Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

Subscribe to Recent Research Articles from UNTHSC  feed Recent Research Articles from UNTHSC
NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
Updated: 2 hours 13 min ago

A technique for setting analytical thresholds in massively parallel sequencing-based forensic DNA analysis.

Sat, 09/16/2017 - 07:44
Related Articles

A technique for setting analytical thresholds in massively parallel sequencing-based forensic DNA analysis.

PLoS One. 2017;12(5):e0178005

Authors: Young B, King JL, Budowle B, Armogida L

Abstract
Amplicon (targeted) sequencing by massively parallel sequencing (PCR-MPS) is a potential method for use in forensic DNA analyses. In this application, PCR-MPS may supplement or replace other instrumental analysis methods such as capillary electrophoresis and Sanger sequencing for STR and mitochondrial DNA typing, respectively. PCR-MPS also may enable the expansion of forensic DNA analysis methods to include new marker systems such as single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) that currently are assayable using various instrumental analysis methods including microarray and quantitative PCR. Acceptance of PCR-MPS as a forensic method will depend in part upon developing protocols and criteria that define the limitations of a method, including a defensible analytical threshold or method detection limit. This paper describes an approach to establish objective analytical thresholds suitable for multiplexed PCR-MPS methods. A definition is proposed for PCR-MPS method background noise, and an analytical threshold based on background noise is described.

PMID: 28542338 [PubMed - indexed for MEDLINE]

Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development.

Sat, 09/16/2017 - 07:44
Related Articles

Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development.

Development. 2017 Mar 01;144(5):876-888

Authors: Home P, Kumar RP, Ganguly A, Saha B, Milano-Foster J, Bhattacharya B, Ray S, Gunewardena S, Paul A, Camper SA, Fields PE, Paul S

Abstract
GATA transcription factors are implicated in establishing cell fate during mammalian development. In early mammalian embryos, GATA3 is selectively expressed in the extraembryonic trophoblast lineage and regulates gene expression to promote trophoblast fate. However, trophoblast-specific GATA3 function is dispensable for early mammalian development. Here, using dual conditional knockout mice, we show that genetic redundancy of Gata3 with paralog Gata2 in trophoblast progenitors ensures the successful progression of both pre- and postimplantation mammalian development. Stage-specific gene deletion in trophoblasts reveals that loss of both GATA genes, but not either alone, leads to embryonic lethality prior to the onset of their expression within the embryo proper. Using ChIP-seq and RNA-seq analyses, we define the global targets of GATA2/GATA3 and show that they directly regulate a large number of common genes to orchestrate stem versus differentiated trophoblast fate. In trophoblast progenitors, GATA factors directly regulate BMP4, Nodal and Wnt signaling components that promote embryonic-extraembryonic signaling cross-talk, which is essential for the development of the embryo proper. Our study provides genetic evidence that impairment of trophoblast-specific GATA2/GATA3 function could lead to early pregnancy failure.

PMID: 28232602 [PubMed - indexed for MEDLINE]

Potential Audiological and MRI Markers of Tinnitus.

Fri, 09/15/2017 - 07:33
Related Articles

Potential Audiological and MRI Markers of Tinnitus.

