Publications by authors named "David Powell"

433 Publications

c-Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice.

Eur J Immunol 2021 May 7. Epub 2021 May 7.

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.

The NF-κB transcription factor c-Rel is a critical regulator of regulatory T cell (Treg) ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg development defect in c-Rel-deficient (cRel ) mice is quantitative not qualitative based on analyses of T cell receptor (TCR) repertoire and TCR signalling strength. However, these parameters were altered in the thymic Treg-precursor population, which is also markedly diminished in cRel mice. Moreover, c-Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signalling, and separately in the periphery, cell cycle progression. Lastly, the immune suppressive function of peripheral cRel tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c-Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation and function via distinct mechanisms. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.202048900DOI Listing
May 2021

Tacrolimus protects against age-associated microstructural changes in the beagle brain.

J Neurosci 2021 May 4. Epub 2021 May 4.

Department of Pathology & Laboratory Medicine, University of California, Irvine, USA - 92697.

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathological aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index (NDI), as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index (ODI). Tacrolimus also protects against an age-related decrease in fractional anisotropy (FA) in the prefrontal cortex (p<0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle-age.Hyperactive calcineurin signaling causes neuroinflammation and other neurobiological changes often associated with pathological aging and Alzheimer's disease (AD). Controlling the expression of calcineurin before gross cognitive deficits are observable might serve as a promising avenue for preventing AD pathology. In this study, we show that administration of the calcineurin inhibitor, tacrolimus, over one year prevents age and AD-associated microstructural changes in the hippocampus, parahippocampal cortex, and prefrontal cortex of the middle-aged beagle brain, with no noticeable adverse effects. Tacrolimus is already FDA-approved for use in humans to prevent solid organ transplant rejection, and our results bolster the promise of this drug to prevent AD and aging-related pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0361-21.2021DOI Listing
May 2021

Acute Severe Mitral Regurgitation Secondary to Ischemic Papillary Muscle Rupture: A Case Report.

Cureus 2021 Mar 19;13(3):e13996. Epub 2021 Mar 19.

Cardiology, Overlook Medical Center, Summit , USA.

Mitral valve rupture secondary to ischemic papillary muscle necrosis is rare in the contemporary era due to improved revascularization techniques. However, when it does occur, prompt diagnosis and urgent surgical intervention can be lifesaving. A 69-year-old male with morbid obesity, hypothyroidism, and a family history of coronary artery disease presented to the hospital with chest pain and dyspnea that began five hours prior. He had an acute infero-postero-lateral myocardial infarction due to total occlusion of the left circumflex artery that was revascularized with the deployment of a drug-eluting stent. Two days after the myocardial infarction, the patient had an episode of ventricular tachycardia. He subsequently went into respiratory distress from flash pulmonary edema and developed cardiogenic shock due to acute mitral valve rupture. The patient underwent surgical mitral valve replacement, extracorporeal membranous oxygenation (ECMO), and hemodialysis. His course was complicated by an acute lower gastrointestinal bleed that progressed into multiorgan failure and eventually his demise. This case highlights the need to include papillary muscle rupture high on the differential when evaluating a hemodynamically unstable patient in the setting of an acute myocardial infarction (MI). Rapid diagnosis by urgent bedside echocardiogram and surgical intervention is crucial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.13996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053317PMC
March 2021

Can electronic prescribing mandates reduce opioid-related overdoses?

Econ Hum Biol 2021 Apr 9;42:101000. Epub 2021 Apr 9.

RAND, United States. Electronic address:

As the opioid crisis has escalated, states have enacted numerous policies targeting opioid access and monitoring possible misuse. Recently, the majority of states have passed electronic prescribing mandates for controlled substances. These mandates require that controlled substances be prescribed electronically directly to the pharmacy. The electronic system maintains a rich patient history that prescribers will observe when issuing a prescription while also reducing opportunities for fraud. The first enforced mandate was implemented in New York in March 2016; thus empirical evidence about the effects of such mandates is limited. We study how adoption of the New York e-prescribing mandate affected opioid supply and opioid-related overdoses. We estimate that the mandate reduced the rate of overdoses involving natural and semi-synthetic opioids by 22 %. We find little evidence of any corresponding changes in overdose rates involving illicit opioids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ehb.2021.101000DOI Listing
April 2021

Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.

