Publications by authors named "Joseph Wilson"

85 Publications

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters.

Neuropharmacology 2021 Apr 20;190:108570. Epub 2021 Apr 20.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. Electronic address:

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108570DOI Listing
April 2021

T cell phenotypes in COVID-19 - a living review.

Oxf Open Immunol 2021 29;2(1):iqaa007. Epub 2020 Dec 29.

Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.
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http://dx.doi.org/10.1093/oxfimm/iqaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798577PMC
December 2020

Framing the past (and future): Effects of generic photos on autobiographical judgments.

Mem Cognit 2021 Jan 4. Epub 2021 Jan 4.

Department of Psychology, Binghamton University, Vestal, NY, USA.

Do the images we see every day influence how we remember our lives? Research on this matter often concerns how entire memories of events can be created or shaped through the use of doctored photographs of personal (Wade et al., Psychonomic bulletin & review, 9 (3), 597-603, 2002) and public events (Sacchi et al., Applied Cognitive Psychology, 21 (8), 1005-1022, 2007). Although this paradigm has yielded insights into false memory production, it may underestimate the extent to which photographs can bias or distort memory in a subtler manner (i.e., without the use of doctored photographs or suggestion). In Experiments 1 (N = 95) and 2 (N = 186) of the present study, we examined whether the mere presence of generic images, typical of stock photography, could influence aspects of our memories. Given the parallel between autobiographical remembering and forecasting (Berntsen & Bohn, Memory & Cognition, 38(3), 265-278, 2010), we also examined (Experiment 3: N=204) how such images would influence future autobiographical judgments. Specifically, three experiments investigated whether photographs would bias autobiographical judgments for either quantitative (e.g., How many movies have you seen in the past year?) or affective (e.g., How enjoyable do you think your next date will be?) aspects of events in everyday life. We found that photographs reliably influenced judgments related to quantitative aspects of autobiographical events. Moreover, though less robustly, there was an indication that these photos could bias our affective construal of such events as well. Overall, we conclude that the mere presence of generic photographs may exert an influence on the way we think about our lives to an extent previously under-recognized.
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http://dx.doi.org/10.3758/s13421-020-01132-3DOI Listing
January 2021

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

iScience 2020 Nov 14;23(11):101668. Epub 2020 Oct 14.

Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK.

Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.
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http://dx.doi.org/10.1016/j.isci.2020.101668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588853PMC
November 2020

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

Bioorg Med Chem 2020 12 3;28(23):115791. Epub 2020 Oct 3.

GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
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http://dx.doi.org/10.1016/j.bmc.2020.115791DOI Listing
December 2020

Implementing a negative pressure isolation space within a skilled nursing facility to control SARS-CoV-2 transmission.

Am J Infect Control 2021 04 3;49(4):438-446. Epub 2020 Oct 3.

The College of Business and Leadership, Eastern University, St. Davids, PA.

Background: Isolation space must be expanded during pandemics involving airborne transmission. Little to no work has been done to establish optimal design strategies and implementation plans to ease surge capacity and expand isolation capacity over long periods in congregate living facilities. The COVID-19 pandemic has an airborne transmission component and requires isolation, which is difficult to accomplish in skilled nursing facilities.

Methods: In this study we designed, implemented, and validated an isolation space at a skilled nursing facility in Lancaster, PA. The overall goal was to minimize disease transmission between residents and staff within the facility. We created an isolation space by modifying an existing HVAC system of the SNF. We measured pressure on-site and performed computational fluid dynamics and Lagrangian particle-based modeling to test containment and possible transmission extent given the isolation space is considered negative rather than individual rooms.

Results: Pressure data shows the isolation space maintained an average (standard deviation) hourly value of -2.3 Pa (0.12 Pa) pressure differential between it and the external hallway connected to the rest of the facility. No transmission of SARS-CoV-2 between residents isolated to the space occurred, nor did any transmission to the staff or other residents occur. The isolation space was successfully implemented and, as of writing, continues to be operational through the pandemic.

Conclusion: Skilled nursing facilities can be retrofitted to provide negative pressure isolation space in a reasonable time frame and a cost effective manner to minimize airborne disease transmission within that space.
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http://dx.doi.org/10.1016/j.ajic.2020.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532347PMC
April 2021

Recurrent anterior cutaneous nerve entrapment syndrome (ACNES) in three consecutive pregnancies.

