Australia Bioinformatics Resource

INTRODUCTION: Sepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing. METHODS: This was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes. RESULTS: Based on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%. CONCLUSIONS: This novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients.

The multidrug-resistant bacterium Enterococcus faecium has become increasingly tolerant to the alcohols in hospital disinfectants.

BACKGROUND: Schema Therapy is based on the theory that trauma and neglect in childhood lead to early maladaptive schemas and psychopathology in adulthood. The aim of this review was to evaluate support for this theory by synthesizing the literature on childhood adversity and schemas. METHODS: A systematic review and meta-analysis were completed in compliance with PRISMA. PsycInfo, CINAHL and PubMed were searched to identify eligible studies that reported unadjusted association(s) between adverse childhood events and schema scores when participants were 18 years or older. Meta-analyses were conducted to estimate the pooled effect size of associations between schemas and experiences of childhood adversity. RESULTS: A total of 33 studies met inclusion criteria and provided sufficient data for meta-analyses on childhood experiences relating to toxic frustration of needs (emotional neglect and physical neglect) and trauma and victimization (emotional abuse, physical abuse and sexual abuse). Of the 124 meta-analyses, 65 indicated that schemas show small to large correlations with emotional neglect (range: r = .16 [Failure] to r = .51 [Emotional Deprivation]); small to moderate correlations with emotional abuse (range: r = .20 [Vulnerability to Harm] to r = .44 [Emotional Deprivation]); and small correlations with physical neglect, physical abuse and sexual abuse (range: r = .16 [Vulnerability to Harm] to .26 [Emotional Deprivation and Social Isolation]). CONCLUSIONS: Of the 33 included studies, only one used a longitudinal design. However, based on the correlational studies available, early maladaptive schemas in adulthood are associated with a history of childhood abuse and neglect.

Until recently, West Nile (WN) and Kunjin (KUN) viruses were classified as distinct types in the Flavivirus genus. However, genetic and antigenic studies on isolates of these two viruses indicate that the relationship between them is more complex. To better define this relationship, we performed sequence analyses on 32 isolates of KUN virus and 28 isolates of WN virus from different geographic areas, including a WN isolate from the recent outbreak in New York. Sequence comparisons showed that the KUN virus isolates from Australia were tightly grouped but that the WN virus isolates exhibited substantial divergence and could be differentiated into four distinct groups. KUN virus isolates from Australia were antigenically homologous and distinct from the WN isolates and a Malaysian KUN virus. Our results suggest that KUN and WN viruses comprise a group of closely related viruses that can be differentiated into subgroups on the basis of genetic and antigenic analyses.

Linkage analysis is a successful procedure to associate diseases with specific genomic regions. These regions are often large, containing hundreds of genes, which make experimental methods employed to identify the disease gene arduous and expensive. We present two methods to prioritize candidates for further experimental study: Common Pathway Scanning (CPS) and Common Module Profiling (CMP). CPS is based on the assumption that common phenotypes are associated with dysfunction in proteins that participate in the same complex or pathway. CPS applies network data derived from protein-protein interaction (PPI) and pathway databases to identify relationships between genes. CMP identifies likely candidates using a domain-dependent sequence similarity approach, based on the hypothesis that disruption of genes of similar function will lead to the same phenotype. Both algorithms use two forms of input data: known disease genes or multiple disease loci. When using known disease genes as input, our combined methods have a sensitivity of 0.52 and a specificity of 0.97 and reduce the candidate list by 13-fold. Using multiple loci, our methods successfully identify disease genes for all benchmark diseases with a sensitivity of 0.84 and a specificity of 0.63. Our combined approach prioritizes good candidates and will accelerate the disease gene discovery process.