ACS Med Chem Lett 2021 Apr 7;12(4):540-547. Epub 2021 Mar 7.

MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.1c00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040053PMC
April 2021

Documenting nocturnal activity of dragon-headed katydids (Lesina blanchardi) under artificial light.

Zoo Biol 2021 Apr 8. Epub 2021 Apr 8.

Department of Reproductive and Behavioral Sciences, Saint Louis Zoo, St. Louis, Missouri, USA.

Across the genera of katydids from the family Tettigoniidae, both diurnal and nocturnal species have been identified. The Saint Louis Zoo Bayer Insectarium filmed dragon-headed katydids (Lesina blanchardi) overnight using red light-emitting diodes (LEDs) to examine the activity of this presumed nocturnal species to provide quantitative information about these insects that are otherwise immobile when keepers are present. Evidence from the literature suggests that LED bulbs emitting long-wavelength red and infrared lights are less likely to cause changes to the subjects' behavioral budgets and movements through the habitat. Three katydids were filmed for 5 nights, and time-interval scan sampling was used to record their positions and whether they were active every 15 min for two 2-h periods starting at midnight and noon. A modified Shannon's diversity index determined that katydids were recorded in more areas when under only red LEDs at night as compared to artificial daytime working lights. Similarly, repeated measures analysis of variance indicated that insects were significantly more active under nighttime red LEDs when compared to daytime working lights. While we cannot be sure if behaviors recorded under red LEDs are the same as those that would be performed under total darkness in situ, the use of red LED illumination ex situ to facilitate overnight filming did not suppress nocturnal movement or activity for our subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/zoo.21608DOI Listing
April 2021

The past, present and future of hormonal contraceptive use in managed captive female tiger populations with a focus on the current use of deslorelin acetate.

Zoo Biol 2021 Mar 16. Epub 2021 Mar 16.

Association of Zoos & Aquariums (AZA) Reproductive Management Center, Saint Louis Zoo, One Government Drive, Saint Louis, Missouri, United States.

Tigers (Panthera tigris spp.) are endangered in the wild; ensuring sustainable insurance populations requires careful planning within zoological collections. In captive situations, contraceptives are often used to control breeding and ensure genetically viable populations that contain manageable numbers of animals; reversible contraceptives are ideal because they offer flexibility for breeding management. Historically, synthetic progestins, such as melengestrol acetate implants, were used in female tigers, but these are associated with an increased risk of reproductive pathology and subsequent infertility. Recent management advice to ex-situ collections has been to transition to the use of gonadotropin-releasing hormone agonists, such as deslorelin acetate implants, which do not appear to have a similar risk of reproductive pathology but are associated with highly variable reversal times in exotic felids. Using data from 917 contraceptive records in female tigers captured by the Association of Zoos and Aquariums Reproductive Management Center and the European Association of Zoos and Aquaria Reproductive Management Group's joint Contraception Database and from supplementary surveys, this study reviews the changing use of contraceptives in captive female tigers. The aim was to describe the historical and current use of contraceptives and provide a comprehensive assessment on the use of deslorelin implants, including data on product protocols, efficacy, pathology, and reversibility. This study determined that current dose, frequency, reversibility, and anatomical placement sites of deslorelin implants are highly variable, indicating that specific, readily available, unified, evidence-based recommendations on the use of deslorelin would be useful for future contraceptive use in managed tiger populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/zoo.21601DOI Listing
March 2021

Disentangling Moral Hazard and Adverse Selection in Private Health Insurance.

J Econom 2021 May 7;222(1):141-160. Epub 2020 Aug 7.

