant platelet lysate. Combinations of multiple strategies, including genetic modifications and stem cells, biomimetic scaffolds, and novel vehicles, such as nanoparticles, are also discussed as future approaches.
Central obesity and risks of pre‐ and postmenopausal breast cancer: a dose–response meta‐analysis of prospective studies
Authors: Chen G. ‐C. , Chen S. ‐J. , Zhang R. , Hidayat K. , Qin J. ‐B. , Zhang Y. ‐S. , Qin L. ‐Q.
Published: July 2016

Epidemiologic evidence has shown inconsistent findings regarding the relationships between abdominal fatness, as measured by waist circumferences (WC) or waist‐to‐hip ratio (WHR), and risks of pre‐ and postmenopausal breast cancer (BC). A dose–response meta‐analysis of prospective studies was conducted to address these issues. Potentially eligible studies were identified by searching PubMed and EMBASE databases, and by carefully reviewing the bibliographies of retrieved publications and related reviews. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random‐effects model. When the most fully adjusted RRs were combined, both WC (14 studies, RR per 10‐cm increase = 1.06, 95% CI: 1.04–1.09, I2 = 29.9%) and WHR (15 studies, RR per 0.1‐unit increase = 1.07, 95% CI: 1.01–1.14, I2 = 52.9%) were significantly positively associated with postmenopausal BC, but neither WC (eight studies, RR per 10‐cm increase = 1.05, 95% CI: 0.99–1.10, I2 = 0%) nor WHR (11 studies, RR per 0.1‐unit increase = 1.07, 95% CI: 0.95–1.21, I2 = 59.7%) were associated with premenopausal BC. The WHR‐postmenopausal BC association lost statistical significance after correcting publication bias (RR per 0.1‐unit increase = 1.06, 95% CI: 0.99–1.13). When considering BMI‐adjusted RRs, WC was associated with both pre‐ (five studies, RR per 10‐cm increase = 1.09, 95% CI: 1.02–1.16, I2 = 0%) and postmenopausal BC (seven studies, RR per 10‐cm increase = 1.05, 95% CI: 1.02–1.08, I2 = 6.3%), whereas WHR was not associated with either pre‐ (seven studies, RR per 0.1‐unit increase = 1.12, 95% CI: 0.94–1.34, I2 = 70.9%) or postmenopausal BC (eight studies, RR per 0.1‐unit increase = 1.05, 95% CI: 0.98–1.13, I2 = 57.3%). Among non‐current (former or never) users of hormone replacement therapy, the summary RR per 10‐cm increase of postmenopausal BC associated with WC was 1.08 (95% CI: 1.03–1.05, I2 = 69.2%, seven studies; BMI‐adjusted RR = 1.05, 95% CI: 1.02–1.09, I2 = 22.8%, four studies). This meta‐analysis indicates that central obesity measured by WC, but not by WHR, is associated with modestly increased risks of both pre‐ and postmenopausal BC independent of general obesity.
Modes of Remembering in the Contemporary Spanish Novel
Authors: Hansen Hans Lauge
Published: July 2016

This article examines the way in which the topic of civil war and Francoist repression has been narrated and understood in the contemporary Spanish novel after the turn of the millennium. The boom in what the article calls ‘the affiliative memory novel’ has been intimately related to the activities conducted by popular movements dedicated to the so‐called recuperation of the historical memory, but whether and to what extent is it possible to describe the phenomenon at hand as a coherent sub‐genre? It is a hypothesis that the way in which the relation between past, present and future is imagined in the text is, at least to some extent, related to the narrative form in which the novels are told, and by combining two paradigms of modal description, one narrative and the other ethico‐political, the article proposes eight different modes of remembering, among which three are considered more typical or generic. Finally, these three modes, the essentializing, the reconciliatory and the metamodernist modes, are examined and discussed within a transnational perspective.
Feasibility testing of a home‐based sensor system to monitor mobility and daily activities in Korean American older adults
Authors: Chung Jane , Demiris George , Thompson Hilaire J. , Chen Ke‐Yu , Burr Robert , Patel Shwetak , Fogarty James
Published: July 2016

Aims and objectives:

This study aimed to test feasibility of a home‐based sensor system that is designed to assess mobility and daily activity patterns among Korean American older adults (KAOAs; n = 6) and explore sensor technology acceptance among participants.

