Publications by authors named "Michelle Taylor"

122 Publications

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Acta Neuropathol 2021 Sep 6. Epub 2021 Sep 6.

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Pathology Building 509, 600 N. Wolfe St., Baltimore, Md, 21287, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3/GFAP cells) and significant RGC loss (RBPMS cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3 EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3 EAE mice. C3 EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.
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http://dx.doi.org/10.1007/s00401-021-02366-4DOI Listing
September 2021

Design of an individualised questionnaire to measure the impact of cancer on quality of life: The cancer dependent quality of life (CancerDQoL) questionnaire.

Psychooncology 2021 Aug 26. Epub 2021 Aug 26.

Department of Psychology, Royal Holloway, University of London, Egham, UK.

Aim: To design an individualised questionnaire to measure the impact of cancer and its treatments on quality of life (QoL). MATERIALS & METHODS: Design of the Cancer-Dependent Quality of Life (CancerDQoL) questionnaire was based on the Audit of Diabetes Dependent QoL (ADDQoL) questionnaire and related -DQoLs for other conditions. Item selection, face validity and content validity were established through clinician and patient ratings of the importance and relevance of 60 domains from the -DQoL Item Library, and semi-structured interviews with 25 English-speaking participants with a range of cancers attending a cancer centre in Zimbabwe (age range: 25-78 years; 16 women, 9 men). Ten interviews were subsequently conducted with UK English-speaking participants with a range of cancers attending Maggie's Centres in London and Dundee (age range: 40-76; 5 women, 5 men) to adapt the CancerDQoL for UK use.

Results: The first draft of the CancerDQoL contained 25 domain-specific items from the -DQoL Item Library plus four overview items. Zimbabwean participants indicated that cancer negatively impacted on all life domains included, except 'having children'. Weighted impact (impact ratings multiplied by importance) was most negative for 'sex life', 'depend on others' and 'physical capability'. The least negative weighted impact was found for 'having children', 'spiritual/religious life' and 'past medical/self-care'. UK interviews confirmed no new items were required.

Conclusions: Face and content validity of the CancerDQoL is established for an adult sample of English-speaking cancer patients in Zimbabwe and confirmed in an adaptation following UK interviews.
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http://dx.doi.org/10.1002/pon.5786DOI Listing
August 2021

Schizophrenia-associated variation at ZNF804A correlates with altered experience-dependent dynamics of sleep slow waves and spindles in healthy young adults.

Sleep 2021 Jul 30. Epub 2021 Jul 30.

School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol BS8 1TD, UK.

The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated 'A' allele (N=22) or the alternative 'C' allele (N=18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleep-dependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function.
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http://dx.doi.org/10.1093/sleep/zsab191DOI Listing
July 2021

Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis.

Neurotherapeutics 2021 Jul 14. Epub 2021 Jul 14.

Department of Neurology, Johns Hopkins, Baltimore, MD, USA.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, gliosis, and neurodegeneration. While the currently available disease-modifying therapies effectively suppress the immune attack on the CNS, there are no therapies to date that directly mitigate neurodegeneration. Glucagon-like peptide-1 (GLP-1) is a small peptide hormone that maintains glucose homeostasis. A novel GLP-1 receptor (GLP-1R) agonist, NLY01, was recently shown to have neuroprotective effects in the animal models of Parkinson's disease and is now in a phase 2 clinical trial. In this study, we investigated the therapeutic potential of NLY01 in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our data show that NLY01 delays the onset and attenuates the severity of EAE in a prevention paradigm, when given before disease onset. NLY01 inhibits the activation of immune cells in the spleen and reduces their trafficking into the CNS. In addition, we show that NLY01 suppresses the production of chemokines that are involved in leukocyte recruitment to the site of inflammation. The anti-inflammatory effect of NLY01 at the early stage of EAE may block the expression of the genes associated with neurotoxic astrocytes in the optic nerves, thereby preventing retinal ganglion cell (RGC) loss in the progressive stage of EAE. In the therapeutic paradigm, NLY01 significantly decreases the clinical score and second attack in a model of relapsing-remitting EAE. GLP-1R agonists may have dual efficacy in MS by suppressing peripheral and CNS inflammation, thereby limiting neuronal loss.
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http://dx.doi.org/10.1007/s13311-021-01088-5DOI Listing
July 2021

Evaluation of Substituted -Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands.