BMJ Case Rep 2020 Sep 7;13(9). Epub 2020 Sep 7.

Department of Family Medicine, East Carolina University Brody School of Medicine, Greenville, North Carolina, USA.

A 31-year-old G2P1001 woman at a 30-week gestation presented with a recurrence of pinpoint right upper abdominal wall pain. She had been diagnosed with an anterior cutaneous nerve entrapment syndrome (ACNES) during her first pregnancy at a similar gestational age, a well-described but frequently under-recognised entity. The pain during that pregnancy resolved immediately and completely following normal spontaneous vaginal delivery, however,the pain was worse with this presenting pregnancy. She underwent an ultrasound-guided rectus sheath nerve block at 30 weeks with complete and immediate relief for the remainder of the pregnancy. During a third pregnancy, she suffered another recurrence; however, it was less severe than in the prior pregnancies and was managed conservatively. It again resolved completely and immediately with normal spontaneous vaginal delivery. The pattern of ACNES recurrence during the same gestational age in all three pregnancies with total relief following deliveries demonstrates a clear primary mechanical aetiology.
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http://dx.doi.org/10.1136/bcr-2020-234619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478025PMC
September 2020

Berbamine Analogs Exhibit Differential Protective Effects From Aminoglycoside-Induced Hair Cell Death.

Front Cell Neurosci 2020 29;14:234. Epub 2020 Jul 29.

Integrative Physiology and Neuroscience, Washington State University, Vancouver, WA, United States.

Hearing loss is the third most common chronic health condition in the United States and largely results from damage to sensory hair cells. Major causes of hair cell damage include aging, noise exposure, and medications such as aminoglycoside antibiotics. Due to their potent antibacterial properties and low cost, aminoglycosides are often used for the treatment of gram-negative bacterial infections, surpassing expensive antibiotics with fewer harmful side effects. However, their use is coupled with permanent hearing loss in over 20% of patients requiring these life-sustaining antibiotics. There are currently no FDA-approved drugs that prevent hearing loss from aminoglycosides. A previous study by our group identified the plant alkaloid berbamine as a strong protectant of zebrafish lateral line hair cells from aminoglycoside damage. This effect is likely due to a block of the mechanotransduction channel, thereby reducing aminoglycoside entry into hair cells. The present study builds on this previous work, investigating 16 synthetic berbamine analogs to determine the core structure underlying their protective mechanisms. We demonstrate that nearly all of these berbamine analogs robustly protect lateral line hair cells from ototoxic damage, with ED values nearing 20 nM for the most potent analogs. Of the 16 analogs tested, nine strongly protected hair cells from both neomycin and gentamicin damage, while one conferred strong protection only from gentamicin. These data are consistent with prior research demonstrating that different aminoglycosides activate somewhat distinct mechanisms of damage. Regardless of the mechanism, protection required the entire berbamine scaffold. Phenolic alkylation or acylation with lipophilic groups appeared to improve protection compared to berbamine, implying that these structures may be responsible for mitigating damage. While the majority of analogs confer protection by blocking aminoglycoside uptake, 18% of our analogs also confer protection an uptake-independent mechanism; these analogs exhibited protection when delivered after aminoglycoside removal. Based on our studies, berbamine analogs represent a promising tool to further understand the pathology of aminoglycoside-induced hearing loss and can serve as lead compounds to develop otoprotective drugs.
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http://dx.doi.org/10.3389/fncel.2020.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403526PMC
July 2020

Adoptive T Cell Therapy with IL-12-Preconditioned Low-Avidity T Cells Prevents Exhaustion and Results in Enhanced T Cell Activation, Enhanced Tumor Clearance, and Decreased Risk for Autoimmunity.

J Immunol 2020 09 31;205(5):1449-1460. Epub 2020 Jul 31.

Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455;

Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12-induced optimal CD8 T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12-primed T cells are resistant to PD-1/PD-L1-mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12-primed, low-avidity T cells cause less autoimmune vitiligo.
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http://dx.doi.org/10.4049/jimmunol.2000007DOI Listing
September 2020

Thistledown velvet ants in the Desert Mimicry Ring and the evolution of white coloration: Müllerian mimicry, camouflage and thermal ecology.