Scientific research relies on computer software, yet software is not always developed following practices that ensure its quality and sustainability. This manuscript does not aim to propose new software development best practices, but rather to provide simple recommendations that encourage the adoption of existing best practices. Software development best practices promote better quality software, and better quality software improves the reproducibility and reusability of research. These recommendations are designed around Open Source values, and provide practical suggestions that contribute to making research software and its source code more discoverable, reusable and transparent. This manuscript is aimed at developers, but also at organisations, projects, journals and funders that can increase the quality and sustainability of research software by encouraging the adoption of these recommendations.

Abstract Red blood cells (RBCs) have been shown to affect immune function and can induce inflammatory responses after transfusion. The transfusion of washed RBCs can significantly reduce adverse effects, however, the soluble factors that may mediate these effects have not been identified. Previous studies have identified, but not quantified, a small number of chemokines associated with RBCs. We isolated RBCs from healthy volunteers and quantified of a panel of 48 cytokines, chemokines, and growth factors in the lysate, cytosol, and conditioned media of these cells using Luminex ® technology. This analysis revealed that, after correcting for white blood cell and platelet contamination, 46 cytokines were detected in RBC lysates, and the median concentration in RBCs was 12-fold higher than in the plasma. In addition, extensive washing of RBCs, such as that performed in proteomics analyses or prior to some RBC transfusions, significantly attenuated the release of six cytokines following incubation at 37 °C. This supports the hypothesis that, alongside its gas exchange function, RBCs play a role in cytokine signalling. This discovery may help supplement disease biomarker research and may shed light on adverse inflammatory processes that can follow RBC transfusion.

Until recently, West Nile (WN) and Kunjin (KUN) viruses were classified as distinct types in the Flavivirus genus. However, genetic and antigenic studies on isolates of these two viruses indicate that the relationship between them is more complex. To better define this relationship, we performed sequence analyses on 32 isolates of KUN virus and 28 isolates of WN virus from different geographic areas, including a WN isolate from the recent outbreak in New York. Sequence comparisons showed that the KUN virus isolates from Australia were tightly grouped but that the WN virus isolates exhibited substantial divergence and could be differentiated into four distinct groups. KUN virus isolates from Australia were antigenically homologous and distinct from the WN isolates and a Malaysian KUN virus. Our results suggest that KUN and WN viruses comprise a group of closely related viruses that can be differentiated into subgroups on the basis of genetic and antigenic analyses.

A control technique is proposed in this paper for control of modular multilevel converters (MMC) in high-voltage direct current (HVDC) transmission systems. Six independent dynamical state variables are considered in the proposed control technique, including two ac currents, three circulating currents, and the dc-link voltage, for effectively attaining the switching state functions of MMCs, as well as for an accurate control of the circulating currents. Several analytical expressions are derived based on the reference values of the state variables for obtaining the MMC switching functions under steady state operating conditions. In addition, dynamic parts of the switching functions are accomplished by the direct Lyapunov method to guarantee stable operation of the proposed technique for control of MMCs in HVDC systems. Moreover, the capability curve of MMC is developed to validate maximum power injection from MMCs into the power grid and/or loads. The impacts of the variations of MMC output and dc-link currents on the stability of dc-link voltage are also evaluated in detail by small-signal analysis.

Summary: ArachnoServer is a manually curated database that consolidates information on the sequence, structure, function and pharmacology of spider-venom toxins. Although spider venoms are complex chemical arsenals, the primary constituents are small disulfide-bridged peptides that target neuronal ion channels and receptors. Due to their high potency and selectivity, these peptides have been developed as pharmacological tools, bioinsecticides and drug leads. A new version of ArachnoServer (v3.0) has been developed that includes a bioinformatics pipeline for automated detection and analysis of peptide toxin transcripts in assembled venom-gland transcriptomes. ArachnoServer v3.0 was updated with the latest sequence, structure and functional data, the search-by-mass feature has been enhanced, and toxin cards provide additional information about each mature toxin. Availability and implementation: http://arachnoserver.org. Contact: support@arachnoserver.org. Supplementary information: Supplementary data are available at Bioinformatics online.