Molecules 2021 May 26;26(11). Epub 2021 May 26.

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USA.

phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted -phenylpiperazine analogs were evaluated. Compound was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease.
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http://dx.doi.org/10.3390/molecules26113182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198181PMC
May 2021

Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes.

J Chem Inf Model 2021 06 14;61(6):2829-2843. Epub 2021 May 14.

Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States.

Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 μs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.
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http://dx.doi.org/10.1021/acs.jcim.1c00036DOI Listing
June 2021

Testicular Adrenal Rest Tumors or Bilateral Leydig Cell Tumors?

Urology 2021 Jul 3;153:17-18. Epub 2021 Apr 3.

Advanced Urology and West Virginia School of Osteopathic Medicine, 1717 Harper Road, Third Floor, Suite A, Beckley, WV 25801.

Testicular Adrenal Rest Tumors, also known as Testicular Tumors of the Androgenital Syndrome, are benign tumors found in the testes of patients with congenital adrenal hyperplasia. While considered benign, they are significant in that they can proliferate within the rete testis and cause infertility. We present a patient who appeared to have findings consistent with testicular adrenal rest tumors and is in the process of malignancy rule out.
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http://dx.doi.org/10.1016/j.urology.2021.03.027DOI Listing
July 2021

Testicular Adrenal Rest Tumors or Bilateral Leydig Cell Tumors?

Urology 2021 Jul 3;153:17-18. Epub 2021 Apr 3.

Advanced Urology and West Virginia School of Osteopathic Medicine, 1717 Harper Road, Third Floor, Suite A, Beckley, WV 25801.

Testicular Adrenal Rest Tumors, also known as Testicular Tumors of the Androgenital Syndrome, are benign tumors found in the testes of patients with congenital adrenal hyperplasia. While considered benign, they are significant in that they can proliferate within the rete testis and cause infertility. We present a patient who appeared to have findings consistent with testicular adrenal rest tumors and is in the process of malignancy rule out.
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http://dx.doi.org/10.1016/j.urology.2021.03.027DOI Listing
July 2021

Substances and your senses: The sensory patterns of young people within an alcohol and drug treatment service.

Subst Abus 2021 Mar 22:1-9. Epub 2021 Mar 22.

Metro North Mental Health - Alcohol and Drug Service, Brisbane, Australia.

Substance use disorders (SUD) and trauma histories in adults have been linked with sensory processing patterns that are significantly different from the general population. Nevertheless, no studies have investigated sensory patterns, or the variables with which they are related, in youth with SUD. This study aimed to compare sensory patterns of this sample with normative data and consider associations between sensory patterns and: substance use, trauma, quality-of-life, mental and physical health. A cross-sectional quantitative research design was employed with a sample of 87 young people (mean age = 20.8 years) with SUD voluntarily attending a specialist youth outpatient alcohol and other drug (AOD) service. For participants, the Adolescent Adult Sensory Profile was added to measures routinely collected at the service. Participants' sensory processing patterns for low registration, sensory sensitivity, and sensation avoiding were significantly higher than the normative population, while sensation seeking was both lower and higher. Ninety-one percent reported atypical scores on one or more sensory patterns. High rates of probable Post-Traumatic-Stress-Disorder (PTSD), psychological distress, and low quality-of-life were also reported, which were meaningfully related with sensory patterns. Young people reported complex combinations of sensory processing patterns, with comorbid probable PTSD, psychological distress, and low quality-of-life. Findings reflect studies with adult AOD, trauma, and other clinical conditions, and highlight the potential value of screening for sensory patterns and applying transdiagnostic approaches which simultaneously address substance use, mental health, trauma and sensory needs to optimize outcomes for young people with SUD.
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http://dx.doi.org/10.1080/08897077.2021.1901177DOI Listing
March 2021

Low Back Pain and Substance Use: Diagnostic and Administrative Coding for Opioid Use and Dependence Increased in U.S. Older Adults with Low Back Pain.

