Publications by authors named "Michael C Davis"

31 Publications

Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression.

Toxicol Rep 2020 25;7:188-197. Epub 2020 Jan 25.

Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USA.

Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.
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http://dx.doi.org/10.1016/j.toxrep.2020.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994827PMC
January 2020

N-acetylcysteine improves EEG measures of auditory deviance detection and neural synchronization in schizophrenia: A randomized, controlled pilot study.

Schizophr Res 2019 06 31;208:479-480. Epub 2019 Jan 31.

VISN22 MIRECC Greater Los Angeles Veterans Affairs Healthcare System, United States of America.

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http://dx.doi.org/10.1016/j.schres.2019.01.036DOI Listing
June 2019

The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A randomized controlled study.

Schizophr Res 2018 05 29;195:572-573. Epub 2017 Sep 29.

Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Mental Illness Research, Education and Clinical Center, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

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http://dx.doi.org/10.1016/j.schres.2017.09.046DOI Listing
May 2018

Efficient Trial Design - FDA Approval of Valbenazine for Tardive Dyskinesia.

N Engl J Med 2017 Jun 10;376(26):2503-2506. Epub 2017 May 10.

From the Division of Psychiatry Products (M.C.D., B.J.M., J.K.K., M.V.M.) and the Division of Biometrics I (T.B.), Center for Drug Evaluation and Research, Silver Spring, MD; and the University of North Carolina Kenan-Flagler School of Business, Chapel Hill (B.J.M.).

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http://dx.doi.org/10.1056/NEJMp1704898DOI Listing
June 2017

Possible Clozapine Overdose-Associated Thromboembolic Event.

J Clin Psychopharmacol 2017 06;37(3):364-366

Psychiatry, Audie L. Murphy VA Medical Center, San Antonio, TX Psychiatry, Michael E. DeBakey VA Medical Center, Houston, TX Division of Psychiatry Products, Office of New Drugs, Center for Drug Evaluation & Research, US Food and Drug Administration, Silver Spring, MD.

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http://dx.doi.org/10.1097/JCP.0000000000000706DOI Listing
June 2017

Serotonin Reuptake Inhibitor Use During Pregnancy.

JAMA Psychiatry 2017 05;74(5):539

Center for Drug Evaluation and Research, Division of Psychiatry Products, US Food and Drug Administration, Silver Spring, Maryland.

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http://dx.doi.org/10.1001/jamapsychiatry.2016.4073DOI Listing
May 2017

N-Acetylcysteine Supplementation in an Individual With Glucose-6-Phosphate Dehydrogenase Deficiency-Associated Psychosis.

Biol Psychiatry 2016 10 2;80(8):e71-2. Epub 2016 Mar 2.

Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas; Mental Health Care Line, Michael E. DeBakey VA Medical Center, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2016.02.028DOI Listing
October 2016

Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population.

Psychoneuroendocrinology 2016 06 5;68:140-7. Epub 2016 Mar 5.

Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Literature suggests that alterations in the inflammatory and immune systems are involved in the pathogenesis of schizophrenia. Specifically, patients diagnosed with schizophrenia exhibit increased IL-18, a pleiotropic proinflammatory cytokine in type 1 T-helper (Th1) responses. The functional 607A/C promoter polymorphism of the IL-18 gene is also associated with the psychopathology of this disorder. However, no current study has explored its role in the clinical symptoms of schizophrenia as mediated through IL-18 levels. We recruited 772 inpatients with schizophrenia and 775 healthy controls in a Han Chinese population and genotyped the IL-18-607A/C polymorphism. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Serum IL-18 levels were measured in 80 patients and 93 healthy controls. Our results showed that there were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls. Both increased IL-18 serum level and the IL-18-607A/C polymorphism were positively associated with the PANSS general psychopathology subscore and the PANSS total score. Moreover, interaction of increased IL-18 serum level and the IL-18-607A/C polymorphism influenced the clinical psychopathological symptoms, indicating that association of IL-18 level with the PANSS general psychopathology subscale or the total scores was present only among patients carrying the C allele. We demonstrate an association between the IL-18-607A/C variant and clinical psychopathological symptoms in schizophrenia. Findings suggest that the association between higher IL-18 levels and clinical symptoms in schizophrenia is dependent on the IL-18-607A/C polymorphism.
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http://dx.doi.org/10.1016/j.psyneuen.2016.03.002DOI Listing
June 2016

Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population.

