Blood biomarker discovery in drug-free schizophrenia: the contribution of proteomics and multiplex immunoassays

Introduction: Recent evidence supports an association between systemic abnormalities and the pathology of psychotic disorders which has led to the search for peripheral blood-based biomarkers.

Areas covered: Here, we summarize blood biomarker findings in schizophrenia from the literature identified by two methods currently driving biomarker discovery in the human proteome; mass spectrometry and multiplex immunoassay. From a total of 14 studies in the serum or plasma of drug-free schizophrenia patients; 47 proteins were found to be significantly altered twice or more, in the same direction. Pathway analysis was performed on these proteins, and the resulting pathways discussed in relation to schizophrenia pathology. Future directions are also discussed, with particular emphasis on the potential for high-throughput validation techniques such as data-independent analysis for confirmation of biomarker candidates.

Expert commentary: We present promising findings that point to a convergence of pathophysiological mechanisms in schizophrenia that involve the acute-phase response, glucocorticoid receptor signalling, coagulation, and lipid and glucose metabolism.     

Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium

Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.     

Plasma lipidomic profiling in patients with rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is linked to increased cardiovascular morbidity and mortality, not completely explained by traditional risk factors. Importantly, the increased risk occurs despite lower levels of total and low-density lipoprotein cholesterol. Whilst systemic inflammation may be a factor, it is possible that changes in individual lipid species contribute to the increased cardiovascular risk.

Objectives

In the present study, we characterized plasma lipidomic profiles in patients with RA in comparison with healthy controls.

Methods

Patients with RA (n = 32) and age- and gender-matched healthy volunteers (n = 84) were recruited. Fasting plasma lipid profiles were measured using electrospray-ionisation tandem mass spectrometry. 24 lipid classes and subclasses were measured.

Results

Patients with RA had normal total, low-density lipoprotein and high-density lipoprotein cholesterol, but higher triglycerides than controls. Five lipid classes (dihydroceramides, alkylphosphatidylethanolamine, alkenylphosphatidylethanolamine, lysophosphatidylinositol, phosphatidylserine) differed between patients with RA and controls. Then we measured 36 lipid species within these 5 classes and found that 11 lipid species were different between patients with RA and controls. Three lipid classes (dihydroceramides, lysophosphatidylinositol, phosphatidylserine) and 10 lipid species remained significantly associated with RA after adjusting for age, sex, body mass index, current smoking, systolic blood pressure and anti-hypertensive treatment in a binary logistic regression model.

Conclusion

This study has identified lipid alterations in RA. These alterations of lipids warrant further investigation as they may be associated with accelerated atherosclerosis and joint inflammation in patient with RA.

     

Phase response curve to 1 h light pulses for the European rabbit (Oryctolagus cuniculus)

While much is known about the circadian systems of rodents, chronobiological studies of other mammalian groups have been limited. One of the most extensively studied nonrodent species, both in the laboratory and in the wild, is the European rabbit. The aim of this study was to extend knowledge of the rabbit circadian system by examining its phasic response to light. Twelve Dutch-Himalayan cross rabbits of both sexes were allowed to free-run in constant darkness and then administered 1 h light pulses (1000 lux) at multiple predetermined circadian times. Changes in the phase of the rabbits’ circadian wheel-running rhythms were measured after each light pulse and used to construct a phase–response curve (PRC). The rabbits’ PRC and free-running period (τ) conformed to the empirical regularities reported for other predominantly nocturnal animals, including rodents and predatory marsupials. The results of the study are thus consistent with reports that the rabbit is essentially a nocturnal animal and show that it can entrain to light/dark (LD) cycles via discrete phase shifts. Knowledge about the rabbit’s circadian range of entrainment to LD cycles gained in this study will be useful for examining the putative circadian processes believed to underlie the unusual rhythm of very brief, once-daily nest visits by nursing rabbit mothers and other nursing lagomorphs.     

Estimating the abundance of burrow‐nesting species through the statistical analysis of combined playback and visual surveys

The conservation of elusive species relies on our ability to obtain unbiased estimates of their abundance trends. Many species live or breed in cavities, making it easy to define the search units (the cavity) yet hard to ascertain their occupancy. One such example is that of certain colonial seabirds like petrels and shearwaters, which occupy burrows to breed. In order to increase the chances of detection for these types of species, their sampling can be done using two independent methods to check for cavity occupancy: visual inspection, and acoustic response to a playback call. This double‐detection process allows us to estimate the probability of burrow occupancy by accounting for the probability of detection associated with each method. Here we provide a statistical framework to estimate the occupancy and population size of burrow‐dwelling species. We show how to implement the method using both maximum likelihood and Bayesian approaches, and test its precision and bias using simulated datasets. We subsequently illustrate how to extend the method to situations where two different species may occupy the burrows, and apply it to a dataset on wedge‐tailed shearwaters Puffinus pacificus and tropical shearwaters P. bailloni on Aride Island, Seychelles. The simulations showed that the single‐species model performed well in terms of error and bias except when detection probabilities and occupancies were very low. The two‐species model applied to shearwaters showed that detection probabilities were highly heterogeneous. The population sizes of wedge‐tailed and tropical shearwaters were estimated at 13 716 (95% CI: 12 909–15 874) and 25 550 (23 667–28 777) pairs respectively. The advantages of formulating the call‐playback sampling method statistically is that it provides a framework to calculate uncertainty in the estimates and model assumptions. This method is applicable to a variety of cavity‐dwelling species where two methods can be used to detect cavity occupancy.     

Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors

Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors.     

Dedication: Heinz Floss and Christopher Walsh—pioneers in natural product chemical biology

Journal of Industrial Microbiology & Biotechnology -