Publications by authors named "Andrew Knox"

65 Publications

A water-soluble manganese(II) octanediaoate/phenanthroline complex acts as an antioxidant and attenuates alpha-synuclein toxicity.

Biochim Biophys Acta Mol Basis Dis 2022 10 28;1868(10):166475. Epub 2022 Jun 28.

Departamento de Bioquímica, Instituto de Química, Centro de Tecnologia, Cidade Universitária, Universidade Federal do Rio de Janeiro, Brazil; Rede de Micrologia RJ-FAPERJ, Brazil. Electronic address:

The overproduction of reactive oxygen species (ROS) induces oxidative stress, a well-known process associated with aging and several human pathologies, such as cancer and neurodegenerative diseases. A large number of synthetic compounds have been described as antioxidant enzyme mimics, capable of eliminating ROS and/or reducing oxidative damage. In this study, we investigated the antioxidant activity of a water-soluble 1,10-phenantroline-octanediaoate Mn-complex on cells under oxidative stress, and assessed its capacity to attenuate alpha-synuclein (aSyn) toxicity and aggregation, a process associated with increased oxidative stress. This Mn-complex exhibited a significant antioxidant potential, reducing intracelular oxidation and increasing oxidative stress resistance in S. cerevisiae cells and in vivo, in G. mellonella, increasing the activity of the intracellular antioxidant enzymes superoxide dismutase and catalase. Strikingly, the Mn-complex reduced both aSyn oligomerization and aggregation in human cell cultures and, using NMR and DFT/molecular docking we confirmed its interaction with the C-terminal region of aSyn. In conclusion, the Mn-complex appears as an excellent lead for the design of new phenanthroline derivatives as alternative compounds for preventing oxidative damages and oxidative stress - related diseases.
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http://dx.doi.org/10.1016/j.bbadis.2022.166475DOI Listing
October 2022

Efficacy of Levetiracetam and Phenobarbital as First-Line Treatment for Neonatal Seizures.

J Child Neurol 2022 04 20;37(5):401-409. Epub 2022 Mar 20.

Department of Neurology, Division of Pediatric Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

High neonatal seizure burden is associated with worsened neurodevelopmental outcomes. We compared the efficacy of initial treatment with levetiracetam vs phenobarbital for maintaining low seizure burden in a retrospective cohort of 25 neonates monitored with video electroencephalography (EEG). Video EEG tracing were reviewed and paired with medication bolus times to determine seizure burden after treatment. Initial cumulative dose of phenobarbital was 20 mg/kg in all but 1 case; initial cumulative dose of levetiracetam ranged from 50 to 100 mg/kg. Eleven of 17 (65%) patients sustained seizure burden <10% following initial treatment with levetiracetam, compared with 5 of 8 (63%) with phenobarbital. Thirteen (76%) patients treated with levetiracetam had sustained seizure burden <20% compared with 6 (75%) treated with phenobarbital. The phenobarbital group showed a larger absolute reduction in average seizure burden in the hour before and after treatment (-24.3  vs -14.2 minutes/h). Six of 17 (35%) patients treated with levetiracetam remained seizure free after initial treatment, compared with 2 of 8 (25%) patients treated with phenobarbital. Initial treatment with levetiracetam was associated with shorter average time to seizure freedom (15 vs 21 hours). None of these results were statistically significant. Cumulative doses of levetiracetam 100 mg/kg were well tolerated and associated with substantial decrease in seizure burden in several cases. Levetiracetam remains a promising first-line treatment for neonatal seizures; additional randomized controlled trials evaluating the effects of high-dose levetiracetam on seizure burden and long-term outcomes are warranted.
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http://dx.doi.org/10.1177/08830738221086107DOI Listing
April 2022

Structure-guided stabilization of pathogen-derived peptide-HLA-E complexes using non-natural amino acids conserves native TCR recognition.

Eur J Immunol 2022 04 13;52(4):618-632. Epub 2022 Feb 13.

Immunocore Ltd, Abingdon, Oxfordshire, UK.