Psychoneuroendocrinology 2016 06 5;68:140-7. Epub 2016 Mar 5.

Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Literature suggests that alterations in the inflammatory and immune systems are involved in the pathogenesis of schizophrenia. Specifically, patients diagnosed with schizophrenia exhibit increased IL-18, a pleiotropic proinflammatory cytokine in type 1 T-helper (Th1) responses. The functional 607A/C promoter polymorphism of the IL-18 gene is also associated with the psychopathology of this disorder. However, no current study has explored its role in the clinical symptoms of schizophrenia as mediated through IL-18 levels. We recruited 772 inpatients with schizophrenia and 775 healthy controls in a Han Chinese population and genotyped the IL-18-607A/C polymorphism. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Serum IL-18 levels were measured in 80 patients and 93 healthy controls. Our results showed that there were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls. Both increased IL-18 serum level and the IL-18-607A/C polymorphism were positively associated with the PANSS general psychopathology subscore and the PANSS total score. Moreover, interaction of increased IL-18 serum level and the IL-18-607A/C polymorphism influenced the clinical psychopathological symptoms, indicating that association of IL-18 level with the PANSS general psychopathology subscale or the total scores was present only among patients carrying the C allele. We demonstrate an association between the IL-18-607A/C variant and clinical psychopathological symptoms in schizophrenia. Findings suggest that the association between higher IL-18 levels and clinical symptoms in schizophrenia is dependent on the IL-18-607A/C polymorphism.
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http://dx.doi.org/10.1016/j.psyneuen.2016.03.002DOI Listing
June 2016

Two-dimensional NMR measurement and point dipole model prediction of paramagnetic shift tensors in solids.

J Chem Phys 2015 Jan;142(1):014201

Department of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.

A new two-dimensional Nuclear Magnetic Resonance (NMR) experiment to separate and correlate the first-order quadrupolar and chemical/paramagnetic shift interactions is described. This experiment, which we call the shifting-d echo experiment, allows a more precise determination of tensor principal components values and their relative orientation. It is designed using the recently introduced symmetry pathway concept. A comparison of the shifting-d experiment with earlier proposed methods is presented and experimentally illustrated in the case of (2)H (I = 1) paramagnetic shift and quadrupolar tensors of CuCl2⋅2D2O. The benefits of the shifting-d echo experiment over other methods are a factor of two improvement in sensitivity and the suppression of major artifacts. From the 2D lineshape analysis of the shifting-d spectrum, the (2)H quadrupolar coupling parameters are 〈Cq〉 = 118.1 kHz and 〈ηq〉 = 0.88, and the (2)H paramagnetic shift tensor anisotropy parameters are 〈ζP〉 = - 152.5 ppm and 〈ηP〉 = 0.91. The orientation of the quadrupolar coupling principal axis system (PAS) relative to the paramagnetic shift anisotropy principal axis system is given by (α,β,γ)=(π2,π2,0). Using a simple ligand hopping model, the tensor parameters in the absence of exchange are estimated. On the basis of this analysis, the instantaneous principal components and orientation of the quadrupolar coupling are found to be in excellent agreement with previous measurements. A new point dipole model for predicting the paramagnetic shift tensor is proposed yielding significantly better agreement than previously used models. In the new model, the dipoles are displaced from nuclei at positions associated with high electron density in the singly occupied molecular orbital predicted from ligand field theory.
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http://dx.doi.org/10.1063/1.4904548DOI Listing
January 2015

Associations between oxytocin receptor genotypes and social cognitive performance in individuals with schizophrenia.

Schizophr Res 2014 Nov 20;159(2-3):353-7. Epub 2014 Sep 20.

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, United States; VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, United States. Electronic address:

Individuals with schizophrenia often show substantial deficits in social cognitive abilities, which are strongly associated with social functioning. To advance our understanding of the genetic variation that is associated with social cognitive deficits in schizophrenia, we genotyped 74 schizophrenia outpatients who completed social cognitive performance measures assessing mentalizing, social perception, and emotional intelligence, as well as clinical symptoms. We assessed seven single nucleotide polymorphisms (SNPs) of the oxytocin receptor (OXTR) previously found to show replicable associations with socio-emotional processes. For one of the seven SNPs, rs2268493, the 'T' allele was significantly associated with poorer performance on a composite social cognition index, as well as specific tests of mentalizing and social perception. None of the SNPs were associated with clinical symptoms. Though the sample size is small, these findings provide initial support for the involvement of genetic variants of the OXTR in social cognitive impairments in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2014.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254299PMC
November 2014

NPITxt, a 21st-Century Reporting System: Engaging Residents in a Lean-Inspired Process.

