75 research outputs found
Taking the next-gen step: Comprehensive antimicrobial resistance detection from Burkholderia pseudomallei
Background: Antimicrobial resistance (AMR) poses a major threat to human health. Whole-genome sequencing holds great potential for AMR identification; however, there remain major gaps in accurately and comprehensively detecting AMR across the spectrum of AMR-conferring determinants and pathogens.
Methods: Using 16 wild-type Burkholderia pseudomallei and 25 with acquired AMR, we first assessed the performance of existing AMR software (ARIBA, CARD, ResFinder, and AMRFinderPlus) for detecting clinically relevant AMR in this pathogen. B. pseudomallei was chosen due to limited treatment options, high fatality rate, and AMR caused exclusively by chromosomal mutation (i.e. single-nucleotide polymorphisms [SNPs], insertions-deletions [indels], copy-number variations [CNVs], inversions, and functional gene loss). Due to poor performance with existing tools, we developed ARDaP (Antimicrobial Resistance Detection and Prediction) to identify the spectrum of AMR-conferring determinants in B. pseudomallei.
Findings: CARD, ResFinder, and AMRFinderPlus failed to identify any clinically-relevant AMR in B. pseudomallei; ARIBA identified AMR encoded by SNPs and indels that were manually added to its database. However, none of these tools identified CNV, inversion, or gene loss determinants, and ARIBA could not differentiate AMR determinants from natural genetic variation. In contrast, ARDaP accurately detected all SNP, indel, CNV, inversion, and gene loss AMR determinants described in B. pseudomallei (n≈50). Additionally, ARDaP accurately predicted three previously undescribed determinants. In mixed strain data, ARDaP identified AMR to as low as ~5% allelic frequency.
Interpretation: Existing AMR software packages are inadequate for chromosomal AMR detection due to an inability to detect resistance conferred by CNVs, inversions, and functional gene loss. ARDaP overcomes these major shortcomings. Further, ARDaP enables AMR prediction from mixed sequence data down to 5% allelic frequency, and can differentiate natural genetic variation from AMR determinants. ARDaP databases can be constructed for any microbial species of interest for comprehensive AMR detection
DOSE REQUIREMENTS AND PLASMA CONCENTRATIONS OF PIPECURONIUM DURING BILATERAL RENAL EXCLUSION AND ORTHOTOPIC LIVER TRANSPLANTATION IN PIGS
We have studied five pigs undergoing bilateral clamping of the renal pedicles, seven pigs undergoing orthotopic liver transplantation and three control animals without surgery in order to examine the roles of the kidney and liver in the plasma clearance of pipecuronium. An i.v. infusion of pipecuronium was controlled to maintain a constant 90-95 % twitch depression throughout the investigation. The right sciatic nerve was stimulated continuously with supra-maximal stimuli at 0.1 Hz and the force of the corresponding evoked isometric muscle contraction was recorded continuously. Control pigs needed an infusion rate of pipecuronium 8-10.7 μg kg−1 min−1. In the renal group, it was necessary to reduce the infusion rate of pipecuronium by about 25% after clamping both renal vascular pedicles (P < 0.05 compared with controls); in pigs undergoing liver transplantation, it was necessary to reduce the rate by approximately 80% after clamping hepatic vessels (P < 0.05 compared with controls and from the period after clamping of renal vessels). After hepatic recirculation, the infusion rate of pipecuronium was increased progressively to a rate which corresponded to 50% of baseline values (P < 0.05 compared with the anhepatic phase and from controls). Plasma concentrations of pipecuronium were comparable in the three animal groups and did not change significantly during the study. These data suggest that the liver plays a more important role than the kidney in the plasma clearance of pipecuronium in pig
Description of Generalized Continued Fractions by Finite Automata
A generalized continued fraction algorithm associates with every real number x a sequence of integers; x is rational iff the sequence is finite. For a fixed algorithm, call a sequence of integers valid if it is the result of that algorithm on some input x0. We show that, if the algorithm is sufficiently well-behaved, then the set of all valid sequences is accepted by a finite automaton. I. Introduction. It is well known that every real number x has a unique expansion as a simple continued fraction in the form
Intergenerational Community-Based Research and Creative Practice: Promoting Environmental Sustainability in Jinja, Uganda
This article critically reflects on the methodological approach developed for a recent project based in Jinja, Uganda, that sought to generate new forms of environmental knowledge and action utilizing diverse forms of creative intergenerational practice embedded within a broader framework of community-based participatory research. This approach provided new opportunities for intergenerational dialogue in Jinja, generated increased civic environmental engagement, and resulted in a participant-led campaign to share knowledge regarding sustainable biomass consumption. We term this approach intergenerational community-based research and creative practice. We discuss the advantages of this model while also reflecting throughout on the challenges of the approach
Genomic comparisons reveal biogeographic and anthropogenic impacts in the koala (Phascolarctos cinereus): a dietary-specialist species distributed across heterogeneous environments
The Australian koala is an iconic marsupial with highly specific dietary requirements distributed across heterogeneous environments, over a large geographic range. The distribution and genetic structure of koala populations has been heavily influenced by human actions, specifically habitat modification, hunting and translocation of koalas. There is currently limited information on population diversity and gene flow at a species-wide scale, or with consideration to the potential impacts of local adaptation. Using species-wide sampling across heterogeneous environments, and high-density genome-wide markers (SNPs and PAVs), we show that most koala populations display levels of diversity comparable to other outbred species, except for those populations impacted by population reductions. Genetic clustering analysis and phylogenetic reconstruction reveals a lack of support for current taxonomic classification of three koala subspecies, with only a single evolutionary significant unit supported. Furthermore, similar to 70% of genetic variance is accounted for at the individual level. The Sydney Basin region is highlighted as a unique reservoir of genetic diversity, having higher diversity levels (i.e., Blue Mountains region; AvHe(corr)-0.20, PL% = 68.6). Broad-scale population differentiation is primarily driven by an isolation by distance genetic structure model (49% of genetic variance), with clinal local adaptation corresponding to habitat bioregions. Signatures of selection were detected between bioregions, with no single region returning evidence of strong selection. The results of this study show that although the koala is widely considered to be a dietary-specialist species, this apparent specialisation has not limited the koala's ability to maintain gene flow and adapt across divergent environments as long as the required food source is available
Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent
Background Deoxyribonucleic acid (DNA) vaccines are used for experimental
immunotherapy of equine melanoma. The injection of complexed linear DNA
encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a
clinical study including 27 grey horses. To date, the detailed mechanism of
the anti-tumour effect of this treatment is unknown. Results In the present
study, the clinical and cellular responses of 24 healthy horses were monitored
over 72 h after simultaneous intradermal and intramuscular application of
equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative
substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of
CG). Although the strongest effect was observed in horses treated with
expressing DNA, horses in all groups treated with DNA showed systemic
responses. In these horses treated with DNA, rectal temperatures were elevated
after treatment and serum amyloid A increased. Total leukocyte and neutrophil
counts increased, while lymphocyte numbers decreased. The secretion of tumour
necrosis factor alpha (TNFα) and interferon gamma (IFNγ) from peripheral
mononuclear blood cells ex vivo increased after treatments with DNA, while
IL-10 secretion decreased. Horses treated with DNA had significantly higher
myeloid cell numbers and chemokine (C-X-C motif) ligand (CXCL)-10 expression
in skin samples at the intradermal injection sites compared to horses treated
with transfection reagent only, suggesting an inflammatory response to DNA
treatment. In horses treated with expressing DNA, however, local CXCL-10
expression was highest and immunohistochemistry revealed more intradermal
IL-12-positive cells when compared to the other treatment groups. In contrast
to non-grey horses, grey horses showed fewer effects of DNA treatments on
blood lymphocyte counts, TNFα secretion and myeloid cell infiltration in the
dermis. Conclusion Treatment with complexed linear DNA constructs induced an
inflammatory response independent of the coding sequence and of CG motif
content. Expressing IL-12/IL-18 DNA locally induces expression of the
downstream mediator CXCL-10. The grey horses included appeared to display an
attenuated immune response to DNA treatment, although grey horses bearing
melanoma responded to this treatment with moderate tumour remission in a
preceding study. Whether the different immunological reactivity compared to
other horses may contributes to the melanoma susceptibility of grey horses
remains to be elucidated
Fetal programming of neuropsychiatric disorders by maternal pregnancy depression: a systematic mini review
BACKGROUND: Maternal depression complicates a large proportion of pregnancies. Current evidence shows numerous harmful effects on the offspring. Reviews, which include depression, concluded that stress has harmful effects on the offspring's outcomes neuro-cognitive development, temperament traits, and mental disorders. OBJECTIVE: This mini review of recent studies, sought to narrow the scope of exposure and identify studies specifically assessing prenatal depression and offspring neuropsychiatric outcomes. STUDY ELIGIBILITY CRITERIA: The review included longitudinal, cohort, cross-sectional, clinical, quasi-experimental, epidemiological, or intervention study designs published in English from 2014 to 2018. PARTICIPANTS: Study populations included mother-child dyads, mother-father-child triads, mother-alternative caregiver-child triads, and family studies utilizing sibling comparisons. METHODS: We searched PubMED and Web of Science. Study inclusion and data extraction were based on standardized templates. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Thirteen studies examining neuropsychiatric outcomes were included. We judged the evidence to be moderate to high quality. CONCLUSIONS: Our review supports that maternal prenatal depression is associated with neuropsychiatric adversities in children.Peer reviewe
Ethiopian indigenous goats offer insights into past and recent demographic dynamics and localadaptation in sub-Saharan African goats
Abstract Knowledge on how adaptive evolution and human socio‐cultural and economic interests shaped livestock genomes particularly in sub‐Saharan Africa remains limited. Ethiopia is in a geographic region that has been critical in the history of African agriculture with ancient and diverse human ethnicity and bio‐climatic conditions. Using 52K genome‐wide data analysed in 646 individuals from 13 Ethiopian indigenous goat populations, we observed high levels of genetic variation. Although runs of homozygosity (ROH) were ubiquitous genome‐wide, there were clear differences in patterns of ROH length and abundance and in effective population sizes illustrating differences in genome homozygosity, evolutionary history, and management. Phylogenetic analysis incorporating patterns of genetic differentiation and gene flow with ancestry modelling highlighted past and recent intermixing and possible two deep ancient genetic ancestries that could have been brought by humans with the first introduction of goats in Africa. We observed four strong selection signatures that were specific to Arsi‐Bale and Nubian goats. These signatures overlapped genomic regions with genes associated with morphological, adaptation, reproduction and production traits due possibly to selection under environmental constraints and/or human preferences. The regions also overlapped uncharacterized genes, calling for a comprehensive annotation of the goat genome. Our results provide insights into mechanisms leading to genome variation and differentiation in sub‐Saharan Africa indigenous goats
Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent
Characterisation of the British honey bee metagenome
Numerous microbial symbionts, both commensal and pathogenic, are associated with honey bees. Here, the authors genomically characterize this ‘metagenome’ of the British honey bee, identifying a diversity of commensal microbes as well as known and putative pathogen
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