Publications by authors named "Jonathan Warren"

30 Publications

  • Page 1 of 1

The Role of the Prefrontal Cortex and Functional Connectivity during Maritime Operations: An fNIRS study.

Brain Behav 2021 Jan 4;11(1):e01910. Epub 2020 Nov 4.

School of Psychology, Liverpool John Moores University, Liverpool, UK.

Introduction: Watchkeeping is a significant activity during maritime operations, and failures of sustained attention and decision-making can increase the likelihood of a collision.

Methods: A study was conducted in a ship bridge simulator where 40 participants (20 experienced/20 inexperienced) performed: (1) a 20-min period of sustained attention to locate a target vessel and (2) a 10-min period of decision-making/action selection to perform an evasive maneuver. Half of the participants also performed an additional task of verbally reporting the position of their vessel. Activation of the prefrontal cortex (PFC) was captured via a 15-channel functional near-infrared spectroscopy (fNIRS) montage, and measures of functional connectivity were calculated frontal using graph-theoretic measures.

Results: Neurovascular activation of right lateral area of the PFC decreased during sustained attention and increased during decision-making. The graph-theoretic analysis revealed that density declined during decision-making in comparison with the previous period of sustained attention, while local clustering declined during sustained attention and increased when participants prepared their evasive maneuver. A regression analysis revealed an association between network measures and behavioral outcomes, with respect to spotting the target vessel and making an evasive maneuver.

Conclusions: The right lateral area of the PFC is sensitive to watchkeeping and decision-making during operational performance. Graph-theoretic measures allow us to quantify patterns of functional connectivity and were predictive of safety-critical performance.
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http://dx.doi.org/10.1002/brb3.1910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821565PMC
January 2021

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.

Int J Obes (Lond) 2020 12 9;44(12):2419-2429. Epub 2020 Oct 9.

Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.

Background: Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection.

Methods: Mice were fed normal chow or high-fat diet for 18-19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection.

Results: We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8 T cells. Activated CD4 T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4 T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity.

Conclusions: T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.
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http://dx.doi.org/10.1038/s41366-020-00692-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686301PMC
December 2020

Hypoxia Inducible Factor-1α (HIF-1α) Mediates NLRP3 Inflammasome-Dependent-Pyroptotic and Apoptotic Cell Death Following Ischemic Stroke.

Neuroscience 2020 11 22;448:126-139. Epub 2020 Sep 22.

Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Research & Development Center, John D. Dingell VA Medical Center, Detroit, MI, USA. Electronic address:

Stroke is a major cause of death and long-term disability. Recent evidence suggests that hypoxia-inducible factor 1α (HIF-1α), a transcription factor that regulates oxygen levels, plays a key role in neurological outcomes after ischemic stroke. Accordingly, we investigated the mechanism of HIF-1α on pyroptotic and apoptotic cells during ischemia/reperfusion (I/R). Adult Sprague-Dawley rats underwent 2 h of middle cerebral artery occlusion (MCAO). The rats were then exposed to 6 or 24 h of reperfusion, with or without YC-1 (HIF-1α inhibitor, 5 mg/kg). Infarct volumes, along with mRNA and protein quantities of HIF-1α, NLRP3, IL-1β, IL-18, Caspase-1, and co-localization of HIF-1α, and NLRP3, were assessed. We measured apoptotic and pyroptotic cell death, gasdermin D (GSDMD) activation and lactate dehydrogenase (LDH) activity, and the infiltration of neutrophils and macrophages after ischemic stroke. HIF-1α mRNA and NLRP3 inflammasome components were increased after 24 h of reperfusion. YC-1 significantly reduced the mRNA and protein expression of NLRP3, IL-1β, IL-18, and caspase-1; significantly decreased infarction and pyroptotic cell death after 24 h of reperfusion; attenuated the neuroinflammatory response by reducing infiltration of CD68- and MPO-positive cells after 24 h of reperfusion; and reduced apoptotic cell death following ischemic stroke. We found that HIF-1α likely regulates inflammatory responses through the NLRP3 inflammasome complex, thus influencing both apoptotic and pyroptotic cell death after stroke. These findings suggest that future investigations are needed regarding HIF-1α and its role as a potential molecular target in the treatment of acute ischemic stroke.
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http://dx.doi.org/10.1016/j.neuroscience.2020.09.036DOI Listing
November 2020

PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.