Bacterial species in the plant-beneficial-environmental clade of Burkholderia represent a substantial component of rhizosphere microbes in many plant species. To better understand the molecular mechanisms of the interaction, we combined functional studies with high-resolution dual transcriptome analysis of sugarcane and root-associated diazotrophic Burkholderia strain Q208. We show that Burkholderia Q208 forms a biofilm at the root surface and suppresses the virulence factors that typically trigger immune response in plants. Up-regulation of bd-type cytochromes in Burkholderia Q208 suggests an increased energy production and creates the microaerobic conditions suitable for BNF. In this environment, a series of metabolic pathways are activated in Burkholderia Q208 implicated in oxalotrophy, microaerobic respiration, and formation of PHB granules, enabling energy production under microaerobic conditions. In the plant, genes involved in hypoxia survival are up-regulated and through increased ethylene production, larger aerenchyma is produced in roots which in turn facilitates diffusion of oxygen within the cortex. The detected changes in gene expression, physiology and morphology in the partnership are evidence of a sophisticated interplay between sugarcane and a plant-growth promoting Burkholderia species that advance our understanding of the mutually beneficial processes occurring in the rhizosphere.

Abstract Although biases toward signals of fear may be an evolutionary adaptation necessary for survival, heightened biases may be maladaptive and associated with anxiety or depression. In this study, event-related potentials (ERPs) were used to examine the time course of neural responses to facial fear stimuli (versus neutral) presented overtly (for 500 msec with conscious attention) and covertly (for 10 msec with immediate masking to preclude conscious awareness) in 257 nonclinical subjects. We also examined the impact of trait anxiety and depression, assessed using psychometric ratings, on the time course of ERPs. In the total subject group, controlled biases to overtly processed fear were reflected in an enhancement of ERPs associated with structural encoding (120–220 msec) and sustained evaluation persisting from 250 msec and beyond, following a temporo-occipital to frontal topography. By contrast, covert fear processing elicited automatic biases, reflected in an enhancement of ERPs prior to structural encoding (80–180 msec) and again in the period associated with automatic orienting and emotion encoding (230–330 msec), which followed the reverse frontal to temporo-occipital topography. Higher levels of trait anxiety (in the clinical range) were distinguished by a heightened bias to covert fear (speeding of early ERPs), compared to higher depression which was associated with an opposing bias to overt fear (slowing of later ERPs). Anxiety also heightened early responses to covert fear, and depression to overt fear, with subsequent deficits in emotion encoding in each case. These findings are consistent with neural biases to signals of fear which operate automatically and during controlled processing, feasibly supported by parallel networks. Heightened automatic biases in anxiety may contribute to a cycle of hypervigilance and anxious thoughts, whereas depression may represent a “burnt out” emotional state in which evaluation of fear stimuli is prolonged only when conscious attention is allocated.

The general anesthetic 2,6-diisopropylphenol (propofol) is very poorly soluble in water and is normally administered in the form of an emulsion. We demonstrated that several commercially available nonionic surfactants (Tween 80, Cremophor EL, Poloxamer 188, Poloxamer 407, Solutol HS15, and Vitamin E TPGS) render propofol soluble with a specific solubilization capacity of at least 0.1 g/g. The room-temperature stability of the solutions appeared to be limited only by the chemical stability of the compounds involved. The association between propofol and the surfactants was investigated by various NMR approaches, including measurements of diffusion coefficients, 1H longitudinal relaxation times, and the magnitude of intermolecular nuclear Overhauser effects. The results were consistent with the micellar solubilization mechanism of propofol by the surfactants (unimer solubilization in the case of Poloxamer 188). The 1H longitudinal relaxation and diffusion behavior of propofol were monoexponential in each case. Solubilization caused a considerable shortening of propofol's proton T1's. The values of the diffusion coefficient of propofol were several percent higher than those of surfactants. This was explained by the partitioning of propofol between swollen micelles and the aqueous solution. Diffusion measurements also revealed the presence of a rapidly diffusing ethylene oxide population in surfactant solutions, which is consistent with free poly(ethylene oxide) (PEO) known to be present in commercially produced surfactants. The free PEO blocks exhibited molecular association with the extramicellar propofol.