University of Southern California, Leonard D. Schaeffer Center for Health Policy and Economics.

Moral hazard and adverse selection create inefficiencies in private health insurance markets and understanding the relative importance of each factor is critical for addressing these inefficiencies. We use claims data from a large firm which changed health insurance plan options to isolate moral hazard from plan selection, estimating a discrete choice model to predict household plan preferences and attrition. Variation in plan preferences identifies the differential causal impact of each health insurance plan on the entire distribution of medical expenditures. Our estimates imply that 53% of the additional medical spending observed in the most generous plan in our data relative to the least generous is due to adverse selection. We find that quantifying adverse selection by using prior medical expenditures overstates the true magnitude of selection due to mean reversion. We also statistically reject that individual health care consumption responds solely to the end-of-the-year marginal price.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jeconom.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945045PMC
May 2021

A New Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge.

Mar Drugs 2021 Feb 11;19(2). Epub 2021 Feb 11.

School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.

To tackle the growing problem of antibiotic resistance, it is essential to identify new bioactive compounds that are effective against resistant microbes and safe to use. Natural products and their derivatives are, and will continue to be, an important source of these molecules. Sea sponges harbour a diverse microbiome that co-exists with the sponge, and these bacterial communities produce a rich array of bioactive metabolites for protection and resource competition. For these reasons, the sponge microbiota constitutes a potential source of clinically relevant natural products. To date, efforts in bioprospecting for these compounds have focused predominantly on sponge specimens isolated from shallow water, with much still to be learned about samples from the deep sea. Here we report the isolation of a new strain, designated 28ISP2-46, recovered from the microbiome of a mid-Atlantic deep-sea sponge. Whole-genome sequencing reveals the capacity of this bacterium to produce a diverse array of natural products, including kosinostatin and isoquinocycline B, which exhibit both antibiotic and antitumour properties. Both compounds were isolated from 28ISP2-46 fermentation broths and were found to be effective against a plethora of multidrug-resistant clinical isolates. This study suggests that the marine production of isoquinocyclines may be more widespread than previously supposed and demonstrates the value of targeting the deep-sea sponge microbiome as a source of novel microbial life with exploitable biosynthetic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md19020105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918784PMC
February 2021

Patients with Proliferative Lupus Nephritis Have Autoantibodies That React to Moesin and Demonstrate Increased Glomerular Moesin Expression.

J Clin Med 2021 Feb 16;10(4). Epub 2021 Feb 16.

Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.

Kidney involvement in systemic lupus erythematosus (SLE)-termed lupus nephritis (LN)-is a severe manifestation of SLE that can lead to end-stage kidney disease (ESKD). LN is characterized by immune complex deposition and inflammation in the glomerulus. We tested the hypothesis that autoantibodies targeting podocyte and glomerular cell proteins contribute to the development of immune complex formation in LN. We used Western blotting with SLE sera from patients with and without LN to identify target antigens in human glomerular and cultured human-derived podocyte membrane proteins. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified the proteins in the gel regions corresponding to reactive bands observed with sera from LN patients. We identified 102 proteins that were present in both the podocyte and glomerular samples. We identified 10 high-probability candidates, including moesin, using bioinformatic analysis. Confirmation of moesin as a target antigen was conducted using immunohistochemical analysis (IHC) of kidney biopsy tissue and enzyme-linked immunosorbent assay (ELISA) to detect circulating antibodies. By IHC, biopsies from patients with proliferative lupus nephritis (PLN, class III/IV) demonstrated significantly increased glomerular expression of moesin ( < 0.01). By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against moesin ( < 0.01). This suggests that moesin is a target glomerular antigen in lupus nephritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10040793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920286PMC
February 2021

Behavioral and Hemodynamic Changes Following Dichotic Training in Patients with Neurological Deficits of the Auditory Nervous System: A Case Series.

J Am Acad Audiol 2021 Jan 4;32(1):45-53. Epub 2021 Mar 4.