J Am Acad Audiol. 2017 Sep;28(8):742-757

Authors: Gopal KV, Thomas BP, Nandy R, Mao D, Lu H

Abstract
BACKGROUND: Subjective tinnitus, or ringing sensation in the ear, is a common disorder with no accepted objective diagnostic markers.
PURPOSE: The purpose of this study was to identify possible objective markers of tinnitus by combining audiological and imaging-based techniques.
RESEARCH DESIGN: Case-control studies.
STUDY SAMPLE: Twenty adults drawn from our audiology clinic served as participants. The tinnitus group consisted of ten participants with chronic bilateral constant tinnitus, and the control group consisted of ten participants with no history of tinnitus. Each participant with tinnitus was closely matched with a control participant on the basis of age, gender, and hearing thresholds.
DATA COLLECTION AND ANALYSES: Data acquisition focused on systematic administration and evaluation of various audiological tests, including auditory-evoked potentials (AEP) and otoacoustic emissions, and magnetic resonance imaging (MRI) tests. A total of 14 objective test measures (predictors) obtained from audiological and MRI tests were subjected to statistical analyses to identify the best predictors of tinnitus group membership. The least absolute shrinkage and selection operator technique for feature extraction, supplemented by the leave-one-out cross-validation technique, were used to extract the best predictors. This approach provided a conservative model that was highly regularized with its error within 1 standard error of the minimum.
RESULTS: The model selected increased frontal cortex (FC) functional MRI activity to pure tones matching their respective tinnitus pitch, and augmented AEP wave N₁ amplitude growth in the tinnitus group as the top two predictors of tinnitus group membership. These findings suggest that the amplified responses to acoustic signals and hyperactivity in attention regions of the brain may be a result of overattention among individuals that experience chronic tinnitus.
CONCLUSIONS: These results suggest that increased functional MRI activity in the FC to sounds and augmented N₁ amplitude growth may potentially be the objective diagnostic indicators of tinnitus. However, due to the small sample size and lack of subgroups within the tinnitus population in this study, more research is needed before generalizing these findings.

PMID: 28906245 [PubMed - in process]

Years of Life Lost, Age Discrimination, and the Myth of Productivity.

Thu, 09/14/2017 - 07:32
Related Articles

Years of Life Lost, Age Discrimination, and the Myth of Productivity.

Am J Public Health. 2017 Oct;107(10):1535-1537

Authors: Brenner MH

PMID: 28902541 [PubMed - in process]

The effect of health insurance on childhood cancer survival in the United States.

Tue, 09/12/2017 - 07:33
Related Articles

The effect of health insurance on childhood cancer survival in the United States.

Cancer. 2017 Sep 11;:

Authors: Lee JM, Wang X, Ojha RP, Johnson KJ

Abstract
BACKGROUND: The effect of health insurance on childhood cancer survival has not been well studied. Using Surveillance, Epidemiology, and End Results (SEER) data, this study was designed to assess the association between health insurance status and childhood cancer survival.
METHODS: Data on cancers diagnosed among children less than 15 years old from 2007 to 2009 were obtained from the SEER 18 registries. The effect of health insurance at diagnosis on 5-year childhood cancer mortality was estimated with marginal survival probabilities, restricted mean survival times, and Cox proportional hazards (PH) regression analyses, which were adjusted for age, sex, race/ethnicity, and county-level poverty.
RESULTS: Among 8219 childhood cancer cases, the mean survival time was 1.32 months shorter (95% confidence interval [CI], -4.31 to 1.66) after 5 years for uninsured children (n = 131) versus those with private insurance (n = 4297), whereas the mean survival time was 0.62 months shorter (95% CI, -1.46 to 0.22) for children with Medicaid at diagnosis (n = 2838). In Cox PH models, children who were uninsured had a 1.26-fold higher risk of cancer death (95% CI, 0.84-1.90) than those who were privately insured at diagnosis. The risk for those with Medicaid was similar to the risk for those with private insurance at diagnosis (hazard ratio, 1.06; 95% CI, 0.93-1.21).
CONCLUSIONS: Overall, the results suggest that cancer survival is largely similar for children with Medicaid and those with private insurance at diagnosis. Slightly inferior survival was observed for those who were uninsured in comparison with those with private insurance at diagnosis. The latter result is based on a small number of uninsured children and should be interpreted cautiously. Further study is needed to confirm and clarify the reasons for these patterns. Cancer 2017. © 2017 American Cancer Society.

PMID: 28891067 [PubMed - as supplied by publisher]

A method for identifying discriminative isoform-specific peptides for clinical proteomics application.

Tue, 09/12/2017 - 07:33
Related Articles

A method for identifying discriminative isoform-specific peptides for clinical proteomics application.