The relationship between detritivore diversity and decomposition can provide information on how biogeochemical cycles are affected by ongoing rates of extinction, but such evidence has come mostly from local studies and microcosm experiments. We conducted a globally distributed experiment (38 streams across 23 countries in 6 continents) using standardised methods to test the hypothesis that detritivore diversity enhances litter decomposition in streams, to establish the role of other characteristics of detritivore assemblages (abundance, biomass and body size), and to determine how patterns vary across realms, biomes and climates. We observed a positive relationship between diversity and decomposition, strongest in tropical areas, and a key role of abundance and biomass at higher latitudes. Our results suggest that litter decomposition might be altered by detritivore extinctions, particularly in tropical areas, where detritivore diversity is already relatively low and some environmental stressors particularly prevalent.

Context Reintroduction is a popular tool for conserving endangered species, yet many attempts fail. Soft-release measures, including acclimatisation, have been used for many species around the world, based on the reasoning that gradual and supported reintroductions should improve the success of animals released into an unfamiliar wild environment. However, experimental testing of soft-release methods is rare. Aims To experimentally test the effect of a soft-release method versus a hard-release method on the initial reintroduction success of the eastern barred bandicoot (Perameles gunnii). Methods We released 12 captive-bred eastern barred bandicoots into a predator-proof reserve using two methods: soft-release (7 days of on-site acclimatisation with supplementary food before release) and hard-release (no acclimatisation and no supplementary food). We monitored the bandicoots intensively via radio-tracking and live-trapping for 4 weeks after release. Compared with hard-release bandicoots, we predicted that soft-release bandicoots would have (1) reduced movement (first night dispersal, site fidelity and activity range), (2) more directed patterns of habitat selection, (3) improved bodyweights and (4) improved survival. Key results There was no detectable difference in habitat selection, overall weight change and survival between the soft-release and hard-release groups. There was moderate evidence that, compared with the hard-release group, soft-release bandicoots moved less, demonstrated lower individual variation in all measures of movement, and lost weight more gradually after release. In most cases, effect sizes were moderate to large but had large standard errors owing to both small sample size and high variance. Consequently, statistical testing failed to detect significant differences at the 5% level. Conclusions Despite evidence that the release method influenced some of the monitored behaviours, soft-release did not confer a consistent and substantive advantage for captive-bred eastern barred bandicoots at our site. We conclude that soft-release is unlikely to improve overall reintroduction success for this species at fenced predator-free sites. Implications The present study suggests that the preferred option for reintroductions of eastern barred bandicoots to fenced sites is a hard-release, information that is now being used to guide reintroductions of this species. Similar experiments should be undertaken to improve reintroduction practice for other endangered species.

Autism spectrum disorder (ASD) and borderline personality Disorder (BPD) share features, including social and emotion regulation difficulties. The evidence for the overlap in prevalence and clinical characteristics was systematically reviewed. Ovid Medline, PsycInfo, and PubMed were searched until November 30, 2020 using keywords relating to BPD and ASD. Studies that reported on the overlap of ASD and BPD diagnoses or traits and used a case, cohort, or case-controlled design were included. Of 1633 screened studies, 19 were included, of which 12 reported data suitable for meta-analysis. Most samples were of small, clinically ascertained groups, with 11 having high risk of bias. The pooled prevalence of BPD in ASD was 4% [95% CI 0%-9%] and of ASD in BPD, 3% [95% CI 1%-8%]. There were inconsistent findings across clinical areas. The prevalence of a dual diagnosis of BPD in ASD cohorts and of ASD in BPD cohorts was within population prevalence estimates of each disorder. Based on this data we were not able to assess whether there is misdiagnosis of one in favor of the other. Neurocognitive differences may underlie similar behavioral symptoms, but further research using larger, well-validated samples is needed. LAY SUMMARY: Autism spectrum disorder (ASD) and borderline personality disorder (BPD) have overlaps in their symptoms. The overlap in how frequently they co-occur and their presentation was systematically reviewed. We searched the key databases and including all studies that reported on the overlap of ASD and BPD diagnoses or traits and used a case, cohort or case-controlled design. Of 1633 studies, 19 were included, of which 12 reported data suitable for pooling. Most samples were of small, clinical groups, with 11 having high risk of bias. The pooled prevalence of BPD in ASD was 4% [95% CI 0%-9%] and of ASD in BPD, 3% [95% CI 1%-8%]. There were inconsistent findings across studies comparing ASD and BPD related symptoms and problems. The prevalence of a dual diagnosis of BPD in ASD cohorts and of ASD in BPD cohorts was similar to the population prevalence of each disorder. Further research using larger, well-validated samples is needed.