Pain Med 2021 04;22(4):836-847

Geriatric Research Education and Clinical Center, VA Maryland Health Care System, Baltimore, Maryland.

Objective: Low back pain (LBP) is a leading cause of pain and disability. Substance use complicates the management of LBP, and potential risks increase with aging. Despite implications for an aging, diverse U.S. population, substance use and LBP comorbidity remain poorly defined. The objective of this study was to characterize LBP and substance use diagnoses in older U.S. adults by age, gender, and race.

Design: Cross-sectional study of a random national sample.

Subjects: Older adults including 1,477,594 U.S. Medicare Part B beneficiaries.

Methods: Bayesian analysis of 37,634,210 claims, with 10,775,869 administrative and 92,903,649 diagnostic code assignments.

Results: LBP was diagnosed in 14.8±0.06% of those more than 65 years of age, more in females than in males (15.8±0.08% vs. 13.4±0.09%), and slightly less in those more than 85 years of age (13.3±0.2%). Substance use diagnosis varied by substance: nicotine, 9.6±0.02%; opioid, 2.8±0.01%; and alcohol, 1.3±0.01%. Substance use diagnosis declined with advancing age cohort. Opioid use diagnosis was markedly higher for those in whom LBP was diagnosed (10.5%) than for those not diagnosed with LBP (1.5%). Most older adults (54.9%) with an opioid diagnosis were diagnosed with LBP. Gender differences were modest. Relative rates of substance use diagnoses in LBP were modest for nicotine and alcohol.

Conclusions: Older adults with LBP have high relative rates of opioid diagnoses, irrespective of gender or age. Most older adults with opioid-related diagnoses have LBP, compared with a minority of those not opioid diagnosed. In caring for older adults with LBP or opioid-related diagnoses, health systems must anticipate complexity and support clinicians, patients, and caregivers in managing pain comorbidities. Older adults may benefit from proactive incorporation of non-opioid pain treatments. Further study is needed.
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http://dx.doi.org/10.1093/pm/pnaa428DOI Listing
April 2021

A modern scleractinian coral with a two-component calcite-aragonite skeleton.

Proc Natl Acad Sci U S A 2021 01 15;118(3). Epub 2020 Dec 15.

Center for Advanced Surface Analysis, Institute of Earth Sciences, Université de Lausanne, CH-1015 Lausanne, Switzerland.

One of the most conserved traits in the evolution of biomineralizing organisms is the taxon-specific selection of skeletal minerals. All modern scleractinian corals are thought to produce skeletons exclusively of the calcium-carbonate polymorph aragonite. Despite strong fluctuations in ocean chemistry (notably the Mg/Ca ratio), this feature is believed to be conserved throughout the coral fossil record, spanning more than 240 million years. Only one example, the Cretaceous scleractinian coral (ca. 70 to 65 Ma), is thought to have produced a calcitic skeleton. Here, we report that the modern asymbiotic scleractinian coral living in the Southern Ocean forms a two-component carbonate skeleton, with an inner structure made of high-Mg calcite and an outer structure composed of aragonite. and Cretaceous skeletons share a unique microstructure indicating a close phylogenetic relationship, consistent with the early divergence of within the Vacatina (i.e., Robusta) clade, estimated to have occurred in the Mesozoic (ca. 116 Mya). Scleractinian corals thus join the group of marine organisms capable of forming bimineralic structures, which requires a highly controlled biomineralization mechanism; this capability dates back at least 100 My. Due to its relatively prolonged isolation, the Southern Ocean stands out as a repository for extant marine organisms with ancient traits.
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http://dx.doi.org/10.1073/pnas.2013316117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826372PMC
January 2021

Longitudinal evaluation of a programme for safety culture change in a mental health service.

J Nurs Manag 2021 May 22;29(4):690-698. Epub 2020 Nov 22.

School of Nursing and Midwifery, Western Sydney University, Penrith, NSW, Australia.

Aim: To evaluate whether a two-part culture improvement programme aimed at nurses in clinical and managerial positions in an inpatient mental health service was associated with culture change, and safety-related behaviour and knowledge improvements.