The nonpolymorphic class Ib molecule, HLA-E, primarily presents peptides from HLA class Ia leader peptides, providing an inhibitory signal to NK cells via CD94/NKG2 interactions. Although peptides of pathogenic origin can also be presented by HLA-E to T cells, the molecular basis underpinning their role in antigen surveillance is largely unknown. Here, we solved a co-complex crystal structure of a TCR with an HLA-E presented peptide (pHLA-E) from bacterial (Mycobacterium tuberculosis) origin, and the first TCR-pHLA-E complex with a noncanonically presented peptide from viral (HIV) origin. The structures provided a molecular foundation to develop a novel method to introduce cysteine traps using non-natural amino acid chemistry that stabilized pHLA-E complexes while maintaining native interface contacts between the TCRs and different pHLA-E complexes. These pHLA-E monomers could be used to isolate pHLA-E-specific T cells, with obvious utility for studying pHLA-E restricted T cells, and for the identification of putative therapeutic TCRs.
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http://dx.doi.org/10.1002/eji.202149745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306587PMC
April 2022

Modulating the Blood-Brain Barrier: A Comprehensive Review.

Pharmaceutics 2021 Nov 22;13(11). Epub 2021 Nov 22.

School of Biological and Health Sciences, Technological University Dublin, Central Quad, Grangegorman, D07 XT95 Dublin, Ireland.

The highly secure blood-brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades-their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.
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http://dx.doi.org/10.3390/pharmaceutics13111980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618722PMC
November 2021

Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8 T cell antiviral responses.

Cell Rep 2021 05;35(6):109103

Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford OX4 2PG, UK; Immunocore Ltd, Milton, Abingdon OX14 4RY, UK; Research In Viral Eradication of Reservoirs (RIVER) trial study group. Electronic address:

Persistence of HIV through integration into host DNA in CD4 T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8 T cells are triggered to kill infected CD4 T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial" HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8 T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4 T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.
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http://dx.doi.org/10.1016/j.celrep.2021.109103DOI Listing
May 2021

Unexpected pain with electrocortical stimulation in a teenager with temporal encephalocele.

Epilepsy Behav Rep 2021 31;16:100444. Epub 2021 Mar 31.

Department of Neurology, University of Wisconsin-Madison School of Medicine and Public Health, 1685 Highland Ave, Madison, WI 53705, United States.

Temporal lobe encephalocele has emerged as a potentially unrecognized cause of drug-resistant temporal lobe epilepsy (TLE) that can be effectively treated with epilepsy surgery. Here we present a case in which a 17-year-old male with drug-resistant epilepsy and left temporal encephalocele underwent workup for epilepsy surgery, and experienced unexpected pain with electrocortical stimulation. Stimulation of stereo-EEG electrodes in the left temporal pole resulted in severe, unilateral left-sided facial pain due to inadvertent stimulation of the trigeminal nerve. Stereo-EEG showed seizure onset adjacent to encephalocele with no involvement of mesial temporal structures. A temporal pole resection sparing the mesial temporal structures and repair of the sphenoid bone defect was performed. The patient experienced post-operative seizure freedom, with no loss of language function or sensory deficits in the distribution of the trigeminal nerve. This case highlights temporal encephalocele as a potentially overlooked cause of TLE and underscores the anatomical proximity of the trigeminal nerve to the temporal pole, an important consideration for surgical planning.
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http://dx.doi.org/10.1016/j.ebr.2021.100444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050858PMC
March 2021

Unpaid Professional Work at Home and Work-Life Interference among Employees with Care Responsibilities.

J Psychol 2021 11;155(3):356-374. Epub 2021 Mar 11.

University of Southern Queensland.