Am J Med Qual 2015 May 8;30(3):255-62. Epub 2014 Apr 8.

UCLA Departments of Medicine & Neurosurgery, UCLA Hospitals, Los Angeles, CA.

Operational waste, or workflow processes that do not add value, is a frustrating but nonetheless largely tolerated barrier to efficiency and morale for medical trainees. In this article, the authors tested a novel reporting system using several submission formats (text messaging, e-mail, Web form, mobile application) to allow residents to report various types of operational waste in real time. This system informally promoted "lean" principles of waste identification and continuous improvement. In all, 154 issues were submitted between March 30, 2011, and June 30, 2012, and categorized as closely as possible into lean categories of operational waste; 131 issues were completely addressed with the requested outcome partially or fully implemented or with successful clarification of existing policies. A real-time, voluntary reporting system can effectively capture trainee observations of waste in health care and training processes, give trainees a voice in a hierarchical system, and lead to meaningful operations improvement.
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http://dx.doi.org/10.1177/1062860614528371DOI Listing
May 2015

New-onset extrapyramidal symptoms following oxcarbazepine discontinuation in a child receiving risperidone.

J Child Adolesc Psychopharmacol 2014 Apr 1;24(3):166-7. Epub 2014 Apr 1.

1 Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA , Los Angeles, California.

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http://dx.doi.org/10.1089/cap.2013.0123DOI Listing
April 2014

Oxytocin-augmented social cognitive skills training in schizophrenia.

Neuropsychopharmacology 2014 Aug 18;39(9):2070-7. Epub 2014 Mar 18.

1] Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA [2] VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, USA.

Impairments in social cognition are common in schizophrenia and predict poor functional outcome. The purpose of this proof-of-concept randomized, parallel group clinical trial was to assess whether intranasal oxytocin (OT), given before social cognitive training, enhances learning of social cognitive skills. Twenty seven male outpatients with schizophrenia participated in a 6-week (12 session) training on social cognitive skills. Training focused on three domains: facial affect recognition, social perception, and empathy. Subjects were randomly assigned (double blind) to receive either intranasal OTor placebo 30 min before each session. Participants did not receive OT between sessions or on the day of assessments. We evaluated scores on social-cognition measures, as well as clinical symptoms and neurocognition, at baseline, 1 week following the final training session, and 1 month later. Our prespecified primary outcome measure was a social-cognition composite score comprised of five individual measures. There were main effects of time (indicating improvement across the combined-treatment groups) on the social-cognition composite score at both 1 week and 1 month following completion of training. Subjects receiving OT demonstrated significantly greater improvements in empathic accuracy than those receiving placebo at both posttreatment and 1 month follow up. There were no OT-related effects for the other social cognitive tests, clinical symptoms, or neurocognition. This study provides initial support for the idea that OT enhances the effectiveness of training when administered shortly before social cognitive training sessions. The effects were most pronounced on empathic accuracy, a high-level social cognitive process that is not easily improved in current social cognitive remediation programs.
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http://dx.doi.org/10.1038/npp.2014.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104336PMC
August 2014

Anti-N-methyl-D-aspartate receptor encephalitis: a targeted review of clinical presentation, diagnosis, and approaches to psychopharmacologic management.

Ann Clin Psychiatry 2014 May;26(2):111-9

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.

Background: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review.

Methods: The authors conducted a PubMed search.

Results: Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition.

Conclusions: Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering.
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May 2014

Psychopharmacology of the negative symptoms: current status and prospects for progress.

Eur Neuropsychopharmacol 2014 May 4;24(5):788-99. Epub 2013 Nov 4.