Background

Home‐based sensors have the potential to support older adults' desire to remain at home as long as possible. Despite a growing interest in using home‐based sensors for older adults, there have been no documented attempts to apply this type of technology to a group of ethnic minority older adults.

Design

The study employed descriptive, quantitative and qualitative approaches.

Methods

The system was deployed for 2 months in four homes of KAOAs. Study procedures included (i) sensor‐based data collection, (ii) self‐report mobility instruments, (iii) activity logs and (iv) interviews. To explore changes in activity patterns, line graphs and sequence plots were applied to data obtained from a set of sensors. General linear models (GLMs) were used for motion in each space of the home to examine how much variability of activities is explained by several time variables.

Results

Sensor data had natural fluctuation over time. Different 24‐hr patterns were observed across homes. The GLM estimates showed that effect sizes of the time variables vary across individuals. A hydro sensor deployed in one participant's bathroom inferred various water usage activities. Overall, sensors were acceptable for all participants, despite some privacy concerns.

Conclusions

Study findings demonstrate that sensor technology applications could be successfully used longitudinally in a minority population of older adults that is not often targeted as an end‐user group for the use of innovative technologies.

Implications for practice

The use of home‐based sensors provides nurses with a useful tool to detect deviations from normal patterns and to achieve proactive care for some groups of older adults.
No simple answers for the Finnish and Russian Karelia allergy contrast: Methylation of CD14 gene
Authors: Khoo Siew‐Kim , Mäkelä Mika , Chandler David , Schultz En Nee , Jamieson Sarra E. , Goldblatt Jack , Haahtela Tari , LeSouëf Peter , Zhang Guicheng
Published: July 2016

Background

Finnish and Russian Karelian children have a highly contrasting occurrence of asthma and allergy. In these two environments, we studied associations between total serum immunoglobulin E (IgE) with methylation levels in cluster of differentiation 14 (CD14).

Methods

Five hundred Finnish and Russian Karelian children were included in four groups: Finnish children with high IgE (n = 126) and low IgE (n = 124) as well as Russian children with high IgE (n = 125) and low IgE (n = 125). DNA was extracted from whole blood cells and pyrosequenced. Three CpG sites were selected in the promoter region of CD14.

Results

Methylation levels in two of the three CpG sites were higher in the Finnish compared to Russian Karelian children. In the promoter area of CD14, the Finnish compared to Russian children with low IgE had a significant (p < 0.0001) increase in methylation levels at the Amp5Site 2. Likewise, the Finnish compared to Russian children with high IgE had a significant (p = 0.003) increase in methylation levels at the Amp5Site 3. In Russian children with low vs. high IgE, there were significant differences in methylation levels, but this was not the case on the Finnish side. In the regression analysis, adding the methylation variation of CD14 to the model did not explain the higher asthma and allergy risk in the Finnish children.

Conclusions

The methylation levels in the promoter region of CD14 gene were higher in the Finnish compared to Russian Karelian children. However, the methylation variation of this candidate gene did not explain the asthma and allergy contrast between these two areas.
Exploration of early‐life candidate biomarkers for childhood asthma using antibody arrays
Authors: Xu Haili , Radabaugh Timothy , Lu Zhenqiang , Galligan Michael , Billheimer Dean , Vercelli Donata , Wright Anne L. , Monks Terrence J. , Halonen Marilyn , Lau Serrine S.
Published: July 2016

Background

Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent.

Methods

With an antibody array (RayBiotech, Norcross, GA, USA), the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema, and wheeze.

Results

In the antibody array, four proteins had rank differences between asthma and non‐asthma groups (FDR <0.1). By ELISA, mean log (±s.e.m.) erythropoietin (EPO) level (IU/l) was lower (0.750 ± 0.048 vs. 0.898 ± 0.035; p = 0.006) and mean (±s.e.m.) soluble GP130 (sGP130) level (ng/ml) was higher in the asthma vs. the non‐asthma group (302 ± 13 vs. 270 ± 8; p = 0.041). The other 2 array proteins (galactin‐3 and eotaxin‐3) did not differ by ELISA by asthma. EPO related to the asthma risk factor, first year eczema, whereas sGP130 related to first year wheeze.