Adv Sci (Weinh) 2020 Mar 23;7(5):1900860. Epub 2020 Jan 23.

Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center Durham NC 27710 USA.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers and parkin RBR E3 ubiquitin protein ligase ( in CD138 plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide--chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform () transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.
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http://dx.doi.org/10.1002/advs.201900860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055555PMC
March 2020

What's in a Name? Evaluating the Public Stigma of Gambling Disorder.

J Gambl Stud 2020 Dec;36(4):1205-1228

Department of Psychology, University of Calgary, Calgary, AB, Canada.

Public stigma of gambling disorder has negative effects on the mental health and functioning of affected individuals and impedes treatment-seeking. One factor thought to be implicated in stigma is the label used to describe the condition. The aims of this research were to: (1) evaluate whether different labels for problematic gambling behavior influence public stigma; and (2) compare public stigma of gambling disorder to other health conditions. Separate samples of university student (Study 1) and general population (Study 2) participants were randomly assigned to label conditions and completed questionnaires assessing stigma and attitudes towards the assigned label. In Study 1, the eight conditions included four gambling labels (problem gambling, pathological gambling, gambling disorder, and gambling addiction) and four psychiatric or health comparison labels (depression, obsessive-compulsive disorder, alcohol use disorder, and asthma). In Study 2, compulsive buying disorder was added as a fifth psychiatric comparison for a total of nine conditions. The results indicated that the four gambling label conditions elicited similar attitudes and stigma. Those conditions were also more stigmatized than the depression, obsessive-compulsive disorder, and asthma conditions. The gambling conditions elicited similar stigmatizing attitudes as alcohol use disorder but were slightly more stigmatized than compulsive buying disorder, with these conditions showing both similarities and differences across the stigma-related outcomes. The results were largely consistent across both samples and contribute to knowledge of the nature and origins of gambling-related stigma.
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http://dx.doi.org/10.1007/s10899-019-09924-2DOI Listing
December 2020

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.

Nat Immunol 2020 01 16;21(1):86-100. Epub 2019 Dec 16.

Wellcome Sanger Institute, Hinxton, UK.

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation (http://www.immunophenotype.org). Specifically, high-throughput phenotyping of 530 unique mouse gene knockouts identified 140 monogenic 'hits', of which most had no previous immunologic association. Furthermore, hits were collectively enriched in genes for which humans show poor tolerance to loss of function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with each other and with specific physiologic traits. Such linkages limit freedom of movement for individual immune parameters, thereby imposing genetically regulated 'immunologic structures', the integrity of which was associated with immunocompetence. Hence, we provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.
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http://dx.doi.org/10.1038/s41590-019-0549-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338221PMC
January 2020

Clinical effects from household insecticide: pyrethroid or organophosphate toxicity?

BMJ Case Rep 2019 Nov 21;12(11). Epub 2019 Nov 21.

David Geffen School of Medicine, Los Angeles, California, USA.

A 54-year-old man with a history of schizophrenia presented to the emergency room for weakness with associated lacrimosis, drooling, nausea, emesis, diarrhoea, diplopia and burning sensation on his skin that began 6 hours after spraying five cans of Raid on his carpet. He was noted to have miotic pupils and hyperactive bowel sounds. Given the clinical presentation, the patient was diagnosed with organophosphate (OP) toxicity. After being admitted, he developed symptoms associated with his OP toxicity and was successfully treated with atropine and pralidoxime. Most Raid products contain pyrethroids; however, both OPs and pyrethroids are available in commercial pesticides and patients may misidentify ingestions. There are limited data reporting the toxicity of pyrethroid overdose in humans and to guide its subsequent treatment. It is crucial to keep a low threshold for diagnosing and treating patients with acute onset of symptoms suspicious for an OP or pyrethroid toxidrome.
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http://dx.doi.org/10.1136/bcr-2019-230966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887475PMC
November 2019

Exercise Effects on Mitochondrial Function and Lipid Metabolism during Energy Balance.