Background: Due to serious failings in the delivery of physiological care to mentally disordered inpatients, it was deemed important that interventions be applied to improve service culture.

Methods: A pre-test and post-test study was conducted to evaluate change associated with a mandated intervention aimed at culture change. Nurses in clinical and managerial positions at all levels attended relevant sessions. All were invited to participate in evaluation measures.

Results: N = 241 nurses participated in the evaluation (n = 137 and n = 104, pre-test and post-test, respectively). There was a small but significant change in organisational culture indicating greater adhocracy and less clan culture in the second survey period and a small decline in reported safety behaviour. Measures of safety culture, knowledge and emergency-related educational satisfaction were unchanged.

Conclusion: Only a small change in measured culture was associated with the programme.

Implications For Nursing Management: Attempts to evaluate culture change need to align anticipated outcomes with appropriate outcome measures. A mandated programme of culture change had little tangible effect on the outcomes measured.
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http://dx.doi.org/10.1111/jonm.13205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247291PMC
May 2021

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation.

J Clin Invest 2020 07;130(7):3467-3482

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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http://dx.doi.org/10.1172/JCI129401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324171PMC
July 2020

Biosecurity Dogs Detect Live Insects after Training with Odor-Proxy Training Aids: Scent Extract and Dead Specimens.

Chem Senses 2020 04;45(3):179-186

Chemistry, School of Science and Technology, University of New England, Armidale, NSW, Australia.

Detector dogs could be trained to find invasive insect pests at borders before they establish in new areas. However, without access to the live insects themselves, odor training aids are needed to condition dogs to their scent. This proof-of-concept study assessed 2 potential training aids for insect detection: a scent extract and dead specimens of the target species. Using Musgraveia sulciventris (Hemiptera: Tessaratomidae) as an experimental model, gas chromatography-mass spectrometry (GC-MS) analyses were carried out to compare the chemical headspaces that make up the odors of live specimens and these 2 training aids. This was then followed by canine scent-detection testing to investigate biosecurity detector dogs' (n = 4) responses to training in an ecologically valid context. Both the scent extract and the dead specimens shared the majority of their volatile organic compounds (VOCs) with live insects. Of the dogs trained with scent extract (n = 2), both were able to detect the live insects accurately, and of those trained with dead specimens (n = 2), one detected the live insects accurately. These findings lend support for these training aids as odor-proxies for live insects-particularly scent extract, which is a relatively novel product with the potential for broad application to facilitate and improve insect-detection training.
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http://dx.doi.org/10.1093/chemse/bjaa001DOI Listing
April 2020

The effect of carbohydrate sources: Sucrose, invert sugar and components of mānuka honey, on core bacteria in the digestive tract of adult honey bees (Apis mellifera).

PLoS One 2019 4;14(12):e0225845. Epub 2019 Dec 4.

Microbiome & Metabolism, Food Nutrition & Health, The New Zealand Institute for Plant and Food Research Limited, Palmerston North, New Zealand.

Bacteria within the digestive tract of adult honey bees are likely to play a key role in the digestion of sugar-rich foods. However, the influence of diet on honey bee gut bacteria is not well understood. During periods of low floral abundance, beekeepers often supplement the natural sources of carbohydrate that honey bees collect, such as nectar, with various forms of carbohydrates such as sucrose (a disaccharide) and invert sugar (a mixture of the monosaccharides glucose and fructose). We compared the effect of these sugar supplements on the relative abundance of bacteria in the gut of bees by feeding bees from a single colony, two natural diets: mānuka honey, a monofloral honey with known antibacterial properties, and a hive diet; and artificial diets of invert sugar, sucrose solution, and sucrose solutions containing synthesised compounds associated with the antibacterial properties of mānuka honey. 16S ribosomal RNA (rRNA)-based sequencing showed that dietary regimes containing mānuka honey, sucrose and invert sugar did not alter the relative abundance of dominant core bacteria after 6 days of being fed these diets. However, sucrose-rich diets increased the relative abundances of three sub-dominant core bacteria, Rhizobiaceae, Acetobacteraceae, and Lactobacillus kunkeei, and decreased the relative abundance of Frischella perrara, all which significantly altered the bacterial composition. Acetogenic bacteria from the Rhizobiaceae and Acetobacteraceae families increased two- to five-fold when bees were fed sucrose. These results suggest that sucrose fuels the proliferation of specific low abundance primary sucrose-feeders, which metabolise sugars into monosaccharides, and then to acetate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225845PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892475PMC
March 2020

Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D receptor ligands.