Biol Lett 2020 07 15;16(7):20200242. Epub 2020 Jul 15.

Department of Biology, Utah State University, Logan, UT 84322, USA.

Adaptive coloration among animals is one of the most recognizable outcomes of natural selection. Here, we investigate evolutionary drivers of white coloration in velvet ants (Hymenoptera: Mutillidae), which has previously been considered camouflage with the fruit of creosote bush (). Our analyses indicate instead that velvet ants evolved white coloration millions of years before creosote bush was widespread in North America's hot deserts. Furthermore, velvet ants and the creosote fruit exhibit different spectral reflectance patterns, which appear distinct to potential insectivorous predators. While the white coloration in velvet ants likely did not evolve as camouflage, we find that white-coloured species remain cooler than their red/orange relatives, and therefore we infer the white coloration likely evolved in response to Neogene desertification. This study shows the importance of cross-disciplinary investigation and of testing multiple hypotheses when investigating evolutionary drivers of adaptive coloration.
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http://dx.doi.org/10.1098/rsbl.2020.0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423050PMC
July 2020

Carcinoma of unknown primary with hepatic metastases: a need of judicious and contemplative diagnostic algorithm.

Abdom Radiol (NY) 2021 01 6;46(1):257-267. Epub 2020 Jul 6.

Wake Forest University and Baptist Health, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.

Carcinoma of Unknown Primary presenting primarily as hepatic metastases encompasses a dismal subgroup of tumors with a median survival of 5.9 months. Adenocarcinoma is the most common histological subtype identified upon biopsy and the primary tumor remains undetectable in the majority of cases despite extensive workup. It is important to have a validated and standardized algorithm to follow these tumors to avoid unnecessary tests, as the wishes and health status of the patient represent the principal concerns. The purpose of this paper is to briefly review the current literature on carcinoma of unknown primary with hepatic metastases and propose a standardized diagnostic approach.
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http://dx.doi.org/10.1007/s00261-020-02630-3DOI Listing
January 2021

Identification and characterization of a Triton X-100 replacement for virus inactivation.

Biotechnol Prog 2020 11 6;36(6):e3036. Epub 2020 Jul 6.

Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.

Triton X-100 detergent treatment is a robust enveloped virus inactivation unit operation included in biopharmaceutical manufacturing processes. However, the European Commission officially placed Triton X-100 on the Annex XIV authorization list in 2017 because a degradation product of Triton X-100, 4-(1,1,3,3-tetramethylbutyl) phenol (also known as 4-tert-octylphenol), is considered to have harmful endocrine disrupting activities. As a result, the use of Triton X-100 in the European Economic Area (EEA) would not be allowed unless an ECHA issued authorization was granted after the sunset date of January 4, 2021. This has prompted biopharmaceutical manufacturers to search for novel, environment-friendly alternative detergents for enveloped virus inactivation. In this study, we report the identification of such a novel detergent, Simulsol SL 11W. Simulsol SL 11W is an undecyl glycoside surfactant produced from glucose and C11 fatty alcohol. We report here that Simulsol SL 11W was able to effectively inactive enveloped viruses, such as xenotropic murine leukemia virus (XMuLV) and pseudorabies virus (PRV). By using XMuLV as a representative enveloped virus, the influence of various parameters on the effectiveness of virus inactivation was evaluated. Virus inactivation by Simulsol SL 11W was effective across different clarified bioreactor harvests at broad concentrations, pH, and temperature ranges. Simulsol SL 11W concentration, temperature of inactivation, and treatment time were identified as critical process parameters for virus inactivation. Removal of Simulsol SL 11W was readily achieved by Protein A chromatography and product quality was not affected by detergent treatment. Taken together, these results have shown the potential of Simulsol SL 11W as a desirable alternative to Triton X-100 for enveloped virus inactivation that could be readily implemented into biopharmaceutical manufacturing processes.
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http://dx.doi.org/10.1002/btpr.3036DOI Listing
November 2020

Trauma exposure and stress-related disorders in African-American women with diabetes mellitus.

Endocrinol Diabetes Metab 2020 Apr 14;3(2):e00111. Epub 2020 Jan 14.

Department of Psychiatry and Behavioral Sciences Emory University School of Medicine Atlanta Georgia.