Med Sci Sports Exerc 2020 04;52(4):827-834

Department of Human Studies, University of Alabama at Birmingham, Birmingham, AL.

Introduction/purpose: Aerobic exercise training (AET) has been shown to improve mitochondrial bioenergetics and upregulate proteins related to lipid metabolism. However, it remains to be determined if these alterations associated with AET persist when measured in energy balance (EB) in the days after the last bout of training. The purpose of the study was to test the hypothesis that improvements in skeletal muscle mitochondrial function induced by AET observed in previous literature would persist when measured after restoring EB conditions 72 h removed from the last exercise bout.

Methods: Participants were 14 premenopausal women (age = 31.2 ± 6.7 yr, BMI = 26.6 ± 5.1 kg·m). The AET program required three monitored training sessions per week for 8-16 wk. Skeletal muscle biopsies were obtained at baseline and after 8-16 wk of AET (≥72 h after the last exercise bout). All food was provided for 72 h before biopsies, and EB was managed 24 h before testing within ±100 kcal of measured energy requirements using a whole-room calorimeter. Mitochondrial oxidative capacity was quantified in permeabilized muscle fibers from the vastus lateralis.

Results: We found that AET increased coupled respiration (154%) and uncoupled respiration (90%) rates using a fatty acid substrate (palmitoyl carnitine) (P < 0.05). However, when rates were normalized to complex IV activity (a marker of mitochondrial content), no significant differences were observed. In addition, there were no changes in proteins known to mediate mitochondrial biogenesis or lipid transport and metabolism after AET.

Conclusion: Eight to 16 wk of AET improved mitochondrial capacity under fatty acid substrate when assessed in EB, which appears to be due to mitochondrial biogenesis.
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http://dx.doi.org/10.1249/MSS.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117801PMC
April 2020

Narrowed pulse pressure predicts massive transfusion and emergent operative intervention following penetrating trauma.

Am J Surg 2019 12 10;218(6):1185-1188. Epub 2019 Sep 10.

Division of Trauma/Acute Care Surgery/Surgical Critical Care, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA, 90509, United States; Los Angeles BioMedical Research Institute, 1124 W. Carson St, Torrance, CA, 90502, United States. Electronic address:

Introduction: The early identification of hemorrhagic shock may be challenging. The objective of this study was to examine the utility of a narrowed pulse pressure in identifying the need for emergent interventions following penetrating trauma.

Methods: In this 2.5-year retrospective study of adult patients with a penetrating mechanism, patients with a narrowed pulse pressure (<30 mmHg) were compared to those without. Main outcomes measures were the need for a massive transfusion or emergent operation.

Results: There were 957 patients, of which the majority were male (86%) and 55% presented with gunshot wounds. On multivariate analysis, a narrowed pulse pressure was associated with the need for massive transfusion (OR 3.74, 95% C.I. 1.8-7.7, p = 0.0003) and emergent surgery (OR 1.68, 95% C.I. 1.14-2.48, p = 0.009).

Conclusions: A narrowed pulse pressure is associated with the presence of hemorrhagic shock and need for emergent interventions among patients with penetrating torso trauma.
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http://dx.doi.org/10.1016/j.amjsurg.2019.08.022DOI Listing
December 2019

Regulation of Adaptive Immune Cells by Sirtuins.

Front Endocrinol (Lausanne) 2019 11;10:466. Epub 2019 Jul 11.

Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States.

It is now well-established that the pathways that control lymphocyte metabolism and function are intimately linked, and changes in lymphocyte metabolism can influence and direct cellular function. Interestingly, a number of recent advances indicate that lymphocyte identity and metabolism is partially controlled via epigenetic regulation. Epigenetic mechanisms, such as changes in DNA methylation or histone acetylation, have been found to alter immune function and play a role in numerous chronic disease states. There are several enzymes that can mediate epigenetic changes; of particular interest are sirtuins, protein deacetylases that mediate adaptive responses to a variety of stresses (including calorie restriction and metabolic stress) and are now understood to play a significant role in immunity. This review will focus on recent advances in the understanding of how sirtuins affect the adaptive immune system. These pathways are of significant interest as therapeutic targets for the treatment of autoimmunity, cancer, and transplant tolerance.
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http://dx.doi.org/10.3389/fendo.2019.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637536PMC
July 2019

Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.