Department of Otolaryngology - Head and Neck Surgery, University of Kentucky, Lexington, Kentucky.

Background:  Dichotic listening occurs when one attends to different acoustical messages presented simultaneously to both ears. This is important for understanding speech in compromised listening situations, such as background noise. Deficits in dichotic listening can be remediated by participating in auditory training. We present two patients with binaural integration deficits who underwent dichotic interaural intensity difference (DIID) training.

Purpose:  The purpose of this investigation is to demonstrate improvement of dichotic listening deficits following DIID training in neurological patients seen clinically for hearing issues.

Research Design:  This was a case series utilizing a pre- and posttreatment design.

Study Sample:  This case series utilized two female participants who demonstrated binaural integration deficits during an auditory processing evaluation.

Intervention:  The participants underwent a pretraining auditory processing evaluation and functional magnetic resonance imaging (fMRI). Participants then underwent 12, 30-minute DIID training sessions followed by posttreatment auditory processing evaluations and fMRI.

Data Collection And Analysis:  Data was collected at the pretreatment appointment and then immediately following the completion of the training.

Results:  Each patient demonstrated varying degrees of improvement on the posttreatment assessment. Case 1 showed significant improvement on the Speech-in-Noise-Revised (SPIN-R) test. fMRI showed changes in activation patterns following training. Case 2 demonstrated improved scores on the Dichotic Digits Test and SPIN-R and increased activation of the calcarine sulcus following training.

Conclusion:  Dichotic training can be an efficacious treatment for binaural integration deficits and may show evidence of improving speech understanding in noise. This case series demonstrates a promising therapy to help patients improve auditory function by improving dichotic listening skills.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1719095DOI Listing
January 2021

Individual and Community Factors Associated with Naloxone Co-prescribing Among Long-term Opioid Patients: a Retrospective Analysis.

J Gen Intern Med 2021 Feb 17. Epub 2021 Feb 17.

RAND Corporation, Pittsburgh, PA, USA.

Background: Naloxone co-prescribing to individuals at increased opioid overdose risk is a key component of opioid overdose prevention efforts.

Objective: Examine naloxone co-prescribing in the general population and assess how co-prescribing varies by individual and community characteristics.

Design: Retrospective cross-sectional study. We conducted a multivariable logistic regression of 2017-2018 de-identified pharmacy claims representing 90% of all prescriptions filled at retail pharmacies in 50 states and the District of Columbia.

Patients: Individuals with opioid analgesic treatment episodes > 90 days MAIN MEASURES: Outcome was co-prescribed naloxone. Predictor variables included insurance type, primary prescriber specialty, receipt of concomitant benzodiazepines, high-dose opioid episode, county urbanicity, fatal overdose rates, poverty rates, and primary care health professional shortage areas.

Key Results: Naloxone co-prescribing occurred in 2.3% of long-term opioid therapy episodes. Medicaid (aOR 1.87, 95%CI 1.84 to 1.90) and Medicare (aOR 1.48, 95%CI 1.46 to 1.51) episodes had higher odds of naloxone co-prescribing than commercial insurance episodes, while cash pay (aOR 0.77, 95%CI 0.74 to 0.80) and other insurance episodes (aOR 0.81, 95%CI 0.79 to 0.83) had lower odds. Odds of naloxone co-prescribing were higher among high-dose opioid episodes (aOR 3.19, 95%CI 3.15 to 3.23), when concomitant benzodiazepines were prescribed (aOR 1.12, 95%CI 1.10 to 1.14), and in counties with higher fatal overdose rates.

Conclusion: Co-prescription of naloxone represents a tangible clinical action that can be taken to help prevent opioid overdose deaths. However, despite recommendations to co-prescribe naloxone to patients at increased risk for opioid overdose, we found that co-prescribing rates remain low overall. States, insurers, and health systems should consider implementing strategies to facilitate increased co-prescribing of naloxone to at-risk individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11606-020-06577-5DOI Listing
February 2021

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy.