Conclusions

Through two independent assessments, age 3 plasma levels of EPO and sGP130 were found related to childhood asthma.
The prevalence, natural history and time trends of peanut allergy over the first 10 years of life in two cohorts born in the same geographical location 12 years apart
Authors: Venter Carina , Maslin Kate , Patil Veeresh , Kurukulaaratchy Ramesh , Grundy Jane , Glasbey Gillian , Twiselton Roger , Dean Taraneh , Arshad Syed Hasan
Published: July 2016

Background

The aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England.

Methods

The FAIR birth cohort was established on the Isle of Wight (UK) between 2001 and 2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history.

Results

In the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1, 2, 3 and 10 years, respectively. At 10 years of age, 12 of 828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first 10 years of life, 13 of 934 (1.4%) children were diagnosed with peanut allergy. In the IOW cohort, 6 of 1034 (0.58%) were diagnosed with peanut allergy at 10 years. We found no significant differences between the FAIR and the IOW birth cohort for any of the time points studied.

Conclusion

Peanut allergy appears to be stable over the first 10 years of life in our cohorts. There was no significant difference in peanut sensitization or clinical peanut allergy between 1989 and 2001.
Young children's experiences of living with a parent with bipolar disorder: Understanding the child's perspective
Authors: Backer Clare , Murphy Rebecca , Fox John R. E. , Ulph Fiona , Calam Rachel
Published: July 2016

Objectives

To explore the experiences of young children of living with a parent with bipolar disorder (BD) and how this impacts on their emotional well‐being.

Design

Qualitative study using a computer‐assisted semi‐structured interview, ‘In My Shoes’ (IMS).

Methods

Ten children aged between 4 and 10 years with a parent with BD identified via self‐help groups were interviewed about their experience of family life. Thematic analysis was used following transcription.

Results

Four main themes emerging from thematic analysis were as follows: perception of parents; knowledge and awareness of BD; managing family life with a ‘bipolar’ parent; and living in a family with BD. Four‐year‐old children could participate in the IMS interviews and discuss their parent's mood, behaviour, and mental health. Children had candid and insightful discussions about their parent's BD including symptoms and parenting, and could reflect on how having a parent with BD affected them emotionally and practically. Older children were better able to articulate their parent's illness and its impact.

Conclusions

This exploratory study represents an important step in examining directly experiences of young children whose parents have BD. Using IMS, it was possible to gather insightful information from children to generate hypotheses and influence service development. Children of all ages had some knowledge and understanding of their parent's illness, describing both positive and negative experiences in the family. Further research to build understanding of children's perspectives and the support they feel they and their family would benefit from would enhance the development of appropriate services and interventions.

Practitioner points

Using age‐appropriate tools, it is possible to elicit the views of young children about their parent's mental health and parenting.

Young children have insight into the impact of bipolar disorder in the family on themselves and family members.
An experimental investigation of wave‐induced sediment responses in a natural silty seabed: New insights into seabed stratification
Authors: Liu Xiaolei , Jia Yonggang , Zheng Jiewen , Wen Mingzheng , Shan Hongxian
Published: July 2016

The widely recognized global phenomenon of wave–seabed interactions and the resulting secondary stratification processes are complex and poorly understood. To better understand the mechanisms by which the differentiation between fine‐grained and coarse‐grained materials occurs and how new sedimentary sequences form, laboratory flume experiments were performed under varying wave conditions using natural silty sediment samples collected from the Yellow River Delta (China). Detailed observations led to the description of variations in the grain‐size composition and texture of sediment under waves of progressively increasing height and the recognition of the typical, secondarily formed seabed stratification that forms during processes of increasing pore pressure and subsequent liquefaction. The development of a stratified seabed, which is characterized by a superficial fluid mud layer, a subsurface that alternates between coarse and fine sediment banding, and an internal liquefied layer from top to bottom, is closely related to wave‐driven pore‐water flow through the sediment. Localized fluidization and the onset of piping leads to progressive changes in the grain composition with initial particle dislocation, the development of macro‐voids and micro‐conduits and, finally, pipe formation. Internal liquefaction occurs in the presence of a critical value of excess pore pressure, during which most fine particles can be scoured by the pore‐water flow along the sliding surface while the coarse sediment grains settle, leading to a more compact, homogeneous seabed. These elements are combined to produce the first model of wave‐induced stratification initiation and evolution in an originally uniform silty seabed. In addition, the implications of this model for future studies are explored.
Framing the Gun Control Debate: Press Releases and Framing Strategies of the National Rifle Association and the Brady Campaign*
Authors: Steidley Trent , Colen Cynthia G.
Published: July 2016

Objective

How can social movements increase their presence in the news? We argue that press releases can do so via social movement framing. Press releases from, and news coverage of, social movement organizations (SMOs) in the gun control debate serve as our case.