FASEB J 2019 02 10;33(2):2409-2421. Epub 2018 Oct 10.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The dietary R-3-hydroxybutyrate- R-1,3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1,3-butanediol diacetoacetate (BD-AcAc), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high-fat diet (HFD)-induced obesity. Thirty-five-week-old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups ( n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+30% energy from BD-AcAc. Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs. 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs. 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat-mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein-1, deiodinase-2, and peroxisome proliferator-activated receptor γ coactivator-1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD-AcAc initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD-induced obesity.-Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.
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http://dx.doi.org/10.1096/fj.201800821RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338649PMC
February 2019

Associations of Mitochondrial Fatty Acid Oxidation with Body Fat in Premenopausal Women.

J Nutr Metab 2017 24;2017:7832057. Epub 2017 Oct 24.

Department of Human Studies, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.

Higher fatty acid (FA) oxidation rates have been reported in obese individuals compared to lean counterparts; however whether this reflects a shift in substrate-specific oxidative capacity at the level of the skeletal muscle mitochondria has not been examined. The purpose of this study was to test the hypothesis that in situ measures of skeletal muscle mitochondria FA oxidation would be positively associated with total body fat. Participants were 38 premenopausal women (BMI = 26.5 ± 4.3 kg/m). Total and regional fat were assessed by dual-energy X-ray absorptiometry (DXA). Mitochondrial FA oxidation was assessed in permeabilized myofibers using high-resolution respirometry and a palmitoyl carnitine substrate. We found positive associations of total fat mass with State 3 (ADP-stimulated respiration) ( = 0.379, < 0.05) and the respiratory control ratio (RCR, measure of mitochondrial coupling) ( = 0.348, < 0.05). When participants were dichotomized by high or low body fat percent, participants with high total body fat displayed a higher RCR compared to those with low body fat ( < 0.05). There were no associations between any measure of regional fat and mitochondrial FA oxidation independent of total fat mass. In conclusion, greater FA oxidation in obesity may reflect molecular processes that enhance FA oxidation capacity at the mitochondrial level.
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http://dx.doi.org/10.1155/2017/7832057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674507PMC
October 2017

Effects of acute hyperinsulinemia on skeletal muscle mitochondrial function, reactive oxygen species production, and metabolism in premenopausal women.

Metabolism 2017 12 24;77:1-12. Epub 2017 Aug 24.

Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Department of Human Studies, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA. Electronic address:

Background: Acute metabolic demands that promote excessive and/or prolonged reactive oxygen species production may stimulate changes in mitochondrial oxidative capacity.

Purpose: To assess changes in skeletal muscle HO production, mitochondrial function, and expression of genes at the mRNA and protein levels regulating energy metabolism and mitochondrial dynamics following a hyperinsulinemic-euglycemic clamp in a cohort of 11 healthy premenopausal women.

Methods: Skeletal muscle biopsies of the vastus lateralis were taken at baseline and immediately following the conclusion of a hyperinsulinemic-euglycemic clamp. Mitochondrial production of HO was quantified fluorometrically and mitochondrial oxidation supported by pyruvate, malate, and succinate (PMS) or palmitoyl carnitine and malate (PCM) was measured by high-resolution respirometry in permeabilized muscle fiber bundles. mRNA and protein levels were assessed by real time PCR and Western blotting.

Results: HO emission increased following the clamp (P<0.05). Coupled respiration (State 3) supported by PMS and the respiratory control ratio (index of mitochondrial coupling) for both PMS and PCM were lower following the clamp (P<0.05). IRS1 mRNA decreased, whereas PGC1α and GLUT4 mRNA increased following the clamp (P≤0.05). PGC1α, IRS1, and phosphorylated AKT protein levels were higher after the clamp compared to baseline (P<0.05).

Conclusions: This study demonstrated that acute hyperinsulinemia induced HO production and a concurrent decrease in coupling of mitochondrial respiration with ATP production in a cohort of healthy premenopausal women. Future studies should determine if this uncoupling ameliorates peripheral oxidative damage, and if this mechanism is impaired in diseases associated with chronic oxidative stress.
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http://dx.doi.org/10.1016/j.metabol.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726454PMC
December 2017

Reduction of Syndecan Transcript Levels in the Insulin-Producing Cells Affects Glucose Homeostasis in Adult Drosophila melanogaster.