Department of Veterans Affairs, VISN 22 Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, USA; UCLA Semel Institute of Neuroscience and Human Behavior, Los Angeles, CA, USA. Electronic address:

The past decade has witnessed a resurgence of interest in the development of novel pharmacological agents to treat the negative symptoms of schizophrenia. This review provides an overview of pharmacological approaches that have been evaluated as potential treatments and describes the emergence of several promising new approaches. First, we briefly describe recent methodological developments, including consensus-based clinical trial guidelines for patient selection criteria, symptom assessment, and trial duration. Next, we overview mono- and adjunctive-therapies that have been evaluated, including first- and second-generation antipsychotics, antidepressants, psychostimulants, molecules targeting cholinergic and glutamatergic systems, and hormones. We highlight the most promising pharmacological agents on the horizon, including glycine transporter-1 inhibitors, α7-nicotinic receptor positive allosteric modulators, and oxytocin, as well as non-pharmacological electromagnetic stimulation approaches. Further investigations, using optimal clinical trial design, hold considerable promise for discovering effective treatments for these functionally disabling symptoms in the near future.
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http://dx.doi.org/10.1016/j.euroneuro.2013.10.010DOI Listing
May 2014

Impulsivity and risk taking in bipolar disorder and schizophrenia.

Neuropsychopharmacology 2014 Jan 21;39(2):456-63. Epub 2013 Aug 21.

1] VA Greater Los Angeles Healthcare System, MIRECC, Los Angeles, CA, USA [2] Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.

Impulsive risk taking contributes to deleterious outcomes among clinical populations. Indeed, pathological impulsivity and risk taking are common in patients with serious mental illness, and have severe clinical repercussions including novelty seeking, response disinhibition, aggression, and substance abuse. Thus, the current study seeks to examine self-reported impulsivity (Barratt Impulsivity Scale) and performance-based behavioral risk taking (Balloon Analogue Risk Task) in bipolar disorder and schizophrenia. Participants included 68 individuals with bipolar disorder, 38 with schizophrenia, and 36 healthy controls. Self-reported impulsivity was elevated in the bipolar group compared with schizophrenia patients and healthy controls, who did not differ from each other. On the risk-taking task, schizophrenia patients were significantly more risk averse than the bipolar patients and controls. Aside from the diagnostic group differences, there was a significant effect of antipsychotic (AP) medication within the bipolar group: bipolar patients taking AP medications were more risk averse than those not taking AP medications. This difference in risk taking because of AP medications was not explained by history of psychosis. Similarly, the differences in risk taking between schizophrenia and bipolar disorder were not fully explained by AP effects. Implications for clinical practice and future research are discussed.
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http://dx.doi.org/10.1038/npp.2013.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870783PMC
January 2014

Safeguarding forensic DNA reference samples with nullomer barcodes.

J Forensic Leg Med 2013 Jul 17;20(5):513-9. Epub 2013 Apr 17.

Department of Biology, Boise State University, Science-215, 1910 University Dr., Boise, ID 83725-1515, USA.

Unintended transfer of biological material containing DNA is a concern to all laboratories conducting PCR analysis. While forensic laboratories have protocols in place to reduce the possibility of contaminating casework samples, there is no way to detect when a reference sample is mislabeled as evidence, or contaminates a forensic sample. Thus there is public concern regarding the safeguarding of DNA submitted to crime labs. We demonstrate a method of introducing an internal amplification control to reference samples, in the form of a nullomer barcode which is based upon sequences absent or rare from publically accessible DNA databases. The detection of this barcode would indicate that the source of analyzed DNA was from a reference sample provided by an individual, and not from an evidence sample. We demonstrate that the nullomers can be added directly to collection devices (FTA paper) to allow tagging during the process of sample collection. We show that such nullomer oligonucleotides can be added to existing forensic typing and quantification kits, without affecting genotyping or quantification results. Finally, we show that even when diluted a million-fold and spilled on a knife, the nullomer tags can be clearly detected. These tags support the National Research Council of the National Academy recommendation that "Quality control procedures should be designed to identify mistakes, fraud, and bias" in forensic science (National Academy of Sciences, 2009).
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http://dx.doi.org/10.1016/j.jflm.2013.02.003DOI Listing
July 2013

Effects of single dose intranasal oxytocin on social cognition in schizophrenia.

Schizophr Res 2013 Jul 12;147(2-3):393-7. Epub 2013 May 12.

UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, United States.