Methods

A qualitative framing analysis is conducted to identify frames in press releases from the National Rifle Association and the Brady Campaign. Logistic regressions assess the effect of frames in press releases on New York Times coverage of the gun control debate.

Results

We find that both organizations use systematic framing strategies in their press releases. Only the Brady Campaign has a significant association between specific frames in its press releases and coverage in the New York Times.

Conclusions

Press releases are viable tactics for SMOs, but biases in news media have implications for how effective press releases might be for an SMO.
Pollution Prophylaxis? Social Capital and Environmental Inequality*
Authors: Ard Kerry , Fairbrother Malcolm
Published: July 2016

Objective

One major theory of environmental inequality is that firms follow a political path of least resistance when locating polluting facilities in low‐income and minority communities. Such communities, this theory suggests, lack the social capital that allows others to keep such facilities at bay. We will test this argument.

Methods

We investigate whether communities across the United States are located further from stationary sources of airborne toxins depending on their levels of social capital.

Results

At some scales, we found that communities with more of some types of social capital do indeed tend to be located further from such facilities, though the differences are slight. We also found that, by some measures, minority communities possess no less social capital than others, and that controlling for differences in social capital barely attenuates the associations between demographics and proximity.

Conclusion

The theory that differences in social capital explain environmental inequality is not supported.
Verb‐second in embedded clauses in Faroese
Authors: Angantýsson Ásgrímur
Published: July 2016

There has been considerable controversy in the linguistic literature about the nature of Vfin‐Adv (V2) order in subject‐initial embedded clauses in Faroese: Is it the result of a V‐to‐T movement, as is typically assumed for Icelandic, or is it a root phenomenon, i.e. V‐to‐C movement, as usually assumed for the standard Mainland Scandinavian languages. Heycock et al. (2012) argue that both kinds of Vfin‐Adv order can be found in Faroese embedded clauses and this paper provides further evidence for that claim. On the assumption that V‐to‐T is still a possibility in Faroese, some versions of the so‐called Rich Agreement Hypothesis (e.g. Bobaljik & Thráinsson 1998) predict that transitive expletives should also be possible in Faroese. This prediction is borne out. However, contrary to predictions regarding direct connection between verbal inflection on the one hand and verb movement and transitive expletive constructions on the other hand, it is demonstrated that speakers who distinguish tense and agreement morphemes most clearly in their speech are neither more likely to accept transitive expletives nor V2‐orders in various types of embedded clauses than speakers who do not distinguish tense and agreement morphemes as clearly. It is maintained that while Vfin‐Adv is on its way out in Faroese, presumably because of diminishing morphological support and partially ambiguous syntactic evidence, the language has not yet reached the Mainland Scandinavian state in this respect.
Thrombocytopenia and guideline‐evaluated appropriateness of platelet transfusion in a tertiary care intensive care unit
Authors: Vasu B.K. , Sinha R. , Verghese S.
Published: July 2016

Background and Objectives

Platelet transfusions are common in clinical practice especially in the intensive care unit settings without acceptable clinical evidence. A retrospective audit was undertaken to evaluate the prevalence of thrombocytopenia, transfusion triggers and indications of transfusion and to assess the appropriateness of platelet transfusions based on current guidelines in patients admitted to a tertiary care intensive care unit (ICU) in South Australia.

Methods

Platelet counts on ICU admission, during ICU stay, use of platelet transfusion and clinical outcomes including bleeding for each consecutive admission to ICU over a 12‐month period was collected.

Results

The prevalence of thrombocytopenia (platelet counts <150 × 109/l) was 51·7% in 1790 ICU patients, of which 32·4% (580/1790) were thrombocytopenic at admission while 19·4% (347/1790) of patients developed thrombocytopenia during their ICU stay. Severe thrombocytopenia with platelet counts <50 × 109/l was observed in 4·2%, with 2·6% at admission and 1·6% subsequently. Two hundred and thirteen patients (11·6%) received 480 units of platelets through 319 transfusion episodes. A total of 82·1% (262/319) of these transfusion episodes were therapeutic and 17·9% (57/319) prophylactic. Based on criteria developed from prevailing guidelines and literature, 14·1% (45/319) of platelet transfusion episodes were assessed to be inappropriate, which was 15·8% (9/57) in the prophylactic and 13·7% (36/262) in the therapeutic transfusion episodes.