Bioorg Med Chem Lett 2019 09 11;29(18):2690-2694. Epub 2019 Jul 11.

Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 194140, USA. Electronic address:

As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D ligands. Members of this class are highly selective for D versus D, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.
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http://dx.doi.org/10.1016/j.bmcl.2019.07.020DOI Listing
September 2019

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.

Nicotine Tob Res 2020 05;22(6):900-909

MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS, UK.

Introduction: FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported.

Methods: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts.

Results: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND.

Conclusions: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND.

Implications: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.
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http://dx.doi.org/10.1093/ntr/ntz099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249921PMC
May 2020

Author Correction: Species replacement dominates megabenthos beta diversity in a remote seamount setting.

Sci Rep 2019 May 21;9(1):7844. Epub 2019 May 21.

National Oceanography Centre, University of Southampton Waterfront Campus, Southampton, SO14 3ZH, United Kingdom.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43802-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527584PMC
May 2019

Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D Receptor (DR) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).

J Med Chem 2019 05 6;62(10):5132-5147. Epub 2019 May 6.

Department of Radiology , Perelman School of Medicine, University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4 H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D receptor (DR) affinity (DR K = 12.0 nM) and selectivity (DR/DR ratio = 905). Herein, we present derivatives of 1 with comparable DR affinity (32, DR K = 3.2 nM, DR/DR ratio = 60) and selectivity (30, DR K = 21.0 nM, DR/DR ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low DR affinity ( K = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, DR K = 23.9 nM), 1 was found to be more selective for the DR among D- and D-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing DR scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into DR ligand systems to minimize drug promiscuity at other aminergic GPCR sites.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00412DOI Listing
May 2019

Design and development of the Hypoglycaemia Symptom Rating Questionnaire (HypoSRQ).

Diabetes Res Clin Pract 2019 May 5;151:187-197. Epub 2019 Apr 5.

Health Psychology Research Unit, Orchard Building, Royal Holloway, University of London, Egham, Surrey TW20 0EX, UK; Health Psychology Research Ltd., Orchard Building, Royal Holloway, University of London, Egham, Surrey TW20 0EX, UK. Electronic address:

Aims: To evaluate the Hypoglycaemia Symptom Rating Questionnaire (HypoSRQ©) and relationships between self-reported hypoglycaemia and hypoglycaemia measured using blinded continuous glucose monitoring (CGM).

Methods: Diabetes outpatients (n = 113) recruited from Ashford and St. Peter's Hospital completed the HypoSRQ (recent weeks version) and provided clinical information. Thirty participants used blinded CGM for six days and completed the HypoSRQ (24-hour version) for seven days, at the end of each week (7-day version), and after four weeks (recent weeks version).

Results: The HypoSRQ had a single-factor structure and excellent internal consistency (α = 0.90). There was high correspondence in recalled symptoms, bother ratings and hypoglycaemic episodes across one week and four weeks (r = 0.84-0.98, p < 0.001). HypoSRQ-reported hypoglycaemia correlated significantly with CGM-measured hypoglycaemia (interstitial glucose ≤ 3.9 mmol/l) frequency (r = 0.72, p < 0.001) across six days. The magnitude of the correlation increased when the person's own threshold for detecting hypoglycaemia was used (r = 0.78, p < 0.001). The number of days (out of six) a person reported symptoms of hypoglycaemia was associated with the number of days CGM detected hypoglycaemia (interstitial glucose ≤ 3.9 mmol/l) (r = 0.83, p < 0.001) and remained significant after controlling for covariates.

Conclusions: Psychometric properties of the HypoSRQ make it attractive for use in people with insulin-treated diabetes. The HypoSRQ may be a less-invasive and more-economical alternative to CGM.
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http://dx.doi.org/10.1016/j.diabres.2019.04.010DOI Listing
May 2019

An illustrated key to the species of the genus (Cnidaria, Octocorallia, Primnoidae).

