24 results on '"Welsh SA"'
Search Results
2. Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents
- Author
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Kivell, BM, Paton, KF, Kumar, N, Morani, AS, Culverhouse, A, Shepherd, A, Welsh, SA, Biggerstaff, A, Crowley, RS, Prisinzano, TE, Kivell, BM, Paton, KF, Kumar, N, Morani, AS, Culverhouse, A, Shepherd, A, Welsh, SA, Biggerstaff, A, Crowley, RS, and Prisinzano, TE
- Abstract
The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.
- Published
- 2018
3. Prevalence of Anguillicoloides crassus and growth variation in migrant yellow-phase American eels of the upper Potomac River drainage
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Zimmerman, JL, primary and Welsh, SA, additional
- Published
- 2012
- Full Text
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4. Consumers of natural health products: natural-born pharmacovigilantes?
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Austin Zubin, Barnes Joanne, Boon Heather, Walji Rishma, Welsh Sandy, and Baker G Ross
- Subjects
Other systems of medicine ,RZ201-999 - Abstract
Abstract Background Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies. Methods Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques. Results Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible. Conclusion Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.
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- 2010
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5. Exploring consumer and pharmacist views on the professional role of the pharmacist with respect to natural health products: a study of focus groups
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Heschuk Shirley, Eccott Lynda, Jurgens Tannis, Welsh Sandy, Hirschkorn Kristine, Boon Heather S, Kwan Della, Griener Glenn G, and Cohen-Kohler Jillian C
- Subjects
Other systems of medicine ,RZ201-999 - Abstract
Abstract Background Natural health products (NHPs) such as herbs, vitamins and homeopathic medicines, are currently available for sale in most Canadian pharmacies. However, most pharmacists report that they have limited knowledge about these products which have been regulated in Canada as a specific sub-category of drugs. In this paper, consumers' and practicing pharmacists' perceptions of pharmacists' professional responsibilities with respect to NHPs are examined. Methods A total of 16 focus groups were conducted with consumers (n = 50) and pharmacists (n = 47) from four different cities across Canada (Vancouver, Edmonton, Toronto, and Halifax). Results In this paper, we illustrate the ways in which pharmacists' professional responsibilities are impacted by changing consumer needs. Many consumers in the study utilized a wide range of information resources that may or may not have included pharmacists. Nevertheless, the majority of consumers and pharmacists agreed that pharmacists should be knowledgeable about NHPs and felt that pharmacists should be able to manage drug-NHPs interactions as well as identify and evaluate the variety of information available to help consumers make informed decisions. Conclusion This paper demonstrates that consumers' expectations and behaviour significantly impact pharmacists' perceptions of their professional responsibilities with respect to NHPs.
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- 2008
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6. TICI: a taxon-independent community index for eDNA-based ecological health assessment.
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Wilkinson SP, Gault AA, Welsh SA, Smith JP, David BO, Hicks AS, Fake DR, Suren AM, Shaffer MR, Jarman SN, and Bunce M
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- Animals, DNA Barcoding, Taxonomic methods, Biodiversity, Rivers, Ecosystem, DNA, Environmental genetics
- Abstract
Global biodiversity is declining at an ever-increasing rate. Yet effective policies to mitigate or reverse these declines require ecosystem condition data that are rarely available. Morphology-based bioassessment methods are difficult to scale, limited in scope, suffer prohibitive costs, require skilled taxonomists, and can be applied inconsistently between practitioners. Environmental DNA (eDNA) metabarcoding offers a powerful, reproducible and scalable solution that can survey across the tree-of-life with relatively low cost and minimal expertise for sample collection. However, there remains a need to condense the complex, multidimensional community information into simple, interpretable metrics of ecological health for environmental management purposes. We developed a riverine taxon-independent community index (TICI) that objectively assigns indicator values to amplicon sequence variants (ASVs), and significantly improves the statistical power and utility of eDNA-based bioassessments. The TICI model training step uses the Chessman iterative learning algorithm to assign health indicator scores to a large number of ASVs that are commonly encountered across a wide geographic range. New sites can then be evaluated for ecological health by averaging the indicator value of the ASVs present at the site. We trained a TICI model on an eDNA dataset from 53 well-studied riverine monitoring sites across New Zealand, each sampled with a high level of biological replication ( n = 16). Eight short-amplicon metabarcoding assays were used to generate data from a broad taxonomic range, including bacteria, microeukaryotes, fungi, plants, and animals. Site-specific TICI scores were strongly correlated with historical stream condition scores from macroinvertebrate assessments (macroinvertebrate community index or MCI; R