BMC Genomics. 2016 Aug 22;17 Suppl 7:522

Authors: Zhang F, Chen JY

Abstract
BACKGROUND: Clinical proteomics application aims at solving a specific clinical problem within the context of a clinical study. It has been growing rapidly in the field of biomarker discovery, especially in the area of cancer diagnostics. Until recently, protein isoform has not been viewed as a new class of early diagnostic biomarkers for clinical proteomics. A protein isoform is one of different forms of the same protein. Different forms of a protein may be produced from single-nucleotide polymorphisms (SNPs), alternative splicing, or post-translational modifications (PTMs). Previous studies have shown that protein isoforms play critical roles in tumorigenesis, disease diagnosis, and prognosis. Identifying and characterizing protein isoforms are essential to the study of molecular mechanisms and early detection of complex diseases such as breast cancer. However, there are limitations with traditional methods such as EST sequencing, Microarray profiling (exon array, Exon-exon junction array), mRNA next-generation sequencing used for protein isoform determination: 1) not in the protein level, 2) no connectivity about connection of nonadjacent exons, 3) no SNPs and PTMs, and 4) low reproducibility. Moreover, there exist the computational challenges of clinical proteomics studies: 1) low sensitivity of instruments, 2) high data noise, and 3) high variability and low repeatability, although recent advances in clinical proteomics technology, LC-MS/MS proteomics, have been used to identify candidate molecular biomarkers in diverse range of samples, including cells, tissues, serum/plasma, and other types of body fluids.
RESULTS: Therefore, in the paper, we presented a peptidomics method for identifying cancer-related and isoform-specific peptide for clinical proteomics application from LC-MS/MS. First, we built a Peptidomic Database of Human Protein Isoforms, then created a peptidomics approach to perform large-scale screen of breast cancer-associated alternative splicing isoform markers in clinical proteomics, and lastly performed four kinds of validations: biological validation (explainable index), exon array, statistical validation of independent samples, and extensive pathway analysis.
CONCLUSIONS: Our results showed that alternative splicing isoform makers can act as independent markers of breast cancer and that the method for identifying cancer-specific protein isoform biomarkers from clinical proteomics application is an effective one for increasing the number of identified alternative splicing isoform markers in clinical proteomics.

PMID: 27557076 [PubMed - indexed for MEDLINE]

Transitioning From a Level II to Level I Trauma Center Increases Resident Patient Exposure.

Mon, 09/11/2017 - 07:33

Transitioning From a Level II to Level I Trauma Center Increases Resident Patient Exposure.

J Foot Ankle Surg. 2017 Sep 06;:

Authors: Carpenter B, Levine L, Niacaris T, Suzuki S

Abstract
Increased patient exposure has been shown to improve residency training as determined by better patient outcomes. The transition of John Peter Smith Hospital from a level II to a level I trauma center in 2009 provided a unique opportunity to investigate the direct effects of increased patient exposure on residency training in a relatively controlled setting. We evaluated the effect of the transition to a level I trauma center on residency training. In 2014, we examined the annual facility reports and separated the data into 2 groups: level II (2001 to 2008) and level I (2010 to 2013). The primary outcome measures were patient volume, surgical volume, patient acuity, and scholarly activity by the residents. The patient volume in all units increased significantly (p < .05 for all) after the transition to a level I center. The surgical volume increased significantly for the general surgery, orthopedics, and podiatry departments (p < .05 for all) but remained unchanged in the gynecology and oral maxillofacial surgery departments. The volume measures were performed on all 98 residents (100%). Patient acuity and scholarly activity increased by 17% and 52%, respectively; however, the differences in these data were not statistically significant. The scholarly activity per resident was measured for the orthopedic and podiatry departments. For those departments, the total number of residents was 30, and scholarly activity was measured for 100% of them. Overall, resident education improved when the hospital transitioned to a level I trauma center, although certain subspecialties benefited more than did others from this transition.

PMID: 28888403 [PubMed - as supplied by publisher]

STRSeq: A catalog of sequence diversity at human identification Short Tandem Repeat loci.

Sun, 09/10/2017 - 07:33

STRSeq: A catalog of sequence diversity at human identification Short Tandem Repeat loci.