Employees with caregiving responsibilities often experience work-life interference (WLI), particularly when caring for either disabled persons and/or children. This study examines sample of 288 working Australians from the AWALI national survey data, who care for at least one family member or friend with long-term physical or mental illness, disability, or aging-related problems. We investigated the role of unpaid work at home in predicting WLI, based on a model that included indirect association inferred causes for working unpaid hours at home and a conditional direct relationship based on number of children. The findings supported our prediction that unpaid work at home is positively associated with WLI but its effect is moderated by number of children. There was a conditional direct effect where employees with care responsibilities experienced a stronger relationship between unpaid hours and WLI when having more children. Further, when the perceived reason for unpaid work was excessively demanding work, the relationship with WLI was stronger. Implications for workers with multiple caregiving responsibilities are discussed.
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http://dx.doi.org/10.1080/00223980.2021.1884825DOI Listing
April 2021

Synthesis and optimisation of P substituted vinyl sulfone-based inhibitors as anti-trypanosomal agents.

Bioorg Med Chem 2020 12 20;28(23):115774. Epub 2020 Sep 20.

Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin D04 N2E2, Ireland. Electronic address:

A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P analogues exhibited sub-micromolar EC values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series.
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http://dx.doi.org/10.1016/j.bmc.2020.115774DOI Listing
December 2020

Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells.

Hepatology 2020 11;72(5):1528-1540

Immunocore Ltd, Abingdon, United Kingdom.

Background And Aims: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA).

Approach And Results: ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA.

Conclusions: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.
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http://dx.doi.org/10.1002/hep.31503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702151PMC
November 2020

Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder.

Neuron 2020 07 1;107(1):52-64.e7. Epub 2020 May 1.

Howard Hughes Medical Institute and Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Electronic address:

At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca sensor that synchronizes neurotransmitter release with Ca influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.
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http://dx.doi.org/10.1016/j.neuron.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539681PMC
July 2020

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide-HLA Complex.

J Immunol 2020 04 26;204(7):1943-1953. Epub 2020 Feb 26.

Immunocore, Ltd., Abingdon, Oxfordshire OX14 4RY, United Kingdom; and

The molecular rules driving TCR cross-reactivity are poorly understood and, consequently, it is unclear the extent to which TCRs targeting the same Ag recognize the same off-target peptides. We determined TCR-peptide-HLA crystal structures and, using a single-chain peptide-HLA phage library, we generated peptide specificity profiles for three newly identified human TCRs specific for the cancer testis Ag NY-ESO-1-HLA-A2. Two TCRs engaged the same central peptide feature, although were more permissive at peripheral peptide positions and, accordingly, possessed partially overlapping peptide specificity profiles. The third TCR engaged a flipped peptide conformation, leading to the recognition of off-target peptides sharing little similarity with the cognate peptide. These data show that TCRs specific for a cognate peptide recognize discrete peptide repertoires and reconciles how an individual's limited TCR repertoire following negative selection in the thymus is able to recognize a vastly larger antigenic pool.
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http://dx.doi.org/10.4049/jimmunol.1900915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086387PMC
April 2020

Microfluidics in Haemostasis: A Review.

Molecules 2020 Feb 14;25(4). Epub 2020 Feb 14.

School of Biological and Health Sciences, Technological University Dublin (TU Dublin)-City Campus, Kevin Street D08 NF82, Ireland.

Haemostatic disorders are both complex and costly in relation to both their treatment and subsequent management. As leading causes of mortality worldwide, there is an ever-increasing drive to improve the diagnosis and prevention of haemostatic disorders. The field of microfluidic and Lab on a Chip (LOC) technologies is rapidly advancing and the important role of miniaturised diagnostics is becoming more evident in the healthcare system, with particular importance in near patient testing (NPT) and point of care (POC) settings. Microfluidic technologies present innovative solutions to diagnostic and clinical challenges which have the knock-on effect of improving health care and quality of life. In this review, both advanced microfluidic devices (R&D) and commercially available devices for the diagnosis and monitoring of haemostasis-related disorders and antithrombotic therapies, respectively, are discussed. Innovative design specifications, fabrication techniques, and modes of detection in addition to the materials used in developing micro-channels are reviewed in the context of application to the field of haemostasis.
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http://dx.doi.org/10.3390/molecules25040833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070452PMC
February 2020

Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.