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Department of Neuroscience & Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32669, USA.

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865413PMC
January 2021

Is the rise in illicit opioids affecting labor supply and disability claiming rates?

J Health Econ 2021 Mar 22;76:102430. Epub 2021 Jan 22.

RAND, 1200 S. Hayes St., Arlington, VA, 22202, United States. Electronic address:

This paper examines how the recent transition of the opioid crisis from prescription opioids to more prevalent misuse of illicit opioids, such as heroin and fentanyl, altered labor supply behavior and disability insurance claiming rates. We exploit differential geographic exposure to the reformulation of OxyContin, the largest reduction in access to abusable prescription opioids to date, to study the effects of substitution to illicit markets. We observe meaningful reductions in labor supply measured in terms of employment-to-population ratios, hours worked, and earnings in states more exposed to reformulation relative to those less exposed. We also find evidence of increases in disability applications and beneficiaries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhealeco.2021.102430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965359PMC
March 2021

CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies.

Genome Biol 2021 Jan 26;22(1):47. Epub 2021 Jan 26.

Cancer Research Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.

Introduction: Genes contain multiple promoters that can drive the expression of various transcript isoforms. Although transcript isoforms from the same gene could have diverse and non-overlapping functions, current loss-of-function methodologies are not able to differentiate between isoform-specific phenotypes.

Results: Here, we show that CRISPR interference (CRISPRi) can be adopted for targeting specific promoters within a gene, enabling isoform-specific loss-of-function genetic screens. We use this strategy to test functional dependencies of 820 transcript isoforms that are gained in gastric cancer (GC). We identify a subset of GC-gained transcript isoform dependencies, and of these, we validate CIT kinase as a novel GC dependency. We further show that some genes express isoforms with opposite functions. Specifically, we find that the tumour suppressor ZFHX3 expresses an isoform that has a paradoxical oncogenic role that correlates with poor patient outcome.

Conclusions: Our work finds isoform-specific phenotypes that would not be identified using current loss-of-function approaches that are not designed to target specific transcript isoforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-021-02266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836456PMC
January 2021

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen.

ACS Med Chem Lett 2021 Jan 23;12(1):99-106. Epub 2020 Dec 23.

MRL, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.

By employing a phenotypic screen, a set of compounds, exemplified by , were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812668PMC
January 2021

HEMATOLOGY, PLASMA BIOCHEMISTRY, AND PLASMA PROTEIN ELECTROPHORESIS REFERENCE INTERVALS FOR BLUE IGUANAS () FROM GRAND CAYMAN ISLAND.

J Zoo Wildl Med 2021 Jan;51(4):933-947

Wildlife Conservation Society, Zoological Health Program, Bronx, NY 10460, USA.

The blue iguana () is an endangered rock iguana species native to Grand Cayman, in the Cayman Islands. Health assessments were conducted on captive and free-roaming iguanas in 2001 and 2003-2014 and were performed in the summer wet season (June-July) of 2003-2004 and 2010-2014 and in the winter dry season (November-December) of 2001 and 2005-2009. Morphometric data were recorded from iguanas when blood samples were collected: 903 samples were collected and data from 890 samples from 775 iguanas were included. Samples were analyzed for hematology, plasma biochemistry, protein electrophoresis, mineral panels, 25-hydroxyvitamin D, and testosterone. Reference intervals were created for captive subadults, captive adults, and free-roaming adults when data were sufficient. Significant differences among these groups were described, as were differences on the basis of sex, season, and origin (captive vs free-roaming). In captive iguanas, most analytes were significantly different between subadults and adults, mature heterophils and copper were significantly higher in the dry season, zinc levels were significantly higher in the wet season, and cholesterol and triglycerides were significantly higher in adult females than adult males. Testosterone in adult males was significantly higher in the dry season. These results will aid in future health assessments and disease investigations in wild and captive populations of blue iguanas and are of comparative value for other species that are free-roaming, captive, and, especially, in similar conservation release programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1638/2020-0094DOI Listing
January 2021

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF.