DNA Cell Biol 2017 Nov 25;36(11):959-965. Epub 2017 Sep 25.

1 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham, Alabama.

Signaling by direct cell-matrix interactions has been shown to impact the transcription, secretion, and storage of insulin in mammalian β cells. However, more research is still needed in this area. Syndecans are transmembrane heparan sulfate proteoglycans that function independently and in synergy with integrin-mediated signaling to mediate cell adhesion to the extracellular matrix. In this study, we used the model organism Drosophila melanogaster to determine whether knockdown of the Syndecan (Sdc) gene expression specifically in the insulin-producing cells (IPCs) might affect insulin-like peptide (ILP) production and secretion. IPCs of adult flies produce three ILPs (ILP2, ILP3, and ILP5), which have significant homology to mammalian insulin. We report that flies with reduced Sdc expression in the IPCs did not show any difference in the expression of ilp genes compared to controls. However, they had significantly reduced levels of the circulating ILP2 protein, higher circulating carbohydrates, and were less glucose tolerant than control flies. Finally, we found that IPCs-specific Sdc knockdown led to reduced levels of head Glucose transporter1 gene expression, extracellular signal-regulated kinase phosphorylation, and reactive oxygen species. Taken together, our findings suggest a cell autonomous role for Sdc in insulin release in D. melanogaster.
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http://dx.doi.org/10.1089/dna.2017.3912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684661PMC
November 2017

Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Nat Genet 2017 Aug 26;49(8):1231-1238. Epub 2017 Jun 26.

CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), Illkirch-Graffenstaden, France.

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
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http://dx.doi.org/10.1038/ng.3901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546242PMC
August 2017

Associations of human skeletal muscle fiber type and insulin sensitivity, blood lipids, and vascular hemodynamics in a cohort of premenopausal women.

Eur J Appl Physiol 2017 Jul 11;117(7):1413-1422. Epub 2017 May 11.

Departments of Human Studies, University of Alabama at Birmingham, Birmingham, USA.

Purpose: Cardiometabolic disease remains a leading cause of morbidity and mortality in developed nations. Consequently, identifying and understanding factors associated with underlying pathophysiological processes leading to chronic cardio metabolic conditions is critical. Metabolic health, arterial elasticity, and insulin sensitivity (SI) may impact disease risk, and may be determined in part by myofiber type. Therefore, the purpose of this study was to test the hypothesis that type I myofiber composition would be associated with high SI, greater arterial elasticity, lower blood pressure, and blood lipids; whereas, type IIx myofibers would be associated with lower SI, lower arterial elasticity, higher blood pressure, blood lipids.

Methods: Muscle biopsies were performed on the vastus lateralis in 16 subjects (BMI = 27.62 ± 4.71 kg/m, age = 32.24 ± 6.37 years, 43% African American). The distribution of type I, IIa, and IIx myofibers was determined via immunohistochemistry performed on frozen cross-sections. Pearson correlation analyses were performed to assess associations between myofiber composition, SI, arterial elasticity, blood pressure, and blood lipid concentrations.

Results: The percentage of type I myofibers positively correlated with SI and negatively correlated with systolic blood pressure SBP, diastolic blood pressure, and mean arterial pressure (MAP); whereas, the percentage of type IIx myofibers were negatively correlated with SI and large artery elasticity, and positively correlated with LDL cholesterol, SBP, and MAP.

Conclusions: These data demonstrate a potential link between myofiber composition and cardiometabolic health outcomes in a cohort of premenopausal women. Future research is needed to determine the precise mechanisms in which myofiber composition impacts the pathophysiology of impaired glucose and lipid metabolism, as well as vascular dysfunction.
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http://dx.doi.org/10.1007/s00421-017-3634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963254PMC
July 2017

High-throughput discovery of novel developmental phenotypes.

Nature 2016 09 14;537(7621):508-514. Epub 2016 Sep 14.

Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
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http://dx.doi.org/10.1038/nature19356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295821PMC
September 2016

A mouse informatics platform for phenotypic and translational discovery.