Deficits in social cognition are common in schizophrenia and predict poor community functioning. Given the current limitations of psychosocial treatments and the lack of pharmacological treatments for social cognitive deficits, the development of novel therapeutic agents could greatly enhance functional recovery in schizophrenia. This study evaluated whether a single dose of intranasal oxytocin acutely improves social cognitive functioning in schizophrenia. Twenty-three male veterans with schizophrenia completed baseline assessments of social cognition that were divided into lower-level (facial affect perception, social perception, detection of lies) and higher-level (detection of sarcasm and deception, empathy) processes. One week later, patients received the same battery after being randomized to a single dose of 40 IU intranasal oxytocin or placebo. Though the groups did not differ significantly on the social cognition composite score, oxytocin improved performance for the higher-level social cognitive tasks (Cohen's d=1.0, p=0.045). Subjects were unable to accurately guess which treatment they had received. The improvements found in higher-level social cognition encourage further studies into the therapeutic potential of oxytocin in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2013.04.023DOI Listing
July 2013

The Y-STR genetic diversity of an Idaho Basque population, with comparison to European Basques and US Caucasians.

Hum Biol 2011 Dec;83(6):685-94

Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.

Fifty unrelated Basque males from southwest Idaho were typed for the 17 Y-STR loci in the Yfiler multiplex kit (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, YGATA H4.1 and DYS385a/b). In total, 42 haplotypes were identified, with no more than two individuals sharing a single haplotype. The haplotype diversity (HD) was 0.9935, and gene diversity (D) over loci was 0.457 ± 0.137. The Idaho Basque population was compared to the source population from the Basque autonomous region of Northern Spain and Southern France, as well as a United States Caucasian population. The haplotype diversity for the immigrant Basque sample is within 0.4% of the haplotype diversity of the European Basques (0.9903); thus the power of discrimination is similar for each population. The Idaho Basque population has less diversity in 9 out of 16 loci (considering DYS385a/b together) and 3% less diversity across all loci, compared to the European Basque population. A multidimensional scaling analysis (MDS) was created using pairwise R(ST) values to compare the Idaho Basques to other populations. Based upon R(ST) and F(ST) measures, no significant differentiation was found between the Idaho and source European Basque population.
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http://dx.doi.org/10.3378/027.083.0602DOI Listing
December 2011

Y-STR variation in the Basque diaspora in the Western USA: evolutionary and forensic perspectives.

Int J Legal Med 2012 Mar 13;126(2):293-8. Epub 2011 Nov 13.

BIOMICs Research Group, CIEA Lucio Lascaray Center for Research and Advanced Studies, University of the Basque Country UPV/EHU, Avda. Miguel de Unamuno 3, 01006, Vitoria-Gasteiz, Spain.

Individuals of Basque origin migrated in large numbers to the Western USA in the second half of the nineteenth century, and the flow continued with less intensity during the last century. The European source population, that of the Basque Country, has long been a cultural and geographical isolate. Previous studies have demonstrated that Y-STR frequencies of Basques are different from those of other Spanish and European populations [1]. The Basque diaspora in the Western USA is a recent migration, but the founder effect and the incorporation of new American Y chromosomes into the paternal genetic pool of the Basque diaspora could have influenced its genetic structure and could thus have practical implications for forensic genetics. To check for genetic substructure among the European source and Basque diaspora populations and determine the most suitable population database for the Basque diaspora in the Western USA, we have analysed the haplotype distribution of 17 Y-STRs in both populations. We have found that the Basque diaspora in the Western USA largely conserve the Y chromosome lineage characteristic of the autochthonous European Basque population with no statistically significant differences. This implies that a common 17 Y-STR Basque population database could be used to calculate identification or kinship parameters regardless of whether the Basque individuals are from the European Basque Country or from the Basque diaspora in the Western USA.
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http://dx.doi.org/10.1007/s00414-011-0644-8DOI Listing
March 2012

Mitochondrial DNA analysis of an immigrant Basque population: loss of diversity due to founder effects.

Am J Phys Anthropol 2011 Apr 1;144(4):516-25. Epub 2010 Dec 1.

Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.