Conclusion

Thrombocytopenia is common in ICU patients, and a significant proportion of ICU patients receive platelet transfusions to control bleeding and maintain haemostasis. A minority of patients receive inappropriate platelet transfusions with unclear benefits with a potential to develop serious transfusion‐related adverse events.
Reducing risks of Transfusion‐transmitted infections in a resource‐limited hospital‐based blood bank: the case of the Yaoundé University Teaching Hospital, Cameroon
Authors: Tagny C. T. , Ndoumba A. , Laperche S. , Murphy E. , Mbanya D.
Published: July 2016

Background and Objectives

Although interest in assessing risk of TTIs, very few trends in blood safety epidemiological data from resource‐limited blood services are reported in the literature. This analysis aims at reporting trends in seroprevalences of TTIs in blood donations in the Yaoundé University Teaching Hospital (UTH) from 2011 to 2015 and to describe reasons for these changes.

Materials and Methods

All donations of 2015 were tested for HIV 1&2 antibodies and the P24 antigen, HBsAg, HCV antibody and the Treponema pallidum antibody. Screening for HIV uses a national algorithm based on the systematic use of two assays of different principles: a rapid determination testing assay and an EIA HIV 1 & 2 Ab‐Ag. The tests used for HBsAg and HCVAb screening were all based on EIA techniques. Treponema pallidum antibody screening was based on Treponema Pallidum hemagglutination assay (TPHA) and rapid immunochromatographic test (RIT). Screening techniques and results from 2015 were compared to retrospective data from 2011, 2012, 2013 and 2014.

Results

In 2015, 13·4% (n = 214) of 1,596 blood donations were seropositive for at least one screened TTIs. The most frequent serological marker was HBsAg with 123 (7·7%) blood units contaminated. Nineteen (1·2%) and 18 (1·1%) blood units was positive for HIV and syphilis, respectively. There was a significant decrease in the total number of blood donations (P < 10−4) and HIV, HBsAg and syphilis seroprevalences and an increase in the proportion of voluntary non‐remunerated blood donor (P < 0·05). HCVAb seroprevalence was 3·8% in 2015 and has not decreased significantly over the years (P = 0·09).

Conclusion

Significant progress is noted in reduction in seroprevalences of HIV, HBV, HCV and syphilis since the beginning of a regular registration of data in 1990.
ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings
Authors: Weiss Jonathan M. , Chen Wei , Nyuydzefe Melanie S. , Trzeciak Alissa , Flynn Ryan , Tonra James R. , Marusic Suzana , Blazar Bruce R. , Waksal Samuel D. , Zanin-Zhorov Alexandra
Published: July 2016

Inhibition of the kinase ROCK2 specifically prevents a subset of T cells from contributing to autoimmunity.
Paper of note in
Science Translational Medicine
Authors: Ferrarelli Leslie K.
Published: July 2016

This week’s article describes how gene therapy may be a neuroprotective strategy for spinocerebellar ataxia.
8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis
Authors: Shah Santosh , Dalecki Alex G. , Malalasekera Aruni P. , Crawford Cameron L. , Michalek Suzanne M. , Kutsch Olaf , Sun Jim , Bossmann Stefan H. , Wolschendorf Frank
Published: July 2016

Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of
Mycobacterium tuberculosis
. The MIC of 8HQ in the presence of Cu was 0.16 μM for replicating and nonreplicating
M. tuberculosis
cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill
M. tuberculosis
selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of
M. tuberculosis
. In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against
M. tuberculosis
.
Homologous Recombination within Large Chromosomal Regions Facilitates Acquisition of β-Lactam and Vancomycin Resistance in Enterococcus faecium
Authors: García-Solache Mónica , Lebreton Francois , McLaughlin Robert E. , Whiteaker James D. , Gilmore Michael S. , Rice Louis B.
Published: July 2016