Bioorg Med Chem 2020 03 24;28(5):115261. Epub 2019 Dec 24.

School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland.

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
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http://dx.doi.org/10.1016/j.bmc.2019.115261DOI Listing
March 2020

Nutrition-related interventions targeting childhood overweight and obesity: A narrative review.

Obes Rev 2019 08;20 Suppl 1:45-60

Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.

Systematic reviews of nutritional interventions indicate limited efficacy in reducing childhood obesity, but their blanket conclusions could obscure promising components. This narrative review sought more detail on effective components within nutrition-related interventions involving children aged 2 to 11 years. In May 2016, the World Health Organization (WHO) searched the Cochrane Library and PubMed for relevant reviews. From 36 reviews, we screened 182 nutrition-related randomized trials for inclusion. We then reviewed those that reported at least 1 statistically significant (P < 0.05) treatment benefit on body weight and/or composition outcomes at their longest follow-up assessment. Fourteen trials met inclusion criteria (median n = 554; mean intervention duration = 10.8 mo; follow-up = 4.4 mo). "Effective" approaches included environmental changes such as school water fountain installations and cafeteria menu changes and possibly less sustainable strategies such as health education lessons. However, effect sizes even of these selected significant treatment benefits were modest-significant body mass index z-score effects range from -0.1 to -0.2. Each trial was associated with very small improvements in body composition. Because this is a "best-case" scenario (reflecting our design), trialists should rigorously test these strategies alone and possibly together; be open to novel strategies; and ensure that each strategy is culturally relevant and self-sustainable.
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http://dx.doi.org/10.1111/obr.12768DOI Listing
August 2019

Earlier ingestion of peanut after changes to infant feeding guidelines: The EarlyNuts study.

J Allergy Clin Immunol 2019 11 8;144(5):1327-1335.e5. Epub 2019 Aug 8.

Murdoch Children's Research Institute, Parkville, Australia; School of Population and Global Health, University of Melbourne, Parkville, Australia. Electronic address:

Background: Randomized controlled trials demonstrate that timely introduction of peanut to infants reduces the risk of peanut allergy. However, much debate remains regarding how to best achieve earlier peanut introduction at the population level. Our previous study in 2007-2011 (HealthNuts, n = 5300) indicated that few infants were consuming peanut in the first year. Australian infant feeding guidelines were updated in 2016 to recommend introducing peanut before 12 months for all infants. There were no data available on the subsequent effect on peanut introduction or peanut reactions.

Objective: We sought to assess the consequences of a nonscreening approach to allergenic food introduction in a population-based sample of infants in their first year of life.

Methods: EarlyNuts is a population-based, cross-sectional study of 12-month-old infants in Melbourne, Australia, recruited by using an identical sampling frame and methods to HealthNuts (72% response rate vs 73% response rate in HealthNuts). We report here on the first 860 participants recruited between November 2016 and October 2018.

Results: Most infants (88.6%; 95% CI, 86.1% to 90.7%) had introduced peanut by 12 months (median age, 6 months), an increase from 28.4% (95% CI, 27.2% to 29.7%) in the HealthNuts study. By 12 months, the majority of these (76.4%) had consumed peanut more than 4 times, and 28% were eating peanut more than once per week. Preliminary results on parent-reported reactions show that 4.0% of those consuming peanut by 12 months had possible IgE-mediated reactions.

Conclusions: There has been a striking shift toward earlier peanut introduction, with a 3-fold increase in peanut introduction by age 1 year in 2018 compared with 2007-2011.
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http://dx.doi.org/10.1016/j.jaci.2019.07.032DOI Listing
November 2019

Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.

Bioorg Med Chem Lett 2019 08 16;29(16):2410-2414. Epub 2019 May 16.

GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, USA.

The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
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http://dx.doi.org/10.1016/j.bmcl.2019.05.028DOI Listing
August 2019

Interactions and activities of factors involved in the late stages of human 18S rRNA maturation.