Objective: The purpose of the study was to assess demographic features, rates of trauma exposure, prevalence of post-traumatic stress and depressive symptoms in a group of urban, low-income, African-American women with type 1 or type 2 diabetes mellitus.

Research Design And Methods: We conducted a survey of (n = 290) low-income, African-American women seeking care in the diabetes clinic of an urban hospital and collected data on the demographic characteristics, childhood and nonchildhood abuse trauma exposure, and the severity of post-traumatic stress and depressive symptoms using the Post-traumatic Stress Disorder (PTSD) Symptom Scale (PSS) and the Beck Depression Inventory (BDI). In a subset of women with type 2 diabetes (n = 96), we assessed haemoglobin A1c to examine the relationship between psychopathology and glycaemic control.

Results: Of the overall sample, 61.7% reported exposure to trauma in their lifetime, and 30.4% and 29.3% had current PTSD and MDD, respectively. Exposure to both childhood and nonchildhood abuse trauma was associated with an increased PTSD and depressive symptom severity ('s < .05). PTSD diagnosis, but not depression, was associated with increased haemoglobin A1c ( = .002).

Conclusions: These data document high levels of trauma exposure, PTSD and depressive symptoms in diabetic African-American women treated in a specialty clinic of an urban hospital setting. Furthermore, these data indicate that the presence of PTSD is negatively associated with glycaemic control.
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http://dx.doi.org/10.1002/edm2.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170451PMC
April 2020

Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity.

Aging Cell 2020 04 31;19(4):e13142. Epub 2020 Mar 31.

CRUK Cambridge Centre Early Detection Programme, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal β-galactosidase (SA-β-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-β-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
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http://dx.doi.org/10.1111/acel.13142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189993PMC
April 2020

Corrigendum: Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Front Oncol 2020;10:210. Epub 2020 Feb 25.

Department of Oncology, The Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.

[This corrects the article DOI: 10.3389/fonc.2019.01563.].
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http://dx.doi.org/10.3389/fonc.2020.00210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053480PMC
February 2020

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Front Oncol 2019 17;9:1563. Epub 2020 Jan 17.

Department of Oncology, The Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.

Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.
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http://dx.doi.org/10.3389/fonc.2019.01563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979639PMC
January 2020

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes.

J Immunol 2019 08 19;203(4):844-852. Epub 2019 Jul 19.

Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455; and

Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers (GC) is controversial. To address the role of PD-1 in the GC reaction in type 1 diabetes, we used tetramers to phenotype insulin-specific CD4 T and B cells in NOD mice. PD-1 or PD-L1 deficiency, and PD-1 but not PD-L2 blockade, unleashed insulin-specific T follicular helper CD4 T cells and enhanced their survival. This was concomitant with an increase in GC B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on the GC was reduced when mice were treated with a mAb targeting the insulin peptide:MHC class II complex. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition and suggests that targeting the self-peptide:MHC class II complex might limit autoimmunity arising from checkpoint blockade.
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http://dx.doi.org/10.4049/jimmunol.1801535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083260PMC
August 2019

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

Bioorg Med Chem 2019 04 11;27(8):1456-1478. Epub 2019 Feb 11.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
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http://dx.doi.org/10.1016/j.bmc.2019.02.017DOI Listing
April 2019

The "trumpeting elephant" sign.

Abdom Radiol (NY) 2019 05;44(5):1953-1954

Department of Radiology, Wake Forest Baptist Medical Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.

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http://dx.doi.org/10.1007/s00261-019-01921-8DOI Listing
May 2019

Reducing protected lands in a hotspot of bee biodiversity: bees of Grand Staircase-Escalante National Monument.

PeerJ 2018 4;6:e6057. Epub 2018 Dec 4.

Santa Fe, NM, USA.