Zookeys 2019 4(822):1-15. Epub 2019 Feb 4.

School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK University of Essex Colchester United Kingdom.

A history of the description of the 50 valid species of is given, beginning with the first species described in 1860. To help differentiate the various species, a tabular and a polychotomous key are provided. The species in the keys are arranged using nine characters or character sets that are believed to be of value at the species level. New characters or new significance given to previously described characters used in our keys include: 1) the nature of the dorsolateral edge of the basal scale, being ridged or not, 2) the thickness of the body wall scales, and 3) the arrangement of the coenenchymal scales (imbricate or mosaic), their thickness (thin or massive), and their outer surface ornamentation (ridged or not). All characters used in the keys are illustrated.
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http://dx.doi.org/10.3897/zookeys.822.29922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370750PMC
February 2019

Associations among teachers' depressive symptoms and students' classroom instructional experiences in third grade.

J Sch Psychol 2018 08 6;69:154-168. Epub 2018 Jun 6.

University of California, Irvine - School of Education, 3200 Education Building, Irvine, CA 92697, United States. Electronic address:

Recent studies have established connections among teachers' mental health and student outcomes, however there is limited understanding of how these teacher characteristics manifest in the classroom to affect students. The present study informed this gap by examining the associations among third grade teachers' (N = 32) self-reported symptoms of clinical depression and their students' (N = 326) classroom instructional experiences. Eight student experiences described by the Individualizing Student Instruction framework were investigated, including academic instruction facilitated by the teacher in various student groupings, students' independent and group work, teachers' planning/organizing instruction, and students' time off-task and in transitions. Multilevel modeling revealed negative associations between teachers' depressive symptoms and (a) teacher-facilitated academic instruction provided to the whole class and (b) teachers' planning/organizing instruction. Results suggest that teachers experiencing more symptoms may under-utilize instructional approaches that require more effort on their part. We discussed the implications of our findings for students' academic and social-emotional learning, and the potential benefits of incorporating mental health support components into teacher training and professional development aimed at improving instructional practices.
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http://dx.doi.org/10.1016/j.jsp.2018.05.002DOI Listing
August 2018

Exceptional biodiversity of the cryptofaunal decapods in the Chagos Archipelago, central Indian Ocean.

Mar Pollut Bull 2018 Oct 31;135:636-647. Epub 2018 Jul 31.

Department of Zoology, South Parks Road, University of Oxford, Oxford OX1 3PS, UK.

The Chagos Archipelago is geographically remote and isolated from most direct anthropogenic pressures. Here, we quantify the abundance and diversity of decapod crustaceans inhabiting dead coral colonies, representing a standardised microhabitat, across the Archipelago. Using morphological and molecular techniques we recorded 1868 decapods from 164 nominal species within 54 dead coral colonies, but total species estimates (Chao1 estimator) calculate at least 217 species. Galatheids were the most dominant taxa, though alpheids and hippolytids were also very abundant. 32% of species were rare, and 46% of species were found at only one atoll. This prevalence of rarer species has been reported in other cryptofauna studies, suggesting these assemblages maybe comprised of low-abundance species. This study provides the first estimate of diversity for reef cryptofauna in Chagos, which will serve as a useful baseline for global comparisons of coral reef biodiversity.
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http://dx.doi.org/10.1016/j.marpolbul.2018.07.063DOI Listing
October 2018

Gender Differences in HIV Testing, Diagnosis, and Linkage to Care in Healthcare Settings: Identifying African American Women with HIV in Chicago.

