Biochemistry and Molecular Biology - Research Publications
Now showing items 1-12 of 1226
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
(OXFORD UNIV PRESS, 2019-10-29)
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview.
The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease.
(Springer Science and Business Media LLC, 2021-02-08)
Giant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.
The Complexity of the cGAS-STING Pathway in CNS Pathologies
(FRONTIERS MEDIA SA, 2021-02-09)
Neuroinflammation driven by type-I interferons in the CNS is well established to exacerbate the progression of many CNS pathologies both acute and chronic. The role of adaptor protein Stimulator of Interferon Genes (STING) is increasingly appreciated to instigate type-I IFN-mediated neuroinflammation. As an upstream regulator of type-I IFNs, STING modulation presents a novel therapeutic opportunity to mediate inflammation in the CNS. This review will detail the current knowledge of protective and detrimental STING activity in acute and chronic CNS pathologies and the current therapeutic avenues being explored.
Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation.
(Springer Science and Business Media LLC, 2021-02-17)
Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1-revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1-to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.
Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process
Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer's disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer's disease is also provided.
Cognition, The Menstrual Cycle, and Premenstrual Disorders: A Review
Sex hormones, such as estrogens, progesterone, and testosterone, have a significant influence on brain, behavior, and cognitive functioning. The menstrual cycle has been a convenient model to examine how subtle fluctuations of these hormones can relate to emotional and cognitive functioning. The aim of the current paper is to provide a narrative review of studies investigating cognitive functioning in association with the menstrual cycle in biological females, with a focus on studies that have investigated cognitive functioning across the menstrual cycle in females with premenstrual mood disorders, such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). In line with previous reviews, the current review concluded that there is a lack of consistent findings regarding cognitive functioning across the menstrual cycle. Most studies focused on changes in levels of blood estrogen, and neglected to explore the role of other hormones, such as progesterone, on cognitive functioning. Cognitive research involving premenstrual disorders is in its infancy, and it remains unclear whether any cognitive disturbances that are identified may be attributed to negative experience of mood and psychological symptoms or be a more direct effect of hormonal dysregulation or sensitivity. Suggestions for future research are provided.
Borderline personality disorder, trauma, and the hypothalamus-pituitary-adrenal axis
(DOVE MEDICAL PRESS LTD, 2019-01-01)
Borderline personality disorder (BPD) is a complex psychiatric illness for which treatment poses a significant challenge due to limited effective pharmacologic treatments, and under-resourced psychological interventions. BPD is one of the most stigmatized conditions in psychiatry today, but can be understood as a modifiable, neurodevelopmental disorder that arises from maladaptive responses to trauma and stress. Stress susceptibility and reactivity in BPD is thought to mediate both the development and maintenance of BPD symptomatology, with trauma exposure considered an early life risk factor of development, and acute stress moderating symptom trajectory. An altered stress response has been characterized in BPD at the structural, neural, and neurobiological level, and is believed to underlie the maladaptive behavioral and cognitive symptomatology presented in BPD. The endocrine hypothalamus-pituitary-adrenal (HPA) axis represents a key stress response system, and growing evidence suggests it is dysfunctional in the BPD patient population. This theoretical review examines BPD in the context of a neurodevelopmental stress-related disorder, providing an overview of measurements of stress with a focus on HPA-axis measurement. Potential confounding factors associated with measurement of the HPA system are discussed, including sex and sex hormones, genetic factors, and the influence of sample collection methods. HPA-axis dysfunction in BPD largely mirrors findings demonstrated in post-traumatic stress disorder and may represent a valuable neuroendocrine target for diagnostic or treatment response biomarkers, or for which novel treatments can be investigated.
Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial
Oral contraceptives (OCs) containing estrogen and progesterone analogues are widely used amongst reproductive-aged women, but their neurocognitive impact is poorly understood. Preliminary studies suggest that OCs improve verbal memory and that OCs with greater androgenic activity may improve visuospatial ability. We sought to explore the cognitive impact of OCs by assessing performance of OC users at different stages of the OC cycle, and comparing this performance between users of different OC formulations according to known androgenic activity. We conducted a prospective, observational trial of OC users, evaluating cognitive performance with CogState software on two occasions: days 7-10 of active hormonal pill phase, and days 3-5 of the inactive pill phase (coinciding with the withdrawal bleed resembling menstruation). Thirty-five OC users (18 taking androgenic formulations, 17 taking anti-androgenic) were assessed. Analysis by androgenic activity showed superior performance by users of androgenic OCs, as compared to anti-androgenic OCs, in visuospatial ability and facial affect discrimination tasks. A growing understanding of cognitive effects of OC progestin androgenicity may have implications in choice of OC formulation for individuals and in future OC development.
Molecular Characterization of Lipopolysaccharide Binding to Human α-1-Acid Glycoprotein.
(Hindawi Limited, 2012)
The ability of AGP to bind circulating lipopolysaccharide (LPS) in plasma is believed to help reduce the proinflammatory effect of bacterial lipid A molecules. Here, for the first time we have characterized human AGP binding characteristics of the LPS from a number of pathogenic Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Pseudomonas aeruginosa, and Serratia marcescens. The binding affinity and structure activity relationships (SAR) of the AGP-LPS interactions were characterized by surface plasma resonance (SPR). In order to dissect the contribution of the lipid A, core oligosaccharide and O-antigen polysaccharide components of LPS, the AGP binding affinity of LPS from smooth strains, were compared to lipid A, Kdo2-lipid A, R(a), R(d), and R(e) rough LPS mutants. The SAR analysis enabled by the binding data suggested that, in addition to the important role played by the lipid A and core components of LPS, it is predominately the unique species- and strain-specific carbohydrate structure of the O-antigen polysaccharide that largely determines the binding affinity for AGP. Together, these data are consistent with the role of AGP in the binding and transport of LPS in plasma during acute-phase inflammatory responses to invading Gram-negative bacteria.
Multiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis.
(Springer Science and Business Media LLC, 2016-07-20)
The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available. Our 4.3-Å resolution structure of HPeV3 on its own and at 15 Å resolution in complex with human monoclonal antibody Fabs demonstrates the expected picornavirus capsid structure with three distinct features. First, 25% of the HPeV3 RNA genome in 60 sites is highly ordered as confirmed by asymmetric reconstruction, and interacts with conserved regions of the capsid proteins VP1 and VP3. Second, the VP0 N terminus stabilizes the capsid inner surface, in contrast to other picornaviruses where on expulsion as VP4, it forms an RNA translocation channel. Last, VP1's hydrophobic pocket, the binding site for the antipicornaviral drug, pleconaril, is blocked and thus inappropriate for antiviral development. Together, these results suggest a direction for development of neutralizing antibodies, antiviral drugs based on targeting the RNA-protein interactions and dissection of virus assembly on the basis of RNA nucleation.
Intrinsically-disordered N-termini in human parechovirus 1 capsid proteins bind encapsidated RNA
(NATURE PUBLISHING GROUP, 2018-04-11)
Human parechoviruses (HPeV) are picornaviruses with a highly-ordered RNA genome contained within icosahedrally-symmetric capsids. Ordered RNA structures have recently been shown to interact with capsid proteins VP1 and VP3 and facilitate virus assembly in HPeV1. Using an assay that combines reversible cross-linking, RNA affinity purification and peptide mass fingerprinting (RCAP), we mapped the RNA-interacting regions of the capsid proteins from the whole HPeV1 virion in solution. The intrinsically-disordered N-termini of capsid proteins VP1 and VP3, and unexpectedly, VP0, were identified to interact with RNA. Comparing these results to those obtained using recombinantly-expressed VP0 and VP1 confirmed the virion binding regions, and revealed unique RNA binding regions in the isolated VP0 not previously observed in the crystal structure of HPeV1. We used RNA fluorescence anisotropy to confirm the RNA-binding competency of each of the capsid proteins' N-termini. These findings suggests that dynamic interactions between the viral RNA and the capsid proteins modulate virus assembly, and suggest a novel role for VP0.