The transfer of DNA between
Enterococcus faecium
strains has been characterized both by the movement of well-defined genetic elements and by the large-scale transfer of genomic DNA fragments. In this work, we report on the whole-genome analysis of transconjugants resulting from mating events between the vancomycin-resistant
E. faecium
C68 strain and the vancomycin-susceptible D344RRF strain to discern the mechanism by which the transferred regions enter the recipient chromosome. Vancomycin-resistant transconjugants from five independent matings were analyzed by whole-genome sequencing. In all cases but one, the penicillin binding protein 5 (
pbp5
) gene and the Tn
5382
vancomycin resistance transposon were transferred together and replaced the corresponding
pbp5
region of D344RRF. In one instance, Tn
5382
inserted independently downstream of the D344RRF
pbp5
gene. Single nucleotide variant (SNV) analysis suggested that entry of donor DNA into the recipient chromosome occurred by recombination across regions of homology between donor and recipient chromosomes, rather than through insertion sequence-mediated transposition. The transfer of genomic DNA was also associated with the transfer of C68 plasmid pLRM23 and another putative plasmid. Our data are consistent with the initiation of transfer by cointegration of a transferable plasmid with the donor chromosome, with subsequent circularization of the plasmid-chromosome cointegrant in the donor prior to transfer. Entry into the recipient chromosome most commonly occurred across regions of homology between donor and recipient chromosomes.
Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an
In Vitro
Pharmacokinetic-Pharmacodynamic Model
Authors: Hall Snyder Ashley D. , Werth Brian J. , Nonejuie Poochit , McRoberts John P. , Pogliano Joe , Sakoulas George , Yim Juwon , Singh Nivedita , Rybak Michael J.
Published: July 2016

Daptomycin (DAP) is being used more frequently to treat infections caused by vancomycin-resistant enterococcus (VRE). DAP tends to be less active against enterococci than staphylococci and may require high doses or combination therapy to be bactericidal. Fosfomycin (FOF) has activity against VRE and has demonstrated synergistic bactericidal activity with DAP
in vitro
. The objective of this study was to evaluate the activity of DAP alone and in combination with FOF against VRE in an
in vitro
pharmacokinetic/pharmacodynamic (PK/PD) model. The activity of DAP at 8 and 12 mg/kg of body weight/day (DAP 8 and DAP 12, respectively) and FOF of 40 mg/kg intravenously every 8 h, alone and in combination, were evaluated against 2 vancomycin-resistant
Enterococcus faecium
strains (8019 and 5938) and 2 vancomycin-resistant
E. faecalis
strains (V583 and R7302) in an
in vitro
PK/PD model over 72 h. Cell surface charge in the presence and absence of FOF was evaluated by zeta potential analysis. Daptomycin-boron-dipyrromethene (bodipy) binding was assessed by fluorescence microscopy. The addition of FOF to DAP 8 and DAP 12 resulted in significantly increased killing over DAP alone at 72 h for 8019, V583, and R7302 (
P
< 0.05). Therapeutic enhancement was observed with DAP 12 plus FOF against 8019, V583, and R7302. Cell surface charge became more negative after exposure to FOF by ∼2 to 8mV in all 4 strains. Daptomycin-bodipy binding increased by 2.6 times in the presence of fosfomycin (
P
< 0.0001). The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge. Further studies to clarify the role of intravenous FOF are warranted.
Cryptosporidium and Toxoplasma Parasites Are Inhibited by a Benzoxaborole Targeting Leucyl-tRNA Synthetase
Authors: Palencia Andrés , Liu Ru-Juan , Lukarska Maria , Gut Jiri , Bougdour Alexandre , Touquet Bastien , Wang En-Duo , Li Xianfeng , Alley M. R. K. , Freund Yvonne R. , Rosenthal Philip J. , Hakimi Mohamed-Ali , Cusack Stephen
Published: July 2016

The apicomplexan parasites
Cryptosporidium
and
Toxoplasma
are serious threats to human health. Cryptosporidiosis is a severe diarrheal disease in malnourished children and immunocompromised individuals, with the only FDA-approved drug treatment currently being nitazoxanide. The existing therapies for toxoplasmosis, an important pathology in immunocompromised individuals and pregnant women, also have serious limitations. With the aim of developing alternative therapeutic options to address these health problems, we tested a number of benzoxaboroles, boron-containing compounds shown to be active against various infectious agents, for inhibition of the growth of
Cryptosporidium
parasites in mammalian cells. A 3-aminomethyl benzoxaborole, AN6426, with activity in the micromolar range and with activity comparable to that of nitazoxanide, was identified and further characterized using biophysical measurements of affinity and crystal structures of complexes with the editing domain of
Cryptosporidium
leucyl-tRNA synthetase (LeuRS). The same compound was shown to be active against
Toxoplasma
parasites, with the activity being enhanced in the presence of norvaline, an amino acid that can be mischarged by LeuRS. Our observations are consistent with AN6426 inhibiting protein synthesis in both
Cryptosporidium
and
Toxoplasma
by forming a covalent adduct with tRNA
Leu
in the LeuRS editing active site and suggest that further exploitation of the benzoxaborole scaffold is a valid strategy to develop novel, much needed antiparasitic agents.
Bacterial Spheroplasts as a Model for Visualizing Membrane Translocation of Antimicrobial Peptides
Authors: Wei Lei , LaBouyer Maria A. , Darling Louise E. O. , Elmore Donald E.
Published: July 2016