Cardiovasc Diabetol 2021 Jan 7;20(1). Epub 2021 Jan 7.

Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.

Background: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.

Methods: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca release were recorded by ratiometric microscopy using Ca-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable.

Results: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca accumulation upon glycolytic inhibition.

Conclusion: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca buffer capacity, diastolic Ca accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-020-01208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792219PMC
January 2021

Melengestrol acetate contraceptive implant use in colobus monkeys (Colobus guereza): Patterns through time and differences in reproductive potential and live births.

Zoo Biol 2021 Mar 25;40(2):124-134. Epub 2020 Nov 25.

Reproductive Management Center at the Saint Louis Zoo, St. Louis, Missouri, USA.

Melengestrol acetate (MGA) implants are progestin-based reversible contraceptives used to manage fertility in zoo populations. Although it is recommended that MGA implants should be replaced every 2 years, the duration of efficacy has not been systematically evaluated in most species. Anecdotal reports for Old World monkeys indicate that reproduction may be suppressed longer if the implant is not removed. This study uses Guereza colobus monkey (Colobus guereza) as a model Old World monkey species to examine the effects of MGA implants on reproductive potential. In particular, we investigate whether the probability of reproducing (pR) and rates of stillbirth differ among (1) non-implanted females, (2) females who have had MGA implants removed, and (3) females whose implants were left in past expiration. We found no significant difference in pR between non-implanted and implant-removed groups, but when implants were left in past expiration, the pR was significantly lower than in other groups. Both parity and age significantly impacted pR for the non-implanted group (i.e., younger females and those who were parous increased pR), but neither were significant factors for the implant-removed group. Stillbirth rates were significantly higher post-contraception as compared with pre-contraception. These results support similar analyses in other taxa that show a shorter time to reversal after MGA contraception when implants are removed, making this a good contraceptive option for females likely to receive a breeding recommendation, especially when a more predictable time to reversal is important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/zoo.21581DOI Listing
March 2021

's political stance-where is the balance?

Authors:
David E B Powell

BMJ 2020 11 18;371:m4391. Epub 2020 Nov 18.

Peniel SA32 7HF, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m4391DOI Listing
November 2020

High-density transposon libraries utilising outward-oriented promoters identify mechanisms of action and resistance to antimicrobials.

FEMS Microbiol Lett 2020 Dec;367(22)

Summit Therapeutics plc, The Merrifield Centre, 12 Rosemary Lane, Cambridge, CB1 3LQ, UK.

The use of bacterial transposon mutant libraries in phenotypic screens is a well-established technique for determining which genes are essential or advantageous for growth in conditions of interest. Standard, inactivating, transposon libraries cannot give direct information about genes whose over-expression gives a selective advantage. We report the development of a system wherein outward-oriented promoters are included in mini-transposons, generation of transposon mutant libraries in Escherichia coli and Pseudomonas aeruginosa and their use to probe genes important for growth under selection with the antimicrobial fosfomycin, and a recently-developed leucyl-tRNA synthase inhibitor. In addition to the identification of known mechanisms of action and resistance, we identify the carbon-phosphorous lyase complex as a potential resistance liability for fosfomycin in E. coli and P. aeruginosa. The use of this technology can facilitate the development of novel mechanism-of-action antimicrobials that are urgently required to combat the increasing threat worldwide from antimicrobial-resistant pathogenic bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/femsle/fnaa185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735965PMC
December 2020

/ABIN1 and lupus nephritis: review.