RNA Biol 2019 02 13;16(2):196-210. Epub 2019 Jan 13.

a Institute for Cell and Molecular Biosciences, The Medical School , Newcastle University , Newcastle upon Tyne , UK.

Ribosome production is an essential cellular process involving a plethora of trans-acting factors, such as nucleases, methyltransferases, RNA helicases and kinases that catalyse key maturation steps. Precise temporal and spatial regulation of such enzymes is essential to ensure accurate and efficient subunit assembly. Here, we focus on the maturation of the 3' end of the 18S rRNA in human cells. We reveal that human RIO2 is an active kinase that phosphorylates both itself and the rRNA methyltransferase DIM1 in vitro. In contrast to yeast, our data confirm that human DIM1 predominantly acts in the nucleus and we further demonstrate that the 21S pre-rRNA is the main target for DIM1-catalysed methylation. We show that the PIN domain of the endonuclease NOB1 is required for site 3 cleavage, while the zinc ribbon domain is essential for pre-40S recruitment. Furthermore, we also demonstrate that NOB1, PNO1 and DIM1 bind to a region of the pre-rRNA encompassing the 3' end of 18S and the start of ITS1, in vitro. Interestingly, NOB1 is present in the cell at higher levels than other pre-40S factors. We provide evidence that NOB1 is multimeric within the cell and show that NOB1 multimerisation is lost when ribosome biogenesis is blocked. Taken together, our data indicate a dynamic interplay of key factors associated with the 3' end of the 18S rRNA during human pre-40S biogenesis and highlight potential mechanisms by which this process can be regulated.
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http://dx.doi.org/10.1080/15476286.2018.1564467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380343PMC
February 2019

Topotactic anion-exchange in thermoelectric nanostructured layered tin chalcogenides with reduced selenium content.

Chem Sci 2018 Apr 23;9(15):3828-3836. Epub 2018 Mar 23.

WestCHEM , School of Chemistry , University of Glasgow , Glasgow , G12 8QQ , UK . Email:

Anion exchange has been performed with nanoplates of tin sulfide (SnS) "soft chemical" organic-free solution syntheses to yield layered pseudo-ternary tin chalcogenides on a 10 g-scale. SnS undergoes a topotactic transformation to form a series of S-substituted tin selenide (SnSe) nano/micro-plates with tuneable chalcogenide composition. SnSSe nanoplates were spark plasma sintered into phase-pure, textured, dense pellets, the of which has been significantly enhanced to ≈1.16 from ≈0.74 at 923 K microstructure texturing control. These approaches provide versatile, scalable and low-cost routes to p-type layered tin chalcogenides with controllable composition and competitive thermoelectric performance.
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http://dx.doi.org/10.1039/c7sc05190eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939836PMC
April 2018

Modeling pathogenesis and treatment response in childhood absence epilepsy.

Epilepsia 2018 01 18;59(1):135-145. Epub 2017 Dec 18.

Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Objective: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE.

Methods: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABA , and GABA synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABA conductance.

Results: Decreasing cortical GABA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type.

Significance: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.
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http://dx.doi.org/10.1111/epi.13962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776688PMC
January 2018

The Diagnostic Accuracy of Video Electroencephalography Without Event Capture.

Pediatr Neurol 2018 02 3;79:8-13. Epub 2017 Nov 3.

Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Objective: The aim of this study was to quantify the accuracy of 24-hour video electroencephalography (vEEG) for the diagnosis of epilepsy when a patient's typical paroxysmal event was not captured (no-event vEEG).

Methods: We performed a retrospective chart review of all first-time 24 hour no-event vEEG studies at Cincinnati Children's Hospital Medical Center. Clinician diagnosis of epilepsy with a minimum of one year follow-up was used as the reference standard to calculate diagnostic accuracy. Sensitivity and specificity of routine EEG (rEEG) and vEEG were compared in patients with both studies, and factors affecting the accuracy of vEEG were explored with a multivariable analysis.