2 = 0.82), and TICI variation between sample replicates was minimal (CV = 0.013). Taken together, this demonstrates the potential for taxon-independent eDNA analysis to provide a reliable, robust and low-cost assessment of ecological health that is accessible to environmental managers, decision makers, and the wider community., Competing Interests: Shaun P. Wilkinson, Amy A. Gault and Susan A. Welsh are current employees of Wilderlab NZ Ltd., a commercial eDNA processing laboratory. Megan Shaffer was employed by Wilderlab NZ Ltd. during the course of this study. Joshua P. Smith is an employee of Waikato Regional Council, Hamilton, New Zealand. Bruno O. David was employed by Waikato Regional Council, Hamilton, New Zealand, during the course of this study. Andy S. Hicks is currently employed by the Ministry for the Environment, Wellington, New Zealand, and was employed by Hawke’s Bay Regional Council, Napier, New Zealand, during the course of this study. Daniel R. Fake was employed by Hawke’s Bay Regional Council, Napier, New Zealand, during the course of this study. Alastair M Suren is employed by Bay of Plenty Regional Council, Whakatāne, New Zealand., (©2024 Wilkinson et al.)- Published
- 2024
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7. Constructing a quality frailty index: you get out what you put in.
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Hanlon P, Welsh SA, and Evans NR
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- Humans, Frailty diagnosis
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- 2024
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8. Frailty Assessment in Vascular OUtpatients Review (FAVOUR) protocol: single-centre prospective cohort study comparing feasibility and prognostic value of commonly used frailty assessment tools.
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Welsh SA, Hussey K, Brittenden J, Orr DJ, and Quinn T
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- Adult, Humans, Aged, Prospective Studies, Outpatients, Prognosis, Feasibility Studies, State Medicine, Geriatric Assessment methods, Frail Elderly, Frailty diagnosis, Frailty complications
- Abstract
Introduction: Frailty has consistently demonstrated associations with poorer healthcare outcomes. Vascular guidelines have recognised the importance of frailty assessment. However, an abundance of frailty tools and a lack of prospective studies confirming suitability of routine frailty assessment in clinical practice has delayed the uptake of these guidelines. The Frailty Assessment in Vascular OUtpatients Review study speaks to this evidence gap. The primary aim is to assess feasibility of implementing routine frailty assessment in a reproducible outpatient setting. Secondary objectives include comparing prognostic values and interuser agreement across five frailty assessment tools., Methods and Analysis: This single-centre prospective cohort study of feasibility is conducted in a rapid-referral vascular surgery clinic, serving a population of 2 million. Adults with capacity (>18 years), attending a clinic for any reason, are eligible for inclusion. Five assessments are completed by patient (Rockwood Clinical Frailty Scale (CFS) and Frail NonDisabled Questionnaire), clinician (CFS, Healthcare Improvement Scotland FRAIL tool and 'Initial Clinical Evaluation') and researcher (11-item modified Frailty Index). Consistent with feasibility objectives, outcome measures include recruitment rates, frailty assessment completion rates, time-to-complete assessments and interuser variability. Electronic follow-up at 30 days and 1 year will assess home-time and mortality as prognostic indicators. Patients treated surgically/endovascularly will undergo additional 30-day and 1-year postoperative follow-up, outcome measures include: surgical procedure, mortality, complications (according to Clavien-Dindo Classification), length of stay, readmission rates, non-home discharge, home-time, higher social care requirements on discharge and amputation-free survival. Prognostic value will be compared by area under receiver operating characteristic curves. Continuous outcome variables will be analysed using Spearman's rank correlation coefficient. Interuser agreement will be compared by percentage agreement in Cohen's kappa coefficient. ETHICS AND DISSEMINATION: The study is sponsored by National Health Service Greater Glasgow and Clyde (R&IUGN23CE014). London-Riverside REC (23/PR/0062) granted ethical approval. Results will be disseminated through publication in peer-reviewed vascular surgery and geriatric medicine themed journals and presentation at similar scientific conferences., Trials Registration Number: NCT06040658. Stage of study: pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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9. A systematic review of frailty assessment tools used in vascular surgery research.