The Basques have a well-documented history of migration and settlement in the Americas, and they often retain cultural identity across generations. Numerous genetic studies have been carried out on European Basques; thus, immigrant Basques are an ideal population for investigating the genetic consequences of a recent human migration event. We have sampled 53 unrelated individuals with Basque ancestry in Boise, Idaho and determined the mitochondrial DNA (mtDNA) sequence variation of the first and second hypervariable regions. Thirty-six mtDNA haplotypes were detected in our sample. We found evidence of genetic changes consistent with founder effects, which is compatible with the known history of migration. Compared with the European Basque population, the immigrant Basques are significantly different in terms of haplogroup frequency distribution and diversity. They have a lower measure of weighted intralineage mean pairwise diversity (WIMP) and greater genetic distance from other European populations. These data indicate that this immigrant Basque population has experienced a reduction in genetic diversity compared with the putative source population. However, this loss of diversity is not detectable using indices of demographic history such as Tajima's D and Fu's F. This study represents the first description of mtDNA diversity in an immigrant Basque population, and our findings indicate that founder effects accompanying this relatively recent migration event have shaped the genetic diversity of this population.
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http://dx.doi.org/10.1002/ajpa.21432DOI Listing
April 2011

TOP-PASS: a processing algorithm to reduce 2D PASS acquisition time.

J Magn Reson 2011 May 4;210(1):51-8. Epub 2011 Mar 4.

Department of Chemistry, The Ohio State University, Columbus, OH 43210-1173, USA.

A slow speed MAS spectrum contains a pattern of spinning sideband resonances separated by integer multiples of the rotor frequency and centered about an isotropic frequency. The 2D signal acquired in a two-dimensional Phase Adjusted Spinning Sideband (PASS) experiment correlates this slow speed MAS spectrum, obtained in the direct dimension, to an indirect dimension spectrum containing the same pattern of spinning sideband resonances centered about a frequency of zero. An affine transformation is used to convert the acquired 2D PASS signal into a 2D signal that correlates a spectrum of pure isotropic frequencies to a spectrum of spinning sideband resonances with no isotropic frequency contributions. The conventional affine transform applied to 2D PASS consists of an active shear of the signal parallel to the indirect time domain coordinate followed by a passive scaling of the indirect time domain coordinate. Here we show that an alternative affine transform, previously employed in the Two-dimensional One Pulse (TOP) experiment, can be employed to create the same 2D signal correlation with an enhanced spectral width in the anisotropic (spinning sideband) dimension. This enhancement can provide a significant reduction in the minimum experiment time required for a 2D PASS experiment, particularly for spectra where the individual spinning sideband patterns are dispersed over a wider spectral range than the isotropic resonance frequencies. The TOP processing consists of an active shear of the signal parallel to the direct time domain, followed by an active shear of the signal parallel to the new indirect time domain coordinate followed by a passive scaling of the new direct time domain coordinate. A theoretical description of the affine transformation in the context of 2D PASS is given along with illustrative examples of (29)Si in Clinoenstatite and (13)C in l-Histidine.
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http://dx.doi.org/10.1016/j.jmr.2011.02.008DOI Listing
May 2011

Morphology, morphometrics, and molecular characterization of Bryophrya gemmea n. sp. (Ciliophora, Colpodea): implications for the phylogeny and evolutionary scenario for the formation of oral ciliature in the order Colpodida.

J Eukaryot Microbiol 2011 Jan-Feb;58(1):22-36

Department of Biological Sciences, Boise State University MS-1515, 1910 University Avenue, Boise, Idaho 83725-1515, USA.

We studied the morphology, morphometry, resting, and reproductive cysts, as well as the molecular phylogeny of Bryophrya gemmea n. sp., a colpodid ciliate that was discovered in ephemeral puddles in Idaho, northwest United States. This new species is distinguished from congeners by the irregularly pentagonal adoral organelles, four to five vestibular kineties, the single micronucleus, and one to three rows of brightly refractive protuberant interkinetal cortical granules to the right of the preoral suture. Resting cysts have two distinct membranes and an outer mucous coat. As typical for most colpodids, reproduction occurs in division cysts but details of ontogenesis are unknown. The 18S rRNA gene sequence shows only weak support for the phylogenetic relationship between Bryophrya and the bryophryid genus Notoxoma previously inferred from morphologic characters. Further, our molecular phylogenies classify bryophryids rather basal within the order Colpodida, not supporting ordinal status suggested by morphologists. Based on molecular data and morphologic characters, the colpodid genus Ilsiella is removed from the family Marynidae and placed in a new family, Ilsiellidae. Considering the molecular data, an evolutionary scenario for the formation of colpodid oral structures from a cyrtolophosidid ancestor through a bryophryid intermediate is proposed.
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http://dx.doi.org/10.1111/j.1550-7408.2010.00522.xDOI Listing
April 2011

Morphology, morphometrics, and molecular characterization of Bryophrya gemmea n. sp. (Ciliophora, Colpodea): implications for the phylogeny and evolutionary scenario for the formation of oral ciliature in the order Colpodida.