Mamm Genome 2015 Oct 28;26(9-10):413-21. Epub 2015 Aug 28.

MRC Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Harwell, OX11 0RD, UK.

The International Mouse Phenotyping Consortium (IMPC) is providing the world's first functional catalogue of a mammalian genome by characterising a knockout mouse strain for every gene. A robust and highly structured informatics platform has been developed to systematically collate, analyse and disseminate the data produced by the IMPC. As the first phase of the project, in which 5000 new knockout strains are being broadly phenotyped, nears completion, the informatics platform is extending and adapting to support the increasing volume and complexity of the data produced as well as addressing a large volume of users and emerging user groups. An intuitive interface helps researchers explore IMPC data by giving overviews and the ability to find and visualise data that support a phenotype assertion. Dedicated disease pages allow researchers to find new mouse models of human diseases, and novel viewers provide high-resolution images of embryonic and adult dysmorphologies. With each monthly release, the informatics platform will continue to evolve to support the increased data volume and to maintain its position as the primary route of access to IMPC data and as an invaluable resource for clinical and non-clinical researchers.
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http://dx.doi.org/10.1007/s00335-015-9599-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602054PMC
October 2015

Nursing interventions for substance use during psychiatric hospital admissions: Clinical context and predictors.

Int J Ment Health Nurs 2015 Dec 23;24(6):527-37. Epub 2015 Aug 23.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Empirical information about how nurses manage substance use on psychiatric wards is lacking. The aims of the study were to identify the frequency and clinical features of incidents among a sample of inpatients over a 12-month period and how nursing staff intervened. Electronic, anonymized inpatient records were searched for incidents of substance use on 17 acute psychiatric wards in four hospitals in London. Searches were conducted for all patients admitted during 2012 and details of incidents and patient characteristics were extracted for analysis. Substance use was reported for 291 patients, with 25 incidents per 100 patients admitted to hospital. Only half of the incidents were followed by a response that specifically addressed the patients' substance use behaviour. These interactions usually concerned the circumstances and reasons for use, but rarely involved specific support for patients' substance use problems. The likelihood of staff taking any form of action was increased if the patient had been formally admitted, and was reduced if the patient was subject to containment during the shift or had a history of self-harm. The results demonstrate that nurses require specific training and guidance on supporting substance using patients.
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http://dx.doi.org/10.1111/inm.12152DOI Listing
December 2015

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data.

Nucleic Acids Res 2014 Jan 4;42(Database issue):D802-9. Epub 2013 Nov 4.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK and Mouse Informatics Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated 'data wranglers' work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases.
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http://dx.doi.org/10.1093/nar/gkt977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964955PMC
January 2014

Performance evaluation of affinity ligands for depletion of abundant plasma proteins.

J Chromatogr B Analyt Technol Biomed Life Sci 2013 Nov 10;939:10-6. Epub 2013 Sep 10.

Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA.

Human plasma is a commonly used diagnostic fluid in clinical chemistry. In-depth plasma proteomic analysis is performed to search for disease biomarkers, however the large dynamic range of protein abundance in plasma presents a substantial analytical challenge. Removal of abundant plasma proteins using antibody capture approaches is a common and attractive means to reduce sample complexity and to aid the analysis of lower abundance proteins of interest. A novel class of heavy chain camelid-derived affinity ligands produced in Saccharomyces cerevisiae, has recently been developed as an alternative to antibody-based depletion methods. Here, we evaluate the performance characteristics of these ligands for removal of high abundance plasma proteins. Affinity ligands were tested for the removal of 14 abundant human plasma proteins. The performance characteristics were evaluated by gel-electrophoresis and LC-MS/MS of the bound and flow-through fractions. The capacity of a 5.6mL column was found to be 125μL of plasma. Replicate analysis demonstrated high column reproducibility and linearity, efficient removal of abundant proteins, and enrichment of lower abundance proteins observed after depletion. The novel class of affinity ligands provides an attractive alternative to traditional antibody-based immunodepletion methods.
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http://dx.doi.org/10.1016/j.jchromb.2013.09.008DOI Listing
November 2013

Adverse incidents, patient flow and nursing workforce variables on acute psychiatric wards: the Tompkins Acute Ward Study.