Results: No-event vEEG showed sensitivity of 0.54 (95% confidence interval [CI] 0.44 to 0.64) and specificity of 0.88 (95% CI 0.84 to 0.92) respectively, with a diagnostic odds ratio of 7.53 (95% CI 4.45 to 12.76). The sensitivity of vEEG was statistically superior to that of rEEG, whereas specificity was comparable. Age emerged as the only factor that affected the diagnostic accuracy of no-event vEEG.

Conclusion: Even in the absence of a typical seizure or spell, video EEG is a useful test for predicting or excluding epilepsy, with diagnostic accuracy that is superior to rEEG and unaffected by the presence of a chronic neurological condition.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.10.017DOI Listing
February 2018

Large-Scale Surfactant-Free Synthesis of p-Type SnTe Nanoparticles for Thermoelectric Applications.

Materials (Basel) 2017 Feb 26;10(3). Epub 2017 Feb 26.

WestCHEM, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

A facile one-pot aqueous solution method has been developed for the fast and straightforward synthesis of SnTe nanoparticles in more than ten gram quantities per batch. The synthesis involves boiling an alkaline Na₂SnO₂ solution and a NaHTe solution for short time scales, in which the NaOH concentration and reaction duration play vital roles in controlling the phase purity and particle size, respectively. Spark plasma sintering of the SnTe nanoparticles produces nanostructured compacts that have a comparable thermoelectric performance to bulk counterparts synthesised by more time- and energy-intensive methods. This approach, combining an energy-efficient, surfactant-free solution synthesis with spark plasma sintering, provides a simple, rapid, and inexpensive route to p-type SnTe nanostructured materials.
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http://dx.doi.org/10.3390/ma10030233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503326PMC
February 2017

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.

J Med Chem 2018 01 1;61(2):514-534. Epub 2017 May 1.

School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.

Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01917DOI Listing
January 2018

Pretesticular and Testicular Effects of Systemic Sarcoidosis: A Case Report.

J Reprod Med 2017 Mar-Apr;62(3-4):204-6

Background: Sarcoidosis is a multisystem inflammatory disease of unknown etiology. It is uncommon, with an incidence of approximately 16.5 per 100,000 men.1 It is characterized by noncaseating epithelioid granulomata that typically affect the chest, skin, eyes, and, much less commonly, the genital system (<0.2% of cases). Sarcoidosis can affect any of the scrotal structures, although due to its rarity, investigation of solid masses of the testes are largely targeted towards excluding either a malignant or infective etiology.²

Case: We report a rare case of a 27-year-old male who presented with bilateral testicular and neck swellings. He underwent orchidectomy, and histopathology demonstrated sarcoidosis. He subsequently developed both pituitary and testicular sarcoidosis resulting in azoospermia. Through the administration of gonadotropins and surgical sperm retrieval we were able to retrieve sperm suitable for assisted reproductive technologies.

Conclusion: This case illustrates the difficulties faced in managing the fertility of men who develop systemic sarcoidosis. It also highlights the diagnostic and therapeutic challenges faced by physicians when presented with a case of systemic sarcoidosis.
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October 2018

Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells.

J Enzyme Inhib Med Chem 2016 1;31(sup3):117-130. Epub 2016 Aug 1.

a School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute , Trinity College Dublin , Dublin , Ireland and.

The estrogen receptors (ERα and ERβ) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel β-lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERα and ERβ receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC=186 nM) and ERα binding (IC=4.3 nM) with 75-fold ERα/β receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the β-lactam scaffold) on the antiproliferative activity and ER-binding properties of the β-lactam compounds is rationalized in a molecular modeling study.
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http://dx.doi.org/10.1080/14756366.2016.1210136DOI Listing
February 2017

Radiographic Measurements of the Affected and Unaffected Feet in Patients with Unilateral Hallux Limitus A Case-Control Pilot Study.

