A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations. © 2013 Wood et al

Validation of the Alzheimer's disease-resemblance atrophy index in classifying and predicting progression in Alzheimer's disease

BACKGROUND: Automated tools for characterising dementia risk have the potential to aid in the diagnosis, prognosis, and treatment of Alzheimer’s disease (AD). Here, we examined a novel machine learning-based brain atrophy marker, the AD-resemblance atrophy index (AD-RAI), to assess its test-retest reliability and further validate its use in disease classification and prediction. METHODS: Age- and sex-matched 44 probable AD (Age: 69.13 ± 7.13; MMSE: 27–30) and 22 non-demented control (Age: 69.38 ± 7.21; MMSE: 27–30) participants were obtained from the Minimal Interval Resonance Imaging in Alzheimer’s Disease (MIRIAD) dataset. Serial T1-weighted images (n = 678) from up to nine time points over a 2-year period, including 179 pairs of back-to-back scans acquired on same participants on the same day and 40 pairs of scans acquired at 2-week intervals were included. All images were automatically processed with AccuBrain® to calculate the AD-RAI. Its same-day repeatability and 2-week reproducibility were first assessed. The discriminative performance of AD-RAI was evaluated using the receiver operating characteristic curve, where DeLong’s test was used to evaluate its performance against quantitative medial temporal lobe atrophy (QMTA) and hippocampal volume adjusted by intracranial volume (ICV)-proportions and ICV-residuals methods, respectively (HVR and HRV). Linear mixed-effects modelling was used to investigate longitudinal trajectories of AD-RAI and baseline AD-RAI prediction of cognitive decline. Finally, the longitudinal associations between AD-RAI and MMSE scores were assessed. RESULTS: AD-RAI had excellent same-day repeatability and excellent 2-week reproducibility. AD-RAI’s AUC (99.8%; 95%CI = [99.3%, 100%]) was equivalent to that of QMTA (96.8%; 95%CI = [92.9%, 100%]), and better than that of HVR (86.8%; 95%CI = [78.2%, 95.4%]) or HRV (90.3%; 95%CI = [83.0%, 97.6%]). While baseline AD-RAI was significantly higher in the AD group, it did not show detectable changes over 2 years. Baseline AD-RAI was negatively associated with MMSE scores and the rate of the change in MMSE scores over time. A negative longitudinal association was also found between AD-RAI values and the MMSE scores among AD patients CONCLUSIONS: The AD-RAI represents a potential biomarker that may support AD diagnosis and be used to predict the rate of future cognitive decline in AD patients

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1

Improving electrocoagulation floatation for harvesting microalgae

Electro-coagulation floatation (ECF) is a foam-floatation dewatering method that has been shown to be a highly effective, rapid, and scalable separation methodology. In this manuscript, an in-depth analysis of the gas and flocculant levels observed during the process is provided, with microbubbles observed in the 5–80μm size range at a concentration of 102–103 bubbles mL−1. Electrolysis of microalgae culture was then observed, demonstrating both effective separation using aluminium electrodes (nine microalgal species tested, 1–40μm size range, motile and non-motile, marine and freshwater), and sterilisation of culture through bleaching with inert titanium electrodes. Atomic force microscopy was used to visualise floc formation in the presence and absence of algae, showing nanoscale structures on the magnitude of 40–400nm and entrapped microalgal cells. Improvements to aid industrial biotechnology processing were investigated: protein-doping was found to improve foam stability without inducing cell lysis, and an oxalate buffer wash regime was found to dissolve the flocculant whilst producing no observable difference in the final algal lipid or pigment profiles, leaving the cells viable at the end of the process. ECF separated microalgal culture had an algal biomass loading of 13% and as such wasideal for direct down-stream processing through hydrothermal liquefaction. Highbio-crude yieldswere achieved, though this was reduced slightly on addition of the Al(OH)3 after ECF, with carbon being distributed away to the aqueous and solid residue phases. The amenability and compatibility of ECF to integration with, or replacement of, existing centrifugation and settling processes suggests this process may be of significant interest to the biotechnology industry

The health impacts of waste-to-energy emissions: A systematic review of the literature

Waste-to-energy (WtE) processes, or the combustion of refuse-derived fuel (RDF) for energygeneration, has the potential to reduce landfill volume while providing a renewable energy source.We aimed to systematically review and summarise current evidence on the potential health effects(benefits and risks) of exposure to WtE/RDF-related combustion emissions.We searched PubMed and Google Scholar using terms related to health and WtE/RDFcombustion emissions, following PRISMA guidelines. Two authors independently screened titles,abstracts and then full-texts of original, peer-reviewed research articles published until 20th March2020, plus their relevant references. Overall quality of included epidemiological studies were ratedusing an amended Navigation framework.We found 19 articles from 269 search results that met our inclusion criteria, including twoepidemiological studies, five environmental monitoring studies, seven health impact or riskassessments (HIA/HRA), and five life-cycle assessments. We found a dearth of health studiesrelated to the impacts of exposure to WtE emissions. The limited evidence suggests thatwell-designed and operated WtE facilities using sorted feedstock (RDF) are critical to reducepotential adverse health (cancer and non-cancer) impacts, due to lower hazardouscombustion-related emissions, compared to landfill or unsorted incineration. Poorly fed WtEfacilities may emit concentrated toxins with serious potential health risks, such as dioxins/furansand heavy metals; these toxins may remain problematic in bottom ash as a combustion by-product.Most modelling studies estimate that electricity (per unit) generated from WtE generally emits lesshealth-relevant air pollutants (also less greenhouse gases) than from combustion of fossil fuels (e.g.coal). Some modelled estimates vary due to model sensitivity for type of waste processed, modelinputs used, and facility operational conditions.We conclude that rigorous assessment (e.g. HRA including sensitivity analyses) of WtEfacility/technological characteristics and refuse type used is necessary when planning/proposing facilities to protect human health as the technology is adopted worldwide

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Researchers’ publication patterns and their use for author disambiguation

Over the recent years, we are witnessing an increase of the need for advanced bibliometric indicators on individual researchers and research groups, for which author disambiguation is needed. Using the complete population of university professors and researchers in the Canadian province of Québec (N=13,479), of their papers as well as the papers authored by their homonyms, this paper provides evidence of regularities in researchers’ publication patterns. It shows how these patterns can be used to automatically assign papers to individual and remove papers authored by their homonyms. Two types of patterns were found: 1) at the individual researchers’ level and 2) at the level of disciplines. On the whole, these patterns allow the construction of an algorithm that provides assignation information on at least one paper for 11,105 (82.4%) out of all 13,479 researchers—with a very low percentage of false positives (3.2%)

Antiracist Feminism and the Politics of Solidarity in Neoliberal Times

The chapter analyses the establishment and expansion of antiracist feminism in the last decade throughout the Nordic region, with new groups, media sites, and public events organised, especially in the large cities. Keskinen examines antiracist feminist and queer of colour activism in which the main or sole actors belong to groups racialised as non-white or ‘others’ in Nordic societies. A fundamental argument developed in the chapter is the central role and potential of these emerging social movements in the reconfiguring of political agendas and tackling pressing societal issues, due to its capacity to overlap and connect the borders of antiracist, feminist, and (to some extent) class-based politics. The chapter further argues for the usefulness of theorising the neoliberal turn of racial capitalism as the societal condition in which feminist activism takes place.Peer reviewe

Cystic fibrosis gene mutation in two sisters with mild disease and normal sweat electrolyte levels

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