Int J Soc Psychiatry 2007 Jan;53(1):75-84

St Bartholomew School of Nursing and Midwifery, City University, London, UK.

Background: Adverse incidents (violence, self-harm and absconding) can cause significant harm to patients and staff, are difficult to predict, and are driving an increase in security measures and defensive practice.

Aims: To explore the relationship between adverse incidents on acute psychiatric wards, admissions and nursing workforce variables.

Methods: A retrospective analysis of officially collected data covering a period of 30 months on 14 acute wards at three hospitals. This data included 69 serious untoward incidents.

Results: Adverse incidents were more likely during and after weeks of high numbers of male admissions, during weeks when other incidents also occurred, and during weeks of high regular staff absence through leave and vacancy.

Conclusions: It may be possible to predict adverse incidents. Careful staff management and deployment may reduce the risks.
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http://dx.doi.org/10.1177/0020764007075011DOI Listing
January 2007

Junior staffing changes and the temporal ecology of adverse incidents in acute psychiatric wards.

J Adv Nurs 2007 Jan;57(2):153-60

Psychiatric Nursing, St Bartholomew School of Nursing and Midwifery, City University, London, UK.

Aim: This paper reports an examination of the relationship between adverse incident rates, the arrival of new junior staff on wards, and days of the week on acute psychiatric wards.

Background: Incidents of violence, absconding and self-harm in acute inpatient services pose risks to patients and staff. Previous research suggests that the arrival of inexperienced new staff may trigger more adverse incidents. Findings on the relationship between incidents and the weekly routine are inconsistent.

Method: A retrospective analysis was conducted of formally reported incident rates, records of nursing student allocations and junior doctor rotation patterns, using Poisson Regression. Variance between days of the week was explored using contingency table analysis. The data covered 30 months on 17 psychiatric wards, and were collected in 2002-2004.

Findings: The arrival of new and inexperienced staff on the wards was not associated with increases in adverse incident rates. Most types of incidents were less frequent at weekends and midweek. Incident rates were unchanged on ward-round days, but increased rates were found on the days before and after ward rounds.

Conclusion: Increased patient tension is associated with raised incident rates. It may be possible to reduce incident rates by moderating stimulation in the environment and by mobilizing support for patients during critical periods.
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http://dx.doi.org/10.1111/j.1365-2648.2006.04101.xDOI Listing
January 2007

Establishment of a pipeline to analyse non-synonymous SNPs in Bos taurus.

BMC Genomics 2006 Nov 26;7:298. Epub 2006 Nov 26.

AgResearch, Invermay Agricultural Centre, Mosgiel, Private Bag 50034, New Zealand.

Background: Single nucleotide polymorphisms (SNPs) are an abundant form of genetic variation in the genome of every species and are useful for gene mapping and association studies. Of particular interest are non-synonymous SNPs, which may alter protein function and phenotype. We therefore examined bovine expressed sequences for non-synonymous SNPs and validated and tested selected SNPs for their association with measured traits.

Results: Over 500,000 public bovine expressed sequence tagged (EST) sequences were used to search for coding SNPs (cSNPs). A total of 15,353 SNPs were detected in the transcribed sequences studied, of which 6,325 were predicted to be coding SNPs with the remaining 9,028 SNPs presumed to be in untranslated regions. Of the cSNPs detected, 2,868 were predicted to result in a change in the amino acid encoded. In order to determine the actual number of non-synonymous polymorphic SNPs we designed assays for 920 of the putative SNPs. These SNPs were then genotyped through a panel of cattle DNA pools using chip-based MALDI-TOF mass spectrometry. Of the SNPs tested, 29% were found to be polymorphic with a minor allele frequency >10%. A subset of the SNPs was genotyped through animal resources in order to look for association with age of puberty, facial eczema resistance or meat yield. Three SNPs were nominally associated with resistance to the disease facial eczema (P < 0.01).

Conclusion: We have identified 15,353 putative SNPs in or close to bovine genes and 2,868 of these SNPs were predicted to be non-synonymous. Approximately 29% of the non-synonymous SNPs were polymorphic and common with a minor allele frequency >10%. Of the SNPs detected in this study, 99% have not been previously reported. These novel SNPs will be useful for association studies or gene mapping.
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http://dx.doi.org/10.1186/1471-2164-7-298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684264PMC
November 2006

Repeated single-limb postural stability testing elicits a practice effect.