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Welsh SA, Pearson RC, Hussey K, Brittenden J, Orr DJ, and Quinn T
- Subjects
- Humans, Vascular Surgical Procedures adverse effects, Consensus, Databases, Factual, Frailty diagnosis, Specialties, Surgical
- Abstract
Objective: Frailty is common in vascular patients and is recognized for its prognostic value. In the absence of consensus, a multitude of frailty assessment tools exist. This systematic review aimed to quantify the variety in these tools and describe their content and application to inform future research and clinical practice., Methods: Multiple cross-disciplinary electronic literature databases were searched from inception to August 2022. Studies describing frailty assessment in a vascular surgical population were eligible. Data extraction to a validated template included patient demographics, tool content, and analysis methods. A secondary systematic search for papers describing the psychometric properties of commonly used frailty tools was then performed., Results: Screening 5358 records identified 111 eligible studies, with an aggregate population of 5,418,236 patients. Forty-three differing frailty assessment tools were identified. One-third of these failed to assess frailty as a multidomain deficit and there was a reliance on assessing function and presence of comorbidity. Substantial methodological variability in data analysis and lack of methodological description was also identified. Published psychometric assessment was available for only 4 of the 10 most commonly used frailty tools. The Clinical Frailty Scale was the most studied and demonstrates good psychometric properties within a surgical population., Conclusions: Substantial heterogeneity in frailty assessment is demonstrated, precluding meaningful comparisons of services and data pooling. A uniform approach to assessment is required to guide future frailty research. Based on the literature, we make the following recommendations: frailty should be considered a continuous construct and the reporting of frailty tools' application needs standardized. In the absence of consensus, the Clinical Frailty Scale is a validated tool with good psychometric properties that demonstrates usefulness in vascular surgery., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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10. A combinatorial approach to uncover an additional Integrator subunit.
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Offley SR, Pfleiderer MM, Zucco A, Fraudeau A, Welsh SA, Razew M, Galej WP, and Gardini A
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- Transcription, Genetic, RNA Polymerase II metabolism
- Abstract
RNA polymerase II (RNAPII) controls expression of all protein-coding genes and most noncoding loci in higher eukaryotes. Calibrating RNAPII activity requires an assortment of polymerase-associated factors that are recruited at sites of active transcription. The Integrator complex is one of the most elusive transcriptional regulators in metazoans, deemed to be recruited after initiation to help establish and modulate paused RNAPII. Integrator is known to be composed of 14 subunits that assemble and operate in a modular fashion. We employed proteomics and machine-learning structure prediction (AlphaFold2) to identify an additional Integrator subunit, INTS15. We report that INTS15 assembles primarily with the INTS13/14/10 module and interfaces with the Int-PP2A module. Functional genomics analysis further reveals a role for INTS15 in modulating RNAPII pausing at a subset of genes. Our study shows that omics approaches combined with AlphaFold2-based predictions provide additional insights into the molecular architecture of large and dynamic multiprotein complexes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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11. Genomic regulation of transcription and RNA processing by the multitasking Integrator complex.
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Welsh SA and Gardini A
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- Animals, RNA, RNA, Small Nuclear genetics, RNA, Small Nuclear metabolism, Genomics, Transcription, Genetic, RNA Processing, Post-Transcriptional, RNA Polymerase II metabolism
- Abstract
In higher eukaryotes, fine-tuned activation of protein-coding genes and many non-coding RNAs pivots around the regulated activity of RNA polymerase II (Pol II). The Integrator complex is the only Pol II-associated large multiprotein complex that is metazoan specific, and has therefore been understudied for years. Integrator comprises at least 14 subunits, which are grouped into distinct functional modules. The phosphodiesterase activity of the core catalytic module is co-transcriptionally directed against several RNA species, including long non-coding RNAs (lncRNAs), U small nuclear RNAs (U snRNAs), PIWI-interacting RNAs (piRNAs), enhancer RNAs and nascent pre-mRNAs. Processing of non-coding RNAs by Integrator is essential for their biogenesis, and at protein-coding genes, Integrator is a key modulator of Pol II promoter-proximal pausing and transcript elongation. Recent studies have identified an Integrator-specific serine/threonine-protein phosphatase 2A (PP2A) module, which targets Pol II and other components of the basal transcription machinery. In this Review, we discuss how the activity of Integrator regulates transcription, RNA processing, chromatin landscape and DNA repair. We also discuss the diverse roles of Integrator in development and tumorigenesis., (© 2022. Springer Nature Limited.)