Lupus Sci Med 2020 10;7(1)

Department of Medicine, University of Louisville, Louisville, Kentucky, USA

SLE is a complex autoimmune disease with genetic, epigenetic, immune-regulatory, environmental and hormonal factors. Kidney inflammation and injury, termed lupus nephritis (LN), occurs in over half of patients with SLE and is a leading cause of disability and death. There is a high degree of short-term and long-term side effects associated with current LN therapies and they are not effective for many patients. Thus, novel therapies with reduced toxicity and improved efficacy are drastically needed. Many of the known LN susceptibility genes have functions that mediate inflammation via cytokine/chemokine production and activation of myeloid and B cells. Understanding the cellular and molecular mechanisms mediated by these variant gene products provides valuable insight for the development of improved and personalised diagnostics and therapeutics. This review describes variants in the TNIP1 (tumour necrosis factor α-induced protein 3-interacting protein 1) gene associated with risks for SLE and LN and potential roles for loss of function of its protein product ABIN1 in the activation of myeloid and B-cell-mediated injury in LN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/lupus-2020-000437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597513PMC
October 2020

Risk of COVID-19 During Air Travel.

JAMA 2020 11;324(17):1798

International Air Transport Association (IATA), Geneva, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.19108DOI Listing
November 2020

The Right Child/Right Surgeon initiative: A position statement on pediatric surgical training, sub-specialization, and continuous certification from the American Pediatric Surgical Association.

J Pediatr Surg 2020 Dec 13;55(12):2566-2574. Epub 2020 Aug 13.

Department of Surgery, School of Medicine, Jefferson University, Philadelphia, PA.

The past 50 years have witnessed profound changes in the specialty of pediatric surgery in North America. There has been a marked increase in the number of both pediatric surgical training programs and practicing pediatric general and thoracic surgeons. Despite this trend, the population of children in the United States and the birth rate have recently remained relatively flat. Some pediatric surgeons have become "super specialists", concentrating their practices in oncology or colorectal surgery. This has the potential to result in a dilution of experience for both pediatric surgical trainees and practicing pediatric surgeons, thus limiting their ability to acquire and maintain expertise, respectively. Coincident with this, there has been a relative paradigm shift in recognition that "quality of life" is based more on maintaining a creative balance in lifestyle and is not "all about work". There has been a parallel growth in the number of practicing pediatric general and thoracic surgeons in urban settings, but we have not appreciated as much growth in rural and underserved areas, where access to pediatric surgical care remains limited and fewer pediatric general and thoracic surgeons practice. This is a complex issue, as some underserved areas are economically depressed and geographically sparse, but others are just underserved with adult providers taking care of children in settings that are often under resourced for pediatric surgical care. This problem may extend beyond the boundaries of pediatric general and thoracic surgery to other specialties. As the premier association representing all pediatric surgeons in the United States, the American Pediatric Surgical Association (APSA) has concluded that the quality of pediatric surgical care will likely decline should the status quo be allowed to continue. Therefore, APSA has initiated a Right Child/Right Surgeon initiative to consider these issues and propose some potential solutions. What follows is a brief statement of intent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423589PMC
December 2020

Reprogramming roadmap reveals route to human induced trophoblast stem cells.

Nature 2020 10 16;586(7827):101-107. Epub 2020 Sep 16.

Monash Bioinformatics Platform, Monash University, Melbourne, Victoria, Australia.

The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2734-6DOI Listing
October 2020

Cardiorespiratory fitness diminishes the effects of age on white matter hyperintensity volume.

PLoS One 2020 31;15(8):e0236986. Epub 2020 Aug 31.

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States of America.

White matter hyperintensities (WMHs) are among the most commonly observed marker of cerebrovascular disease. Age is a key risk factor for WMH development. Cardiorespiratory fitness (CRF) is associated with increased vessel compliance, but it remains unknown if high CRF affects WMH volume. This study explored the effects of CRF on WMH volume in community-dwelling older adults. We further tested the possibility of an interaction between CRF and age on WMH volume. Participants were 76 adults between the ages of 59 and 77 (mean age = 65.36 years, SD = 3.92) who underwent a maximal graded exercise test and structural brain imaging. Results indicated that age was a predictor of WMH volume (beta = .32, p = .015). However, an age-by-CRF interaction was observed such that higher CRF was associated with lower WMH volume in older participants (beta = -.25, p = .040). Our findings suggest that higher levels of aerobic fitness may protect cerebrovascular health in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458283PMC
October 2020

Cortical iron disrupts functional connectivity networks supporting working memory performance in older adults.