Grand Staircase-Escalante National Monument is a federally protected area found in central southern Utah. Designated in 1996 by President William J. Clinton, it was recently reduced in size by President Donald J. Trump in a proclamation that turned the one large monument into three smaller ones. A long-term, standardized study of the bees had been conducted from 2000-2003, revealing 660 species. The bee communities of the area are characterized by being spatially heterogeneous; most of the bees occur in isolated areas, with only a few being both abundant and widespread. Here we examine what affect the recent resizing of the monument has on the number, and ecology, of the bees now excluded from monument boundaries. Using the new monument boundaries and the geographic coordinates associated with each bee, we derived new species lists for each of the three monuments, and compared them to each other, and to the excluded lands. All three monuments now protect unique faunas, with Bray-Curtis similarity values not exceeding 0.59%. Each monument now harbors species not found in the other two monuments. We found that 84 bee species are no longer protected by any of the three monuments. These 84 species were not concentrated in one area that is now excluded, but were scattered throughout the newly excluded lands. For some of the excluded bee species, there is no evidence that they are rare or imperiled, being widespread throughout the west. However, there is a concentration of bees in the southern and eastern former monument lands that represent range extensions from nearby hot deserts. In addition to numerous range extensions, the list of excluded bees also contains several undescribed species (newly discovered species that have not yet been named and described by taxonomists) and morphospecies (individuals that are morphologically distinct, but that require additional research before species designations can be made). This indicates that the bee communities housed in these excluded areas would benefit from additional scientific inquiry. The areas now excluded from monument protections house a greater proportion of the original GSENM bee community than any of the three new monument units. We conclude this paper by discussing what the smaller monuments might mean for bee conservation in this hot spot of bee biodiversity and suggest that bee communities here and elsewhere should be taken into account when conservation decisions are being made.
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http://dx.doi.org/10.7717/peerj.6057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284448PMC
December 2018

Wild bees of Grand Staircase-Escalante National Monument: richness, abundance, and spatio-temporal beta-diversity.

PeerJ 2018 7;6:e5867. Epub 2018 Nov 7.

Department of Biology, Utah State University - Tooele, Tooele, UT, United States of America.

Interest in bees has grown dramatically in recent years in light of several studies that have reported widespread declines in bees and other pollinators. Investigating declines in wild bees can be difficult, however, due to the lack of faunal surveys that provide baseline data of bee richness and diversity. Protected lands such as national monuments and national parks can provide unique opportunities to learn about and monitor bee populations dynamics in a natural setting because the opportunity for large-scale changes to the landscape are reduced compared to unprotected lands. Here we report on a 4-year study of bees in Grand Staircase-Escalante National Monument (GSENM), found in southern Utah, USA. Using opportunistic collecting and a series of standardized plots, we collected bees throughout the six-month flowering season for four consecutive years. In total, 660 bee species are now known from the area, across 55 genera, and including 49 new species. Two genera not previously known to occur in the state of Utah were discovered, as well as 16 new species records for the state. Bees include ground-nesters, cavity- and twig-nesters, cleptoparasites, narrow specialists, generalists, solitary, and social species. The bee fauna reached peak diversity each spring, but also experienced a second peak in diversity in late summer, following monsoonal rains. The majority of GSENM's bees are highly localized, occurring in only a few locations throughout the monument, and often in low abundance, but consistently across the four years. Only a few species are widespread and super-abundant. Certain flowering plants appear to be inordinately attractive to the bees in GSENM, including several invasive species. GSENM protects one of the richest bee faunas in the west; the large elevational gradient, incredible number of flowering plants, and the mosaic of habitats are all likely contributors to this rich assemblage of bees.
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http://dx.doi.org/10.7717/peerj.5867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230437PMC
November 2018

13 weeks' gestation · heart palpitations · chest tightness · Dx?

J Fam Pract 2018 Aug;67(8):E9-E11

Department of Family Medicine, East Carolina University Brody School of Medicine, Greenville, NC, USA.

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August 2018

The indestructible insect: Velvet ants from across the United States avoid predation by representatives from all major tetrapod clades.

Ecol Evol 2018 Jun 18;8(11):5852-5862. Epub 2018 May 18.

Department of Biology Utah State University-Tooele Tooele Utah.