- Published
- 2023
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12. Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders.
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Pagliaroli L, Porazzi P, Curtis AT, Scopa C, Mikkers HMM, Freund C, Daxinger L, Deliard S, Welsh SA, Offley S, Ott CA, Calabretta B, Brugmann SA, Santen GWE, and Trizzino M
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- Blotting, Western, DNA-Binding Proteins genetics, Flow Cytometry, HEK293 Cells, Humans, Mutation genetics, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Transcription Factors genetics, Chromatin metabolism, DNA-Binding Proteins metabolism, Nanog Homeobox Protein metabolism, Neural Crest metabolism, Transcription Factors metabolism
- Abstract
Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B
+/- Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome., (© 2021. The Author(s).)- Published
- 2021
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13. K-12, college/university, and mass shootings: similarities and differences.
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Kowalski RM, Leary M, Hendley T, Rubley K, Chapman C, Chitty H, Carroll H, Cook A, Richardson E, Robbins C, Wells S, Bourque L, Oakley R, Bednar H, Jones R, Tolleson K, Fisher K, Graham R, Scarborough M, Welsh SA, and Longacre M
- Subjects
- Humans, Schools, Universities, Violence, Firearms, Wounds, Gunshot
- Abstract
In a 2003 study, we examined five antecedents of school shootings - a history of rejection, acute rejection experience, history of psychological problems, fascination with death or violence, and fascination with guns. In three studies, the current project examined the role of these factors in 57 K-12 shootings, 24 college/university shootings, and 77 mass shootings that occurred since the original study. Over half of all shooters had a history of psychological problems. More K-12 shooters than college or mass shooters displayed a history of rejection. However, more mass than school shooters had experienced an acute rejection, such as a workplace firing. The characteristics identified in the original study appeared as common antecedent conditions of not only K-12 shootings but college/university and mass shootings as well. These results identify problems that can be addressed to minimize the occurrence of school and mass shootings.
- Published
- 2021
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14. The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
- Author
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Vervoort SJ, Welsh SA, Devlin JR, Barbieri E, Knight DA, Offley S, Bjelosevic S, Costacurta M, Todorovski I, Kearney CJ, Sandow JJ, Fan Z, Blyth B, McLeod V, Vissers JHA, Pavic K, Martin BP, Gregory G, Demosthenous E, Zethoven M, Kong IY, Hawkins ED, Hogg SJ, Kelly MJ, Newbold A, Simpson KJ, Kauko O, Harvey KF, Ohlmeyer M, Westermarck J, Gray N, Gardini A, and Johnstone RW
- Subjects
- Animals, Cell Line, Tumor, Cyclin-Dependent Kinase 9 antagonists & inhibitors, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Humans, Mice, Inbred NOD, Phosphorylation, Protein Binding, RNA Polymerase II chemistry, RNA Polymerase II metabolism, Substrate Specificity, Mice, Cyclin-Dependent Kinase 9 metabolism, Molecular Targeted Therapy, Neoplasms drug therapy, Neoplasms genetics, Protein Phosphatase 2 metabolism, RNA-Binding Proteins metabolism, Transcription, Genetic, Tumor Suppressor Proteins metabolism
- Abstract
Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically., Competing Interests: Declaration of interests The Johnstone laboratory receives funding support from Roche, BMS, Astra Zeneca, and MecRx. R.W.J. is a shareholder in MecRx and receives consultancy payments., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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15. Cambarus fetzneri sp. nov., a new species of burrowing crayfish (Decapoda: Cambaridae) from the Allegheny Mountains of Virginia and West Virginia, USA.