Phys Ther Sport 2006 Nov 10;7(4):185-90. Epub 2006 Oct 10.

Kennedy Road Physiotherapy, Napier, New Zealand.

Objective: To document the effects of repeated testing on the single-leg stance balance task.

Design: Single cohort repeated measures.

Setting: Laboratory in an educational institution.

Subjects: Thirty-two healthy males and females.

Outcome Measure: The number of errors (deviations from the required posture) during each 20-s trial summed over the eight conditions recorded on six occasions.

Results: There was a statistically significant (p=.0013) decrease in the number of errors recorded over the six sessions, from 26.8 (95% CI: 23.1-30.5) to 19.7 (95% CI: 16.3-23.1). Linear regression confirmed a systematic decrease of 1.5 errors per session on average (95% CI: 1.0-1.9; p<.0001).

Conclusion: The decreased number of errors (increased performance) with repeated testing alerts clinicians to the need for care when using this test protocol to measure rehabilitation interventions.
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http://dx.doi.org/10.1016/j.ptsp.2006.06.002DOI Listing
November 2006

Prevention and management of aggression training and violent incidents on U.K. Acute psychiatric wards.

Psychiatr Serv 2006 Jul;57(7):1022-6

Department of Mental Health and Learning Disability, City University, Philpot Street, Whitechapel, London, E1 2EA, United Kingdom.

Objective: Reports of violence and injuries to staff and patients in acute psychiatric inpatient settings have led to the development and implementation of training courses in the Prevention and Management of Violence and Aggression (PMVA). The purpose of this study was to explore the relationship between PMVA training of acute psychiatric ward nursing staff and officially reported violent incident rates.

Methods: A retrospective analysis was conducted of training records (312 course attendances) and violent incident rates (684 incidents) over two-and-a-half years on 14 acute admission psychiatric wards (5,384 admissions) at three inner-city hospitals in the United Kingdom as part of the Tompkins Acute Ward Study.

Results: A positive association was found between training and rates of violent incidents. There was weak evidence that increased rates of aggressive incidents prompted course attendance, no evidence that course attendance reduced violence, and some evidence that attendance of briefer update courses triggered small short-term rises in rates of physical aggression. Course attendance was associated with a rise in physical and verbal aggression while staff were away from the ward.

Conclusions: The failure to find a drop in incident rates after training, coupled with the small increases in incidents detected, raises concerns about the training course's efficacy as a preventive strategy. Alternatively, the results are consistent with a threshold effect, indicating that once adequate numbers of staff have been trained, further training keeps incidents at a low rate.
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http://dx.doi.org/10.1176/ps.2006.57.7.1022DOI Listing
July 2006

Guidelines for the inter- and intrahospital transport of critically ill patients.

Crit Care Med 2004 Jan;32(1):256-62

Northwest Community Hospital, Arlington Heights, IL, USA.

Objective: The development of practice guidelines for the conduct of intra- and interhospital transport of the critically ill patient.

Data Source: Expert opinion and a search of Index Medicus from January 1986 through October 2001 provided the basis for these guidelines. A task force of experts in the field of patient transport provided personal experience and expert opinion.

Study Selection And Data Extraction: Several prospective and clinical outcome studies were found. However, much of the published data comes from retrospective reviews and anecdotal reports. Experience and consensus opinion form the basis of much of these guidelines.

Results Of Data Synthesis: Each hospital should have a formalized plan for intra- and interhospital transport that addresses a) pretransport coordination and communication; b) transport personnel; c) transport equipment; d) monitoring during transport; and e) documentation. The transport plan should be developed by a multidisciplinary team and should be evaluated and refined regularly using a standard quality improvement process.

Conclusion: The transport of critically ill patients carries inherent risks. These guidelines promote measures to ensure safe patient transport. Although both intra- and interhospital transport must comply with regulations, we believe that patient safety is enhanced during transport by establishing an organized, efficient process supported by appropriate equipment and personnel.
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http://dx.doi.org/10.1097/01.CCM.0000104917.39204.0ADOI Listing
January 2004