J Eukaryot Microbiol 2011 Jan-Feb;58(1):22-36

Department of Biological Sciences, Boise State University MS-1515, 1910 University Avenue, Boise, Idaho 83725-1515, USA.

We studied the morphology, morphometry, resting, and reproductive cysts, as well as the molecular phylogeny of Bryophrya gemmea n. sp., a colpodid ciliate that was discovered in ephemeral puddles in Idaho, northwest United States. This new species is distinguished from congeners by the irregularly pentagonal adoral organelles, four to five vestibular kineties, the single micronucleus, and one to three rows of brightly refractive protuberant interkinetal cortical granules to the right of the preoral suture. Resting cysts have two distinct membranes and an outer mucous coat. As typical for most colpodids, reproduction occurs in division cysts but details of ontogenesis are unknown. The 18S rRNA gene sequence shows only weak support for the phylogenetic relationship between Bryophrya and the bryophryid genus Notoxoma previously inferred from morphologic characters. Further, our molecular phylogenies classify bryophryids rather basal within the order Colpodida, not supporting ordinal status suggested by morphologists. Based on molecular data and morphologic characters, the colpodid genus Ilsiella is removed from the family Marynidae and placed in a new family, Ilsiellidae. Considering the molecular data, an evolutionary scenario for the formation of colpodid oral structures from a cyrtolophosidid ancestor through a bryophryid intermediate is proposed.
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http://dx.doi.org/10.1111/j.1550-7408.2010.00522.xDOI Listing
April 2011

Q(n) species distribution in K2O.2SiO2 glass by 29Si magic angle flipping NMR.

J Phys Chem A 2010 May;114(17):5503-8

Department of Chemistry, The Ohio State University, 120 West 18th Avenue, Columbus, Ohio 43210-1173, USA.

Two-dimensional magic angle flipping (MAF) was employed to measure the Q((n)) distribution in a (29)Si-enriched potassium disilicate glass (K(2)O.2SiO(2)). Relative concentrations of [Q((4))] = 7.2 +/- 0.3%, [Q((3))] = 82.9 +/- 0.1%, and [Q((2))] = 9.8 +/- 0.6% were obtained. Using the thermodynamic model for Q((n)) species disproportionation, these relative concentrations yield an equilibrium constant k(3) = 0.0103 +/- 0.0008, indicating, as expected, that the Q((n)) species distribution is close to binary in the potassium disilicate glass. A Gaussian distribution of isotropic chemical shifts was observed for each Q((n)) species with mean values of -82.74 +/- 0.03, -91.32 +/- 0.01, and -101.67 +/- 0.02 ppm and standard deviations of 3.27 +/- 0.03, 4.19 +/- 0.01, and 5.09 +/- 0.03 ppm for Q((2)), Q((3)), and Q((4)), respectively. Additionally, nuclear shielding anisotropy values of zeta =-85.0 +/- 1.3 ppm, eta = 0.48 +/- 0.02 for Q((2)) and zeta = -74.9 +/- 0.2 ppm, eta = 0.03 +/- 0.01 for Q((3)) were observed in the potassium disilicate glass.
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http://dx.doi.org/10.1021/jp100530mDOI Listing
May 2010

Magnesium silicate dissolution investigated by 29Si MAS, 1H-29Si CPMAS, 25Mg QCPMG, and 1H-25Mg CP QCPMG NMR.

Phys Chem Chem Phys 2009 Aug 14;11(32):7013-21. Epub 2009 Jul 14.

Penn State University, Department of Chemistry, University Park, PA 16802, USA.