Studies attempting to characterize the membrane translocation of antimicrobial and cell-penetrating peptides are frequently limited by the resolution of conventional light microscopy. This study shows that spheroplasts provide a valuable approach to overcome these limits. Spheroplasts produce less ambiguous images and allow for more systematic analyses of localization. Data collected with spheroplasts are consistent with studies using normal bacterial cells and imply that a particular peptide may not always follow the same mechanism of action.
First Occurrence of OXA-72-Producing Acinetobacter baumannii in Serbia
Authors: Dortet Laurent , Bonnin Rémy A. , Bernabeu Sandrine , Escaut Lélia , Vittecoq Daniel , Girlich Delphine , Imanci Dilek , Fortineau Nicolas , Naas Thierry
Published: July 2016

Here, we characterized the first OXA-72-producing
Acinetobacter baumannii
isolate (designated MAL) recovered from a urine sample from a Serbian patient. Antimicrobial susceptibility testing, plasmid analysis, and whole-genome sequencing (WGS) were performed to fully characterize the resistome of the
A. baumannii
MAL clinical isolate. The isolate was multidrug resistant and remained susceptible only to colistin and tigecycline. PCR analysis revealed the presence of the carbapenemase OXA-72, an OXA-40 variant. Extraction by the Kieser method revealed the presence of two plasmids, and one of these, a ca. 10-kb plasmid, harbored the
bla
OXA-72
gene. WGS revealed 206 contigs corresponding to a genome of 3.9 Mbp in size with a G+C content of 38.8%. The isolate belonged to sequence type 492 and to worldwide clone II (WWCII). Naturally occurring β-lactamase-encoding genes (
bla
ADC-25
and
bla
OXA-66
) were also identified. Aminoglycoside resistance genes encoding one aminoglycoside adenyltransferase (
aadA2
), three aminoglycoside phosphatases (
strA
,
strB
,
aphA6
), and one 16S RNA methylase (
armA
) conferring resistance to all aminoglycosides were identified. Resistance to fluoroquinolones was likely due to mutations in
gyrA
,
parC
, and
parE
. Of note, the resistome matched perfectly with the antibiotic susceptibility testing results.
Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax
Authors: Yamamoto Brent J. , Shadiack Annette M. , Carpenter Sarah , Sanford Daniel , Henning Lisa N. , Gonzales Nestor , O'Connor Edward , Casey Leslie S. , Serbina Natalya V.
Published: July 2016

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative toBacillus anthracisaerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.
A Combination Fluorescence Assay Demonstrates Increased Efflux Pump Activity as a Resistance Mechanism in Azole-Resistant Vaginal Candida albicans Isolates
Authors: Bhattacharya Somanon , Sobel Jack D. , White Theodore C.
Published: July 2016

Candida albicansis a pathogenic fungus causing vulvovaginal candidiasis (VVC). Azole drugs, such as fluconazole, are the most common treatment for these infections. Recently, azole-resistant vaginalC. albicansisolates have been detected in patients with recurring and refractory vaginal infections. However, the mechanisms of resistance in vaginalC. albicansisolates have not been studied in detail. In oral and systemic resistant isolates, overexpression of the ABC transporters Cdr1p and Cdr2p and the major facilitator transporter Mdr1p is associated with resistance. Sixteen fluconazole-susceptible and 22 fluconazole-resistant vaginalC. albicansisolates were obtained, including six matched sets containing a susceptible and a resistant isolate, from individual patients. Using quantitative real-time reverse transcriptase PCR (qRT-PCR), 16 of 22 resistant isolates showed overexpression of at least one efflux pump gene, while only 1 of 16 susceptible isolates showed such overexpression. To evaluate the pump activity associated with overexpression, an assay that combined data from two separate fluorescent assays using rhodamine 6G and alanine β-naphthylamide was developed. The qRT-PCR results and activity assay results were in good agreement. This combination of two fluorescent assays can be used to study efflux pumps as resistance mechanisms in clinical isolates. These results demonstrate that efflux pumps are a significant resistance mechanism in vaginalC. albicansisolates.
Coexistence of
mcr-1
and
bla
NDM-1
in Escherichia coli from Venezuela
Authors: Delgado-Blas Jose F. , Ovejero Cristina M. , Abadia-Patiño Lorena , Gonzalez-Zorn Bruno
Published: July 2016