Velvet ants are a group of parasitic wasps that are well known for a suite of defensive adaptations including bright coloration and a formidable sting. While these adaptations are presumed to function in antipredator defense, observations between potential predators and this group are lacking. We conducted a series of experiments to determine the risk of velvet ants to a host of potential predators including amphibians, reptiles, birds, and small mammals. Velvet ants from across the United States were tested with predator's representative of the velvet ants native range. All interactions between lizards, free-ranging birds, and a mole resulted in the velvet ants survival, and ultimate avoidance by the predator. Two shrews did injure a velvet ant, but this occurred only after multiple failed attacks. The only predator to successfully consume a velvet ant was a single American toad (). These results indicate that the suite of defenses possessed by velvet ants, including aposematic coloration, stridulations, a chemical alarm signal, a hard exoskeleton, and powerful sting are effective defenses against potential predators. Female velvet ants appear to be nearly impervious to predation by many species whose diet is heavily derived of invertebrate prey.
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http://dx.doi.org/10.1002/ece3.4123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010712PMC
June 2018

Picture (im)perfect: Illusions of recognition memory produced by photographs at test.

Mem Cognit 2018 10;46(7):1210-1221

Department of Psychology, Binghamton University, State University of New York, PO Box 6000, Binghamton, NY, 13902-6000, USA.

Photographs have been found to affect a variety of psychological judgments. For example, nonprobative but semantically related photographs may increase beliefs in the truth of general knowledge statements (Newman, Garry, Bernstein, Kantner, & Lindsay, Psychonomic Bulletin & Review, 19(5), 969-974, 2012; Newman et al., Journal of Experimental Psychology: Learning, Memory, and Cognition, 41(5), 1337-1348, 2015). Photographs can also create illusions of memory (Cardwell, Henkel, Garry, Newman, & Foster, Memory & Cognition, 44(6), 883-896, 2016; Henkel, Applied Cognitive Psychology, 25(1), 78-86, 2011; Henkel & Carbuto, 2008). A candidate mechanism for these effects is that a photograph increases the fluency with which a statement or an event is processed. The present study was conducted to determine whether photos at test can induce illusions of recognition memory and to test the viability of a conceptual fluency explanation of these effects. The results of the present study suggest that photographs enhance the fluency of related words (Experiment 1), that false memories can be produced by the mere presence of a related photo on a recognition memory test for words (Experiments 2 & 3), and that these effects appear to be limited to conceptually based recognition tests (Experiments 4 & 5). The results support the notion that photograph-based illusions of memory stem from the ability of related photographs to increase the speed and ease of conceptual processing.
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http://dx.doi.org/10.3758/s13421-018-0832-6DOI Listing
October 2018

Is the "breast is best" mantra an oversimplification?

J Fam Pract 2018 06;67(6):E1-E9

Department of Family Medicine, East Carolina University Brody School of Medicine, Greenville, NC, USA.

Recommendations about breastfeeding--absent critical analysis and removed from context--may overvalue its benefit. Here's a look at the evidence.
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June 2018

Stinging wasps (Hymenoptera: Aculeata), which species have the longest sting?

PeerJ 2018 2;6:e4743. Epub 2018 May 2.

Department of Biology, Utah State University-Tooele, Tooele, UT, USA.

The stings of bees, wasps, and ants are something that catches the attention of anyone that experiences them. While many recent studies have focused on the pain inflicted by the stings of various stinging wasps, bees, or ants (Hymenoptera: Aculeata), little is known about how the length of the sting itself varies between species. Here, we investigate the sting length of a variety of aculeate wasps, and compare that to reported pain and toxicity values. We find that velvet ants (Hymenoptera: Mutillidae) have the longest sting compared to their body size out of any bee, wasp, or ant species. We also find that there is no link between relative sting length and pain; however, we did find an inverse relationship between relative sting length and toxicity with taxa having shorter relative stings being more toxic. While we found a significant relationship between host use and relative sting length, we suggest that the long sting length of the velvet ants is also related to their suite of defenses to avoid predation.
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http://dx.doi.org/10.7717/peerj.4743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936069PMC
May 2018

A biogeographic perspective on the evolution of fire syndromes in pine trees (: Pinaceae).

R Soc Open Sci 2018 Mar 21;5(3):172412. Epub 2018 Mar 21.

Department of Biology, Utah State University, Tooele, UT 84074, USA.