Neuroimage 2020 12 27;223:117309. Epub 2020 Aug 27.

Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY 40536-0298 USA; Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536-0298 USA; Magnetic Resonance Imaging and Spectroscopy Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0298 USA. Electronic address:

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2020.117309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821351PMC
December 2020

Obesity of Knockout Mice Suggests That Obesity-Associated Variants Near Human Decrease G2E3 Activity.

Diabetes Metab Syndr Obes 2020 27;13:2641-2652. Epub 2020 Jul 27.

Lexicon Pharmaceuticals Inc, The Woodlands, TX, 77381, USA.

Purpose: In humans, single nucleotide polymorphisms (SNPs) near the adjacent protein kinase D1 () and G2/M-phase-specific E3 ubiquitin protein ligase () genes on chromosome 14 are associated with obesity. To date, no published evidence links inactivation of either gene to changes in body fat. These two genes are also adjacent on mouse chromosome 12. Because obesity genes are highly conserved between humans and mice, we analyzed body fat in adult and knockout (KO) mice to determine whether inactivating either gene leads to obesity in mice and, by inference, probably in humans.

Methods: The and KO lines were generated by gene trapping and by homologous recombination methodologies, respectively. Body fat was measured by DEXA in adult mice fed chow from weaning and by QMR in a separate cohort of mice fed high-fat diet (HFD) from weaning. Glucose homeostasis was evaluated with oral glucose tolerance tests (OGTTs) performed on adult mice fed HFD from weaning.

Results: Body fat was increased in multiple cohorts of KO mice relative to their wild-type (WT) littermates. When data from all KO (n=32) and WT (n=31) mice were compared, KO mice showed increases of 11% in body weight (<0.01), 65% in body fat (<0.001), 48% in % body fat (<0.001), and an insignificant 3% decrease in lean body mass. KO mice were also glucose intolerant during an OGTT (<0.05). In contrast, KO and WT mice had comparable body fat levels and glucose tolerance.

Conclusion: Significant obesity and glucose intolerance were observed in , but not , KO mice. The conservation of obesity genes between mice and humans strongly suggests that the obesity-associated SNPs located near the human and genes are linked to variants that decrease the amount of functional human G2E3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DMSO.S259546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394505PMC
July 2020

Chinchilla (Chinchilla lanigera) behavioral responses to a visual signal preceding handling.

Zoo Biol 2020 Nov 5;39(6):391-396. Epub 2020 Aug 5.

Department of Reproductive and Behavioral Sciences, Saint Louis Zoo, St. Louis, Missouri.

Zoos use ambassador animals in educational programs featuring close contact with humans. Chinchillas (Chinchilla lanigera) at the Saint Louis Zoo are retrieved for programs by a keeper wearing brown handling gloves, but green cleaning gloves are worn during normal husbandry when physical contact with the animal is only incidental. The chinchillas' primary keeper anecdotally reported more reactivity and movement from chinchillas when approached with handling gloves. Animals' behavioral reactions to the presence of humans often include locomotion and vigilance, but these responses may be attenuated by predictability. To investigate these behaviors, handling trials involving brief contact attempts with both cleaning and handling gloves were filmed. Results indicated that chinchillas responded to disturbances by moving, jumping, and adopting more alert body postures. Surprisingly, movement was recorded in longer durations when the keeper attempted to touch the animals with cleaning gloves. This higher arousal may indicate that the animal was not expecting to be handled, yet an attempt to do so was being made. This reaction provides evidence that potentially aversive events should be reliably and consistently signaled.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/zoo.21564DOI Listing
November 2020