Olivine-(Mg,Fe)(2)SiO(4)-has been the subject of frequent investigation in the earth sciences because of its simple structure and rapid dissolution kinetics. Several studies have observed a preferential release of the divalent cation with respect to silicon during weathering under acidic conditions, which has been correlated to the formation of a silicon-rich leached layer. While leached layer formation has been inferred through the changing solution chemistry, a thorough spectroscopic investigation of olivine reacted under acidic conditions has not been conducted. The pure magnesium end member of the olivine series (forsterite-Mg(2)SiO(4)) was chosen for detailed investigations in this study because paramagnetic iron hinders NMR investigations by providing an extra mode of relaxation for neighboring nuclei, causing lineshapes to become significantly broadened and unobservable in the NMR spectrum. For reacting forsterite, spectroscopic interrogations using nuclear magnetic resonance (NMR) can elucidate the changing magnesium coordination and bonding environment. In this study, we combine analysis of the changing solution chemistry with advanced NMR techniques ((29)Si MAS, (1)H-(29)Si CP MAS, (25)Mg QCPMG, and (1)H-(25)Mg CP QCPMG NMR) to probe leached layer formation and secondary phase precipitation during the dissolution of forsterite at 150 degrees C.
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http://dx.doi.org/10.1039/b907494eDOI Listing
August 2009

Dexamethasone-induced inositol 1,4,5-trisphosphate receptor elevation in murine lymphoma cells is not required for dexamethasone-mediated calcium elevation and apoptosis.

J Biol Chem 2008 Apr 13;283(16):10357-65. Epub 2008 Feb 13.

Division of Hematology/Oncology, Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

Glucocorticosteroid hormones, including dexamethasone, have diverse effects on immature lymphocyte function that ultimately lead to cell death. Previous studies established that glucocorticoid-induced alterations in intracellular calcium homeostasis promote apoptosis, but the mechanism by which glucocorticoids disrupt calcium homeostasis is unknown. Through gene expression array analysis, we found that dexamethasone induces a striking elevation of inositol 1,4,5-trisphosphate receptor (IP(3)R) levels in two murine lymphoma cell lines, WEHI7.2 and S49.A2. IP(3)R elevation was confirmed at both mRNA and protein levels. However, there was not a strong correlation between IP(3)R elevation and altered calcium homeostasis in terms of either kinetics or dose response. Moreover, IP(3)R knockdown, by either antisense or small interfering RNA, did not prevent either calcium disruption or apoptosis. Finally, DT40 lymphoma cells lacking all three IP(3)R isoforms were just as sensitive to dexamethasone-induced apoptosis as wild-type DT40 cells expressing all three IP(3)R isoforms. Thus, although alterations in intracellular calcium homeostasis contribute to glucocorticoid-induced apoptosis, these calcium alterations are not directly attributable to IP(3)R elevation.
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http://dx.doi.org/10.1074/jbc.M800269200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447640PMC
April 2008

Live free or die: an immature T cell decision encoded in distinct Bcl-2 sensitive and insensitive Ca2+ signals.

Cell Cycle 2006 Jun 1;5(11):1171-4. Epub 2006 Jun 1.

Department of Medicine, Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

In the developing thymus, strong T cell receptor (TCR) activation by self-antigens induces negative selection and weak TCR activation induces positive selection. Both processes are mediated by Ca(2+) signals, raising the question of how a single second messenger like Ca(2+) can mediate such diverse cell fates. Recent findings indicate that graded TCR activation signals are encoded in distinct patterns of Ca(2+) elevation. The anti-apoptotic protein Bcl-2 discriminates between these Ca(2+) signaling patterns, selectively inhibiting pro-apoptotic Ca(2+) signals induced by strong TCR activation without suppressing pro-survival Ca(2+) signals induced by weak TCR activation.
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http://dx.doi.org/10.4161/cc.5.11.2778DOI Listing
June 2006

Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation.

J Cell Biol 2006 Jan;172(1):127-37

Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.

To investigate the effect of Bcl-2 on Ca2+ signaling in T cells, we continuously monitored Ca2+ concentration in Bcl-2-positive and -negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2-negative cells, high concentrations of anti-CD3 antibody induced a transient Ca2+ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca2+ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca2+ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca2+ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP(3)) receptor subtypes by small interfering RNA inhibited the Ca2+ elevation induced by high but not low anti-CD3, suggesting that Ca2+ responses to high and low anti-CD3 may have different requirements for the InsP(3) receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca2+ elevation induced by strong TCR activation without hindering prosurvival Ca2+ signals induced by weak TCR activation.
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http://dx.doi.org/10.1083/jcb.200506189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063540PMC
January 2006