Our goals were to explore the relationship between biogeography and the evolution of fire-adaptive syndromes in the genus . We used a previously published time-calibrated phylogeny and conducted ancestral trait reconstruction to estimate the likely timing of diversification in , and to determine when fire-adaptive syndromes evolved in the lineage. To explore trait conservation among fire syndromes and to investigate historical biogeography, we constructed ancestral state reconstructions using the program RASP and estimated the degree of conservatism for fire-adapted traits in the program BaTS. Our reconstructions suggest that the Bering land bridge, which connected North America and Asia, probably played a major role in early pine evolution. Our estimates indicated that fire-adaptive syndromes seem to have evolved more frequently in New World taxa and probably are related to the uplift of major North American mountain ranges. Our data suggest that certain geographically widespread adaptations to fire evolved repeatedly, possibly due to localized changes in climate and environment, rather than resulting from large dispersal events of pre-adapted individuals.
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http://dx.doi.org/10.1098/rsos.172412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882747PMC
March 2018

The effect of well-characterized, very low-dose x-ray radiation on fibroblasts.

PLoS One 2018 4;13(1):e0190330. Epub 2018 Jan 4.

Department of Bioengineering, Clemson University, Clemson, South Carolina, United States of America.

The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial "pause" in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190330PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754078PMC
February 2018

Comparison of African and North American velvet ant mimicry complexes: Another example of Africa as the 'odd man out'.

PLoS One 2018 3;13(1):e0189482. Epub 2018 Jan 3.

Plant Pest Diagnostics Center, California Department of Food and Agriculture, Sacramento, California, United States of America.

Africa has the most tropical and subtropical land of any continent, yet has relatively low species richness in several taxa. This depauperate nature of the African tropical fauna and flora has led some to call Africa the "odd man out." One exception to this pattern is velvet ants (Hymenoptera: Mutillidae), wingless wasps that are known for Müllerian mimicry. While North American velvet ants form one of the world's largest mimicry complexes, mimicry in African species has not been investigated. Here we ask do African velvet ant Müllerian mimicry rings exist, and how do they compare to the North American complex. We then explore what factors might contribute to the differences in mimetic diversity between continents. To investigate this we compared the color patterns of 304 African velvet ant taxa using nonmetric multidimensional scaling (NMDS). We then investigated distributions of each distinct mimicry ring. Finally, we compared lizard diversity and ecoregion diversity on the two continents. We found that African female velvet ants form four Müllerian rings, which is half the number of North American rings. This lower mimetic diversity could be related to the relatively lower diversity of insectivorous lizard species or to the lower number of distinct ecoregions in Africa compared to North America.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752001PMC
February 2018

Smoking Urges During Treatment and Long-Term Cessation among Low-Income African Americans.

Ethn Dis 2017 7;27(4):395-402. Epub 2017 Dec 7.

Psychology Department, Binghamton University State University of New York, Binghamton, New York.

Objective: The urge to smoke is a predictor of smoking relapse. Little research has focused on the impact of acute urges during treatment among African Americans. This study examined the relationship between smoking urges and long-term abstinence among treatment seekers.

Design: Longitudinal prospective investigation. Urges to smoke were assessed at the initial (session 1) and final (session 8) sessions among adult smokers (N=308) enrolled in a 4-week group intervention trial. Nicotine patch use was assessed over 30 days.

Main Outcome Measures: Biochemically verified 7-day point prevalence abstinence (7-day ppa) was assessed immediately post-intervention, and at 3-, 6-, and 12-month follow-ups. Hierarchical logistic regressions tested associations between session 1 and session 8 urges and 7-day ppa at each smoking status assessment.

Results: There was a significant overall decrease in smoking urges (M=29, SD=15 at session 1; M=17, SD=11 at session 8). After controlling for covariates, urges to smoke at session 1 were unrelated to 7-day ppa at any of the assessment points. However, session 8 urges were inversely associated with 7-day ppa post-intervention (AOR=.94, CI:.92-.97), at 3-months (AOR=.93, CI: .89-.97), 6-months (AOR=.93, CI: .90-.97), and 12-months (AOR=.96, CI: .96-.99). Nicotine patch use was positively associated with 7-day ppa at each assessment.

Conclusions: The most robust predictors of abstinence through 12-months post-intervention were decreased urges over the 4-week, 8-session group intervention and the frequency of nicotine patch use. Interventions aimed at addressing the needs of African American smokers should address urges and encourage nicotine replacement adherence to increase abstinence rates.
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http://dx.doi.org/10.18865/ed.27.4.395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720949PMC
July 2019