Pre-clinical responses to fast-moving infectious disease outbreaks heavily depend on choosing the best isolates for animal models that inform diagnostics, vaccines and treatments. Current approaches are driven by practical considerations (e.g. first available virus isolate) rather than a detailed analysis of the characteristics of the virus strain chosen, which can lead to animal models that are not representative of the circulating or emerging clusters. Here, we suggest a combination of epidemiological, experimental and bioinformatic considerations when choosing virus strains for animal model generation. We discuss the currently chosen SARS-CoV-2 strains for international coronavirus disease (COVID-19) models in the context of their phylogeny as well as in a novel alignment-free bioinformatic approach. Unlike phylogenetic trees, which focus on individual shared mutations, this new approach assesses genome-wide co-developing functionalities and hence offers a more fluid view of the 'cloud of variances' that RNA viruses are prone to accumulate. This joint approach concludes that while the current animal models cover the existing viral strains adequately, there is substantial evolutionary activity that is likely not considered by the current models. Based on insights from the non-discrete alignment-free approach and experimental observations, we suggest isolates for future animal models.

BACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold.

Pelvic organ prolapse (POP) is a common condition in women. Women with POP often experience pelvic discomfort, urinary and fecal problems, sexual dysfunction, and an overall decrease in their quality of life. Surgical treatment is a feasible option if conservative management fails. Various surgical techniques have been proposed to correct POP with or without the use of graft material. Owing to recent U.S. Food and Drug Administration warnings about mesh-related complications, sacrospinous ligament fixation (SSF), as a traditional vaginal procedure, may play an important role again. To answer this question and evaluate quantitatively the efficacy of SSF in POP, we conducted a systemic review of the available data about SSF and POP. Interventions had to include SSF as a point of attachment. To eliminate confounding bias and effect modification, at least one arm must include SSF without mesh or graft. All follow-up periods were allowed. Information on the following parameters was extracted and entered into a database: study design, type of intervention, number of patients, follow-up in months, cure rate, recurrence rate, intra/postoperative complications, and/or uni/bilateral, preventive/therapeutic, or concomitant procedures. Published papers from the years 1995 to 2011 were selected for analysis.

Bioinformatics and re-sequencing approaches were used for the discovery of sequence polymorphisms in Litopenaeus vannamei. A total of 1221 putative single nucleotide polymorphisms (SNPs) were identified in a pool of individuals from various commercial populations. A set of 211 SNPs were selected for further molecular validation and 88% showed variation in 637 samples representing three commercial breeding lines. An association analysis was performed between these markers and several traits of economic importance for shrimp producers including resistance to three major viral diseases. A small number of SNPs showed associations with test weekly gain, grow-out survival and resistance to Taura Syndrome Virus. Very low levels of linkage disequilibrium were revealed between most SNP pairs, with only 11% of SNPs showing an r(2)-value above 0.10 with at least one other SNP. Comparison of allele frequencies showed small changes over three generations of the breeding programme in one of the commercial breeding populations. This unique SNP resource has the potential to catalyse future studies of genetic dissection of complex traits, tracing relationships in breeding programmes, and monitoring genetic diversity in commercial and wild populations of L. vannamei.