- Author
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Loughman ZJ, Welsh SA, and Thoma RF
- Subjects
- Animal Distribution, Animals, Appalachian Region, Virginia, West Virginia, Astacoidea
- Abstract
The disjunct distribution of Cambarus monongalensis has led to speculation about its taxonomic status. An Appalachian Plateau population occurs in northern and central West Virginia and Southwestern Pennsylvania, and a mountain population occurs in the Allegheny Mountains and Ridge and Valley physiographic provinces of the Virginias. Herein we describe the mountain population as Cambarus fetzneri sp. nov. The two species differ genetically and morphologically, and have different color patterns. Specifically, C. fetzneri sp. nov. chelae lack extensive red coloration on the distal end of the propodus and dactyl, possess rostral margins that lack any red coloration, compared to C. monongalensis, which has extensive red coloration on the dactyl and propodus, as well as red rostral margins. Morphologically, the rostrum of C. fetzneri sp. nov. is shorter and wider than that of C. monongalensis. Also, adult C. fetzneri sp. nov. are considerably smaller in body size than those of C. monongalensis.
- Published
- 2019
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16. Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.
- Author
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Kivell BM, Paton KF, Kumar N, Morani AS, Culverhouse A, Shepherd A, Welsh SA, Biggerstaff A, Crowley RS, and Prisinzano TE
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- Animals, Anxiety drug therapy, Anxiety metabolism, Cocaine-Related Disorders drug therapy, Diterpenes adverse effects, Diterpenes chemistry, Diterpenes, Clerodane adverse effects, Diterpenes, Clerodane chemistry, Learning drug effects, Male, Mesylates adverse effects, Mesylates chemistry, Mice, Motor Activity drug effects, Nociception drug effects, Pain drug therapy, Pain etiology, Pain metabolism, Rats, Recognition, Psychology drug effects, Behavior, Animal drug effects, Cocaine adverse effects, Cocaine-Related Disorders metabolism, Cocaine-Related Disorders psychology, Diterpenes pharmacology, Diterpenes, Clerodane pharmacology, Mesylates pharmacology, Receptors, Opioid, kappa agonists
- Abstract
The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum . We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.
- Published
- 2018
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17. Targeted Enhancer Activation by a Subunit of the Integrator Complex.
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Barbieri E, Trizzino M, Welsh SA, Owens TA, Calabretta B, Carroll M, Sarma K, and Gardini A
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- Cell Line, Early Growth Response Protein 1 genetics, Early Growth Response Protein 2 genetics, Humans, Myeloid Progenitor Cells cytology, Repressor Proteins genetics, Cell Differentiation, Early Growth Response Protein 1 metabolism, Early Growth Response Protein 2 metabolism, Enhancer Elements, Genetic, Monocytes metabolism, Myeloid Progenitor Cells metabolism, Repressor Proteins metabolism
- Abstract
The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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18. The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II.
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Trizzino M, Barbieri E, Petracovici A, Wu S, Welsh SA, Owens TA, Licciulli S, Zhang R, and Gardini A
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- Adenocarcinoma, Clear Cell metabolism, Adenocarcinoma, Clear Cell pathology, Cell Line, Tumor, DNA-Binding Proteins, Enhancer Elements, Genetic, Estrogen Receptor alpha metabolism, Female, Humans, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcription, Genetic, Tumor Suppressor Protein p53 metabolism, Up-Regulation, Nuclear Proteins metabolism, RNA Polymerase II metabolism, Transcription Factors metabolism
- Abstract
AT-rich interactive domain-containing proteins 1A and 1B (ARID1A and ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (∼57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that ARID1A binds active regulatory elements in OCCC. Depletion of ARID1A represses RNA polymerase II (RNAPII) transcription but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide insight into ARID1A-mediated tumorigenesis and unveil functions of SWI/SNF in modulating RNAPII dynamics., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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19. Cambarus ( C. ) appalachiensis , a new species of crayfish (Decapoda: Cambaridae) from the New River Basin of Virginia and West Virginia, USA.
- Author
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Loughman ZJ, Welsh SA, and Thoma RF
- Subjects
- Animal Distribution, Animals, Rivers, Virginia, West Virginia, Astacoidea
- Abstract
Cambarus (Cambarus) appalachiensis is a stream-dwelling crayfish endemic to the greater New River basins of Virginia and West Virginia. The new species is morphologically most similar to Cambarus sciotensis. Cambarus appalachiensis can be differentiated from C. sciotensis by its more elongated chelae which possess a single mesial row of tubercles, reduced to no tuberculation on the dorsal-longitudinal ridge of the dactyl, and reduced lateral impression. Cambarus sciotensis has a more subrectangular chelae with two rows of mesial margin tubercles on the chelae, as well as both a pronounced dorsal-longitudinal ridge and pronounced lateral impression. Several chelae meristic ratios also differentiate C. appalachiensis from C. sciotensis. Within the New, Gauley, and lower portions of the Greenbrier basins C. appalachiensis is the dominant tertiary burrowing Cambarus species, and as such, is considered stable across its range.