AIDS Patient Care STDS 2018 10;32(10):399-407

2 Section of Infectious Diseases and Global Health, University of Chicago , Chicago, Illinois.

Women account for 25% of all people living with HIV and 19% of new diagnoses in the United States. African American (AA) women are disproportionately affected. Yet, differences in the care continuum entry are not well understood between patient populations and healthcare sites. We aim to examine gender differences in diagnosis and linkage to care (LTC) in the Expanded HIV Testing and Linkage to Care (X-TLC) program within healthcare settings. Data were collected from 14 sites on the South and West sides of Chicago. Multivariate logistic regression analysis was used to determine the differences in HIV diagnoses and LTC by gender and HIV status. From 2011 to 2016, X-TLC performed 281,017 HIV tests; 63.7% of those tested were women. Overall HIV seroprevalence was 0.57%, and nearly one third (29.4%) of HIV-positive patients identified were cisgender women. Of newly diagnosed HIV-positive women, 89% were AA. 58.5% of new diagnoses in women were made at acute care hospitals, with the remainder at community health centers. Women who were newly diagnosed had a higher baseline CD4 count at diagnosis compared with men. Overall, women had lower odds of LTC compared with men (adjusted odds ratio = 0.58, 95% confidence interval 0.44-0.78) when controlling for patient demographics and newly versus previously diagnosed HIV status. Thus, interventions that focus on optimizing entry into the care continuum for AA women need to be explored.
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http://dx.doi.org/10.1089/apc.2018.0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909762PMC
October 2018

Analogues of Arylamide Phenylpiperazine Ligands To Investigate the Factors Influencing D3 Dopamine Receptor Bitropic Binding and Receptor Subtype Selectivity.

ACS Chem Neurosci 2018 12 30;9(12):2972-2983. Epub 2018 Jul 30.

Department of Pharmacology and Neuroscience , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.

We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies, we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogues might influence binding affinity at the human D2 and D3 dopamine receptors. Two factors were identified as being important for determining the binding affinity of bitropic arylamide phenylpiperazines at the dopamine D3 receptor subtype. One factor was the strength of the salt bridge between the highly conserved residue Asp with the protonated nitrogen of the nonaromatic ring at the piperazine position. The second factor was the configuration of the unbound ligand in an aqueous solution. These two factors were found to be related to the logarithm of the affinities using a simple correlation model, which could be useful when designing high affinity subtype selective bitropic ligands. While this model is based upon the interaction of arylamide phenylpiperazines with the D2 and D3 D2-like dopamine receptor subtypes, it provides insights into the complexity of the factors that define a bitropic mode of the binding at GPCRs.
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http://dx.doi.org/10.1021/acschemneuro.8b00142DOI Listing
December 2018

Genome-wide association meta-analysis of age at first cannabis use.

Addiction 2018 11 19;113(11):2073-2086. Epub 2018 Aug 19.

Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.

Background And Aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.

Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.

Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.

Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
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http://dx.doi.org/10.1111/add.14368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087375PMC
November 2018

First grade classroom-level adversity: Associations with teaching practices, academic skills, and executive functioning.

Sch Psychol Q 2018 Dec 24;33(4):547-560. Epub 2018 May 24.

T. Denny Sanford School of Social and Family Dynamics.

Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development and a model-building approach, the authors examined direct and indirect associations between first-grade (G1) classroom-level adversity (CLA), G1 teaching practices, and student (N = 1,073; M = 6.64 years; 49% girls; 82% White) academic skills and executive functioning in G1 and third grades (G3). Teachers reported the prevalence of adversity among their students (e.g., poor home/family life, poor academic/social readiness). Observers rated G1 teaching practices: teachers' classroom management, controlling instruction, and amount of academic instruction (classroom observation system). Children completed literacy and math assessments at 54 months, G1, and G3 (Woodcock Johnson Letter-Word Identification and Applied Problems), and executive functioning at G1 and G3 (Tower of Hanoi). Direct associations emerged between CLA and controlling instruction (positive), classroom management, and academic instruction (both negative). In addition, CLA was related to G1 literacy (but not math) directly and indirectly via classroom management (negatively) and controlling instruction (positively). The addition of G3 outcomes revealed a negative direct longitudinal association between CLA and G3 executive functioning, and indirect associations with G3 literacy and math through G1 teaching practices and literacy. Results support the notion that collective student characteristics influence student outcomes in part through teaching practices and suggest that teachers and students may benefit from the diffusion of high-adversity classroom compositions when possible. Moreover, in high-adversity classrooms teachers and students may benefit from supports targeting classroom management and foundational student competencies. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/spq0000235DOI Listing
December 2018
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