We studied the presence of the mobile colistin resistance gene
mcr-1
in human, animal, and environmental
Enterobacteriaceae
samples from Cumana, Venezuela, that were collected in 2015. The
mcr-1
gene was detected in 2/93
Escherichia coli
isolates from swine (novel ST452) and human (ST19) samples that were resistant to colistin. Whole-genome sequencing and transformation experiments identified
mcr-1
on an IncI2 plasmid. One of the isolates also bore the widely spread carbapenemase NDM-1. A One Health approach is necessary to further elucidate the flux of these high-risk genes.
Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework
Authors: Jabra-Rizk Mary Ann , Kong Eric F. , Tsui Christina , Nguyen M. Hong , Clancy Cornelius J. , Fidel Paul L. , Noverr Mairi
Published: July 2016

Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of
Candida albicans
, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably,
C. albicans
infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses.
Arterial damages in acute elbow dislocations: which diagnostic tests are required?
Authors: Lutter Christoph , Pfefferkorn Ronny , Schoeffl Volker
Published: July 2016

Blunt vessel injuries of peripheral arteries caused by a direct trauma are rare. Studies have described the frequency of arterial ruptures following closed elbow dislocations in 0.3–1.7% of all cases. However, arterial damage does not always necessarily appear as a complete rupture of the vessel with a loss of peripheral circulation and ischaemic symptoms; a relatively strong periarticular system of collaterals can maintain circulation. Furthermore, the traumatic dislocation can also cause intimal tears, arterial dissections and aneurysms or thrombosis. In all cases of vessel injury, including total disruption, a peripheral pulse might still be palpable. 3 weeks after an acute elbow dislocation, we have diagnosed a patient with a long-segment stenosis of the brachial artery and a thrombosis of the radial artery. Therefore, the close anatomic proximity to the neurovascular structures should always be considered in cases of elbow dislocations, even if peripheral pulses are traceable.
Understanding HIV-positive patients' preferences for healthcare services: a protocol for a discrete choice experiment
Authors: Youssef Elaney , Cooper Vanessa , Miners Alec , Llewellyn Carrie , Pollard Alex , Lagarde Mylene , Sachikonye Memory , Sabin Caroline , Foreman Claire , Perry Nicky , Nixon Eileen , Fisher Martin
Published: July 2016

Introduction

While the care of HIV-positive patients, including the detection and management of comorbidities, has historically been provided in HIV specialist outpatient clinics, recent years have seen a greater involvement of non-HIV specialists and general practitioners (GPs). The aim of this study is to determine whether patients would prefer to see their GP or HIV physician given general symptoms, and to understand what aspects of care influence their preferences.

Methods/analysis

We have developed and piloted a discrete choice experiment (DCE) to better understand patients' preferences for care of non-HIV-related acute symptoms. The design of the DCE was informed by our exploratory research, including the findings of a systematic literature review and a qualitative study. Additional questionnaire items have been included to measure demographics, service use and experience of non-HIV illnesses and quality of life (EQ5D). We plan to recruit 1000 patients from 14 HIV clinics across South East England. Data will be analysed using random-effects logistic regression and latent class analysis. ORs and 95% CIs will be used to estimate the relative importance of each of the attribute levels. Latent class analysis will identify whether particular groups of people value the service attribute levels differently.

Ethics/dissemination

Ethical approval for this study was obtained from the Newcastle and North Tyneside Research Ethics Committee (reference number 14/NE/1193). The results will be disseminated at national and international conferences and peer-reviewed publications. A study report, written in plain English, will be made available to all participants. The Patient Advisory Group will develop a strategy for wider dissemination of the findings to patients and the public.