J Am Podiatr Med Assoc 2016 May;106(3):172-81

Background: Controversy exists regarding the structural and functional causes of hallux limitus, including metatarsus primus elevatus, a long first metatarsal, first-ray hypermobility, the shape of the first metatarsal head, and the presence of hallux interphalangeus. Some articles have reported on the radiographic evaluation of these measurements in feet affected by hallux limitus, but no study has directly compared the affected and unaffected feet in patients with unilateral hallux limitus. This case-control pilot study aimed to establish whether any such differences exist.

Methods: Dorsoplantar and lateral weightbearing radiographs of both feet in 30 patients with unilateral hallux limitus were assessed for grade of disease, lateral intermetatarsal angle, metatarsal protrusion distance, plantar gapping at the first metatarsocuneiform joint, metatarsal head shape, and hallux abductus interphalangeus angle. Data analysis was performed using a statistical software program.

Results: Mean radiographic measurements for affected and unaffected feet demonstrated that metatarsus primus elevatus, a short first metatarsal, first-ray hypermobility, a flat metatarsal head shape, and hallux interphalangeus were prevalent in both feet. There was no statistically significant difference between feet for any of the radiographic parameters measured (Mann-Whitney U tests, independent-samples t tests, and Pearson χ(2) tests: P > .05).

Conclusions: No significant differences exist in the presence of the structural risk factors examined between affected and unaffected feet in patients with unilateral hallux limitus. The influence of other intrinsic factors, including footedness and family history, should be investigated further.
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http://dx.doi.org/10.7547/14-137DOI Listing
May 2016

Facile Surfactant-Free Synthesis of p-Type SnSe Nanoplates with Exceptional Thermoelectric Power Factors.

Angew Chem Int Ed Engl 2016 05 20;55(22):6433-7. Epub 2016 Apr 20.

WestCHEM, School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.

A surfactant-free solution methodology, simply using water as a solvent, has been developed for the straightforward synthesis of single-phase orthorhombic SnSe nanoplates in gram quantities. Individual nanoplates are composed of {100} surfaces with {011} edge facets. Hot-pressed nanostructured compacts (Eg ≈0.85 eV) exhibit excellent electrical conductivity and thermoelectric power factors (S(2) σ) at 550 K. S(2) σ values are 8-fold higher than equivalent materials prepared using citric acid as a structure-directing agent, and electrical properties are comparable to the best-performing, extrinsically doped p-type polycrystalline tin selenides. The method offers an energy-efficient, rapid route to p-type SnSe nanostructures.
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http://dx.doi.org/10.1002/anie.201601420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074331PMC
May 2016

Reply: To PMID 25770573.

Aust Fam Physician 2015 Jul;44(7):438

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July 2015

Ingrown toenails: the role of the GP.

Aust Fam Physician 2015 Mar;44(3):102-5

BSc (Pod), MSc, PhD, Professor and Head, Podiatric Medicine Unit, School of Surgery, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Crawley, WA.

Background: An ingrown toenail or onychocryptosis may occur at any age and is the mostly commonly encountered toenail problem likely to be seen in general practice.

Objective: This article will discuss the common surgical approaches available for the management of an ingrown toenail.

Discussion: Ingrown toenail can be a painful condition that can become infected and may require surgical treatment. The epidemiology of onychocryptosis is difficult to determine as it is often considered to be a minor medical problem and as such has been some-what neglected in the literature. The few studies that have been conducted suggest a slightly higher male-to-female ratio, particularly in the 14-25 age group,4 but it can affect patients of any age. There are multiple reasons why an ingrown toenail will develop, including improper nail cutting technique, tight-fitting footwear, trauma, anatomical factors such as thickening of the nail plate, pincer-shaped toenail, pressure from abutting digits caused by hallux valgus or lesser toe deformities, the presence of a subungual exostosis and, occasionally, the use of isotretinoin in the treatment of severe acne.
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March 2015

β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.

J Med Chem 2014 Nov 17;57(22):9370-82. Epub 2014 Nov 17.

School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology and ‡School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College , 152-160 Pearse Street, Dublin 2, Ireland.

Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
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http://dx.doi.org/10.1021/jm500670dDOI Listing
November 2014
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