Imidazo[1,2-α]pyridines possess adenosine A1 receptor affinity for the potential treatment of cognition in neurological disorders

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A₁ receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A₁ and A_2A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A₁ receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A₁ and A_2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A₁ or A_2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A₁ or A_2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A₁ receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A₁ receptor with a K_i value of 2.06 µM and (2) adenosine A₁ receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine-based adenosine A₁ receptor antagonists for the treatment of neurodegenerative disorders.     

Frequency and distribution of cyanogenic glycosides in Eucalyptus L'Hérit

In this study approximately 420 of the described species of Eucalyptus were examined for cyanogenesis. Our work has identified an additional 18 cyanogenic species, 12 from living tissues and a further six from herbarium samples. This brings the total of known cyanogenic species to 23, representing approximately 4% of the genus. The taxonomic distribution of the species within the genus is restricted to the subgenus Symphyomyrtus, with only two exceptions. Within Symphyomyrtus, the species are in three closely related sections. The cyanogenic glycoside was found to be predominantly prunasin (1) in the 11 species where this was examined. We conclude that cyanogenesis is plesiomorphic in Symphyomyrtus (i.e. a common basal trait) but has probably arisen independently in the other two subgenera, consistent with recent phylogenetic treatments of the genus. The results of this study have important implications for the selection of trees for plantations to support wildlife, and to preserve genetic diversity.     

Discovery and validation of a colorectal cancer classifier in a new blood test with improved performance for high-risk subjects

Background

The aim was to improve upon an existing blood-based colorectal cancer (CRC) test directed to high-risk symptomatic patients, by developing a new CRC classifier to be used with a new test embodiment. The new test uses a robust assay format—electrochemiluminescence immunoassays—to quantify protein concentrations. The aim was achieved by building and validating a CRC classifier using concentration measures from a large sample set representing a true intent-to-test (ITT) symptomatic population.

Methods

4435 patient samples were drawn from the Endoscopy II sample set. Samples were collected at seven hospitals across Denmark between 2010 and 2012 from subjects with symptoms of colorectal neoplasia. Colonoscopies revealed the presence or absence of CRC. 27 blood plasma proteins were selected as candidate biomarkers based on previous studies. Multiplexed electrochemiluminescence assays were used to measure the concentrations of these 27 proteins in all 4435 samples. 3066 patients were randomly assigned to the Discovery set, in which machine learning was used to build candidate classifiers. Some classifiers were refined by allowing up to a 25% indeterminate score range. The classifier with the best Discovery set performance was successfully validated in the separate Validation set, consisting of 1336 samples.

Results

The final classifier was a logistic regression using ten predictors: eight proteins (A1AG, CEA, CO9, DPPIV, MIF, PKM2, SAA, TFRC), age, and gender. In validation, the indeterminate rate of the new panel was 23.2%, sensitivity/specificity was 0.80/0.83, PPV was 36.5%, and NPV was 97.1%.

Conclusions

The validated classifier serves as the basis of a new blood-based CRC test for symptomatic patients. The improved performance, resulting from robust concentration measures across a large sample set mirroring the ITT population, renders the new test the best available for this population. Results from a test using this classifier can help assess symptomatic patients’ CRC risk, increase their colonoscopy compliance, and manage next steps in their care.

     

Neonatal exposure to UVR alters skin immune system development, and suppresses immunity in adulthood

Neonates have a developing immune response, with a predisposition towards induction of tolerance. As the immune system develops, immunity rather than tolerance is induced, with this development of immunity occurring in response to external factors such as the environment. As ultraviolet radiation (UVR) suppresses immunity, it is likely that the effect of UVR on the neonatal immune system would be augmentation of the suppressive response. In support, childhood exposure to UVR has been linked with an increased incidence of melanoma; consistent with an increase in suppression. To address this, phenotypic and functional immune system studies were undertaken at 8 weeks after one single exposure of solar-simulated UVR to mice, when mice had reached adulthood. Subtle changes were observed in cell populations resident in the skin-draining lymph nodes (LNs) and there also appeared to be a subtle, but not statistically significant, increase in the production of interleukin-10 and interferon-γ. Importantly, these changes also corresponded with significant suppression of the contact hypersensitivity response in irradiated mice compared with their control counterparts. This suppression was apparent when antigen sensitisation occurred during the neonatal or adult period, and thus did not appear to be analogous to UVR-induced suppression in adults. Although the percentage of T regulatory cells was increased in the skin-draining LNs, they were induced in a different manner to those induced following adult UVR exposure, with no increase in function on a per-cell basis. It therefore appears that one single neonatal exposure to UVR alters development of the immune system, leading to long-term implications for induction of immunity.     