- Published
- 2017
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20. Tagging methyl-CpG-binding domain proteins reveals different spatiotemporal expression and supports distinct functions.
- Author
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Wood KH, Johnson BS, Welsh SA, Lee JY, Cui Y, Krizman E, Brodkin ES, Blendy JA, Robinson MB, Bartolomei MS, and Zhou Z
- Subjects
- Animals, Biogenic Amines analysis, Body Weight, Brain metabolism, CpG Islands, DNA-Binding Proteins genetics, Female, Gene Expression Regulation, Gene Knock-In Techniques, Male, Maze Learning, Methyl-CpG-Binding Protein 2 genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Spatio-Temporal Analysis, Transcription Factors genetics, Transcription Factors metabolism, Behavior, Animal, DNA Methylation, DNA-Binding Proteins metabolism, Methyl-CpG-Binding Protein 2 metabolism, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism
- Abstract
Aim: DNA methylation is recognized by methyl-CpG-binding domain (MBD) proteins. Multiple MBDs are linked to neurodevelopmental disorders in humans and mice. However, the functions of MBD2 are poorly understood. We characterized Mbd2 knockout mice and determined spatiotemporal expression of MBDs and MBD2-NuRD (nucleosome remodeling deacetylase) interactions., Experimental Procedures: We analyzed behavioral phenotypes, generated biotin-tagged MBD1 and MBD2 knockin mice, and performed biochemical studies of MBD2-NuRD., Results: Most behavioral measures are minimally affected in Mbd2 knockout mice. In contrast to other MBDs, MBD2 shows distinct expression patterns., Conclusion: Unlike most MBDs, MBD2 is ubiquitously expressed in all tissues examined and appears dispensable for brain functions measured in this study. We provide novel genetic tools and reveal new directions to investigate MBD2 functions in vivo., Competing Interests: Financial & competing interests disclosure This work was supported by a Predoctoral Training Grant T32GM008216 to KH Wood, US NIH grant R01 MH091850 to Z Zhou, and P50MH096891, Project 2 to ES Brodkin. Z Zhou is a Pew Scholar in the biomedical sciences. Additional support was provided by the Analytical Neurochemistry Core of the Intellectual and Developmental Disabilities Research Center at Children's Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
- Published
- 2016
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21. Cambarus (C.) hatfieldi, a new species of crayfish (Decapoda:Cambaridae) from the Tug Fork River Basin of Kentucky, Virginia and West Virginia, USA.
- Author
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Loughman ZJ, Fagundo RA, Lau E, Welsh SA, and Thoma RF
- Subjects
- Animal Distribution, Animal Structures anatomy & histology, Animals, Astacoidea anatomy & histology, Astacoidea genetics, Female, Kentucky, Male, Molecular Sequence Data, Phylogeny, Rivers, Virginia, West Virginia, Astacoidea classification
- Abstract
Cambarus (Cambarus) hatfieldi is a stream-dwelling crayfish that appears to be endemic to the Tug Fork River system of West Virginia, Virginia, and Kentucky. Within this region, it is prevalent in all major tributaries in the basin as well as the Tug Fork River's mainstem. The new species is morphologically most similar to Cambarus sciotensis and Cambarus angularis. It can be differentiated from C. sciotensis by its squamous, subtrinagular chelae compared to the elongate triangular chelae of C. sciotensis; its shorter palm length/palm depth ratio (1.9) compared to C. sciotensis (2.3); and a smaller areola length/total carapace length ratio (30.4% vs.36.5% respectively). Cambarus hatfieldi can be differentiated from C. angularis by its smaller areola length/total carapace length ratio (30.4% vs. 36.7% respectively); a smaller rostrum width/rostral length ratio (59.4% vs. 67.2% respectively); its rounded abdominal pleura as compared to the subtruncated pleura of C. angularis; the length of the central projection and mesial process of C. hatfieldi which both extend to the margin of the gonopod shaft or slightly beyond the margin compared to the central projection of C. sciotensis and C. angularis where both extend well beyond the margin of the gonopod shaft.