Structural characterization of CD81-Claudin-1 hepatitis C virus receptor complexes

Tetraspanins are thought to exert their biological function(s) by co-ordinating the lateral movement and trafficking of associated molecules into tetraspanin-enriched microdomains. A second four-TM (transmembrane) domain protein family, the Claudin superfamily, is the major structural component of cellular TJs (tight junctions). Although the Claudin family displays low sequence homology and appears to be evolutionarily distinct from the tetraspanins, CD81 and Claudin-1 are critical molecules defining HCV (hepatitis C virus) entry; we recently demonstrated that CD81-Claudin-1 complexes have an essential role in this process. To understand the molecular basis of CD81-Claudin-1 complex formation, we produced and purified milligram quantities of full-length CD81 and Claudin-1, alone and in complex, in both detergent and lipid contexts. Structural characterization of these purified proteins will allow us to define the mechanism(s) underlying virus-cell interactions and aid the design of therapeutic agents targeting early steps in the viral life cycle.     

Human aquaporins: Regulators of transcellular water flow

Background

Emerging evidence supports the view that (AQP) aquaporin water channels are regulators of transcellular water flow. Consistent with their expression in most tissues, AQPs are associated with diverse physiological and pathophysiological processes.

Scope of review

AQP knockout studies suggest that the regulatory role of AQPs, rather than their action as passive channels, is their critical function. Transport through all AQPs occurs by a common passive mechanism, but their regulation and cellular distribution varies significantly depending on cell and tissue type; the role of AQPs in cell volume regulation (CVR) is particularly notable. This review examines the regulatory role of AQPs in transcellular water flow, especially in CVR. We focus on key systems of the human body, encompassing processes as diverse as urine concentration in the kidney to clearance of brain oedema.

Major conclusions

AQPs are crucial for the regulation of water homeostasis, providing selective pores for the rapid movement of water across diverse cell membranes and playing regulatory roles in CVR. Gating mechanisms have been proposed for human AQPs, but have only been reported for plant and microbial AQPs. Consequently, it is likely that the distribution and abundance of AQPs in a particular membrane is the determinant of membrane water permeability and a regulator of transcellular water flow.

General significance

Elucidating the mechanisms that regulate transcellular water flow will improve our understanding of the human body in health and disease. The central role of specific AQPs in regulating water homeostasis will provide routes to a range of novel therapies. This article is part of a Special Issue entitled Aquaporins.     

The Kimberley Assessment of Depression of Older Indigenous Australians: Prevalence of Depressive Disorders,Risk Factors and Validation of the KICA-dep Scale

Objective

This study aimed to develop a culturally acceptable and valid scale to assess depressive symptoms in older Indigenous Australians, to determine the prevalence of depressive disorders in the older Kimberley community, and to investigate the sociodemographic, lifestyle and clinical factors associated with depression in this population.

Methods

Cross-sectional survey of adults aged 45 years or over from six remote Indigenous communities in the Kimberley and 30% of those living in Derby, Western Australia. The 11 linguistic and culturally sensitive items of the Kimberley Indigenous Cognitive Assessment of Depression (KICA-dep) scale were derived from the signs and symptoms required to establish the diagnosis of a depressive episode according to the DSM-IV-TR and ICD-10 criteria, and their frequency was rated on a 4-point scale ranging from ‘never’ to ‘all the time’ (range of scores: 0 to 33). The diagnosis of depressive disorder was established after a face-to-face assessment with a consultant psychiatrist. Other measures included sociodemographic and lifestyle factors, and clinical history.

Results

The study included 250 participants aged 46 to 89 years (mean±SD = 60.9±10.7), of whom 143 (57.2%) were women. The internal reliability of the KICA-dep was 0.88 and the cut-point 7/8 (non-case/case) was associated with 78% sensitivity and 82% specificity for the diagnosis of a depressive disorder. The point-prevalence of a depressive disorder in this population was 7.7%; 4.0% for men and 10.4% for women. Heart problems were associated with increased odds of depression (odds ratio = 3.3, 95% confidence interval = 1.2,8.8).

Conclusions

The KICA-dep has robust psychometric properties and can be used with confidence as a screening tool for depression among older Indigenous Australians. Depressive disorders are common in this population, possibly because of increased stressors and health morbidities.     

The crest of the peafowl: a sexually dimorphic plumage ornament signals condition in both males and females

Both male and female peafowl grow crests on top of their head – iridescent blue in males, dull iridescent green and brown in females – but the potential signal function of this plumage ornament is unknown. In this study, peafowl crests were measured in three feral populations, and morphological variation in this ornament was studied in relation to body condition (body mass in relation to tarsus length) and health (white blood cell concentration and ectoparasite load). Prior to the start of the breeding season, male crests are wider with greater pennaceous area, and are more likely to have all feathers grown out compared with female crests. Only crest length changed with measurement date, increasing over time; in males, crest measurements were not related to the extent of train feather development. Crest morphology is a potential signal of individual health and condition in both sexes, but in different ways. In females, the amount of crest plumage grown out to its full extent was related to body condition at the start of the breeding season, whereas in males, the size and pennaceous area of the ornament were related to ectoparasite load. Observations of within‐sex agonistic behaviour suggest a possible role for the crest ornament in status signaling in males, because males that engage in more aggressive interactions tend to have wider crests. There was no evidence for a relation between crest morphology and agonistic behaviour in females.