- Published
- 2013
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22. Cambarus (P) theepiensis, a new species of crayfish (Decapoda:Cambaridae) from the coalfields region of Eastern Kentucky and Southwestern West Virginia, USA.
- Author
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Loughman ZJ, Foltz DA, Garrison NL, and Welsh SA
- Subjects
- Animal Distribution, Animal Structures anatomy & histology, Animal Structures growth & development, Animals, Astacoidea anatomy & histology, Astacoidea growth & development, Body Size, Ecosystem, Female, Kentucky, Male, Organ Size, West Virginia, Astacoidea classification
- Abstract
Cambarus (Puncticambarus) theepiensis is a stream-dwelling crayfish that appears to be endemic to the junction of the Cumberland Mountains with the Appalachian Plateau in West Virginia and Kentucky. Within this region, it is prevalent in the Guyandotte and Twelvepole basins of West Virginia, the Little Sandy River and Levisa Fork basins of Kentucky, and tributaries of the Big Sandy River shared by both states. The new species is morphologically most similar to Cambarus robustus and Cambarus sciotensis. It can be differentiated from C. robustus by its broad rostrum, with subparallel, thick-ened margins compared to the narrow, converging rostrum with reduced rostral margins of C. robustus.; larger areola width/length ratio (26 %) than C. robustus (22 %); and mottled color pattern compared to the monotypic color pattern of C. robustus. Canibarus theepiensis can be differentiated from C. sciotensis by the presence of a distinct lateral impression on the chelae compared to the absence of a lateral impression in C. sciotensis; constant thickness of the rostral margin compared to the gradation of rostral thickness in C. sciotensis; greater rostrum width/ length ratio in C. theepiensis (63.1 %) compared to C. sciotensis (57.2 %); and a central projection on the gonopod that is the same length as the mesial process, compared to a central projection that extends past the tip of the mesial process in C. sciotensis.
- Published
- 2013
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23. Effects of highway construction on stream water quality and macroinvertebrate condition in a mid-atlantic highlands watershed, USA.
- Author
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Chen Y, Viadero RC Jr, Wei X, Fortney R, Hedrick LB, Welsh SA, Anderson JT, and Lin LS
- Subjects
- Animals, West Virginia, Invertebrates, Transportation
- Abstract
Refining best management practices (BMPs) for future highway construction depends on a comprehensive understanding of environmental impacts from current construction methods. Based on a before-after-control impact (BACI) experimental design, long-term stream monitoring (1997-2006) was conducted at upstream (as control, n = 3) and downstream (as impact, n = 6) sites in the Lost River watershed of the Mid-Atlantic Highlands region, West Virginia. Monitoring data were analyzed to assess impacts of during and after highway construction on 15 water quality parameters and macroinvertebrate condition using the West Virginia stream condition index (WVSCI). Principal components analysis (PCA) identified regional primary water quality variances, and paired t tests and time series analysis detected seven highway construction-impacted water quality parameters which were mainly associated with the second principal component. In particular, impacts on turbidity, total suspended solids, and total iron during construction, impacts on chloride and sulfate during and after construction, and impacts on acidity and nitrate after construction were observed at the downstream sites. The construction had statistically significant impacts on macroinvertebrate index scores (i.e., WVSCI) after construction, but did not change the overall good biological condition. Implementing BMPs that address those construction-impacted water quality parameters can be an effective mitigation strategy for future highway construction in this highlands region.
- Published
- 2009
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24. PERMANENT GENETIC RESOURCES: Microsatellite DNA primers for the candy darter, Etheostoma osburni and variegate darter, Etheostoma variatum, and cross-species amplification in other darters (Percidae).
- Author
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Switzer JF, Welsh SA, and King TL
- Abstract
In order to investigate a potential hybrid zone between the candy darter, Etheostoma osburni, and variegate darter, Etheostoma variatum, and examine population variation within E. osburni, a suite of primers for 15 polymorphic microsatellite loci were developed. The average number of alleles per locus was 5.5 in E. osburni and 7.6 in E. variatum, and the average observed heterozygosities were 62.5% and 71.4%, respectively. There were no deviations from Hardy-Weinberg equilibrium and no observed linkage disequilibrium after Bonferroni correction. The utility of these primers was also tested in 11 species of darters representing all four genera of darters. Success of cross-species amplification was largely consistent with phylogenetic relationships of darters., (© 2007 The Authors.)
- Published
- 2008
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