Forensic Sci Int Genet. 2017 Sep 01;31:111-117

Authors: Gettings KB, Borsuk LA, Ballard D, Bodner M, Budowle B, Devesse L, King J, Parson W, Phillips C, Vallone PM

Abstract
The STR Sequencing Project (STRSeq) was initiated to facilitate the description of sequence-based alleles at the Short Tandem Repeat (STR) loci targeted in human identification assays. This international collaborative effort, which has been endorsed by the ISFG DNA Commission, provides a framework for communication among laboratories. The initial data used to populate the project are the aggregate alleles observed in targeted sequencing studies across four laboratories: National Institute of Standards and Technology (N=1786), Kings College London (N=1043), University of North Texas Health Sciences Center (N=839), and University of Santiago de Compostela (N=944), for a total of 4612 individuals. STRSeq data are maintained as GenBank records at the U.S. National Center for Biotechnology Information (NCBI), which participates in a daily data exchange with the DNA DataBank of Japan (DDBJ) and the European Nucleotide Archive (ENA). Each GenBank record contains the observed sequence of a STR region, annotation ("bracketing") of the repeat region and flanking region polymorphisms, information regarding the sequencing assay and data quality, and backward compatible length-based allele designation. STRSeq GenBank records are organized within a BioProject at NCBI (https://www.ncbi.nlm.nih.gov/bioproject/380127), which is sub-divided into: commonly used autosomal STRs, alternate autosomal STRs, Y-chromosomal STRs, and X-chromosomal STRs. Each of these categories is further divided into locus-specific BioProjects. The BioProject hierarchy facilitates access to the GenBank records by browsing, BLAST searching, or ftp download. Future plans include user interface tools at strseq.nist.gov, a pathway for submission of additional allele records by laboratories performing population sample sequencing and interaction with the STRidER web portal for quality control (http://strider.online).

PMID: 28888135 [PubMed - as supplied by publisher]

Forensic human identification using skin microbiomes.

Sun, 09/10/2017 - 07:33
Related Articles

Forensic human identification using skin microbiomes.

Appl Environ Microbiol. 2017 Sep 08;:

Authors: Schmedes SE, Woerner AE, Budowle B

Abstract
The human microbiome contributes significantly to the genetic content of the human body. Genetic and environmental factors help shape the microbiome, and as such, the microbiome can be unique to an individual. Previous studies have demonstrated the potential to use microbiome profiling for forensic applications, however a method has yet to identify stable features of skin microbiomes that produce high classification accuracies for samples collected over reasonably long time intervals. A novel approach is described to classify skin microbiomes to their donors by comparing two features types, Propionibacterium acnes pangenome presence/absence features and nucleotide diversities of stable clade-specific markers. Supervised learning was used to attribute skin microbiomes from 14 skin body sites from 12 healthy individuals sampled at three time points over a >2.5 year period with accuracies up to 100% for three body sites. Feature selection identified a reduced subset of markers from each body site that are highly individualizing, identifying 187 markers from 12 clades. Classification accuracies were compared in a formal model testing framework, and the results of this indicate that learners trained on nucleotide diversity perform significantly better than those trained on presence/absence encodings. This study used supervised learning to identify individuals with high accuracy and associated stable features from skin microbiomes over a period of up to almost 3 years. These selected features provide a preliminary marker panel for future development of a robust and reproducible method for skin microbiome profiling for forensic human identification.Importance A novel approach is described to attribute skin microbiomes, collected over a period of >2.5 years, to their individual hosts with a high degree of accuracy. Nucleotide diversities of stable clade-specific markers with supervised learning was used to classify skin microbiomes from a particular individual with up to 100% classification accuracy for three body sites. Attribute selection was used to identify 187 genetic markers from 12 clades which provide the greatest differentiation of individual skin microbiomes from 14 skin sites. This study performs skin microbiome profiling from a supervised learning approach and obtains high classification accuracy for samples collected from individuals over a relatively long time period for potential application to forensic human identification.

PMID: 28887423 [PubMed - as supplied by publisher]

Insight into Natural History of Congenital Vitiligo: A Case Report of a 23-Year-Old with Stable Congenital Vitiligo.

Sat, 09/09/2017 - 07:34

Insight into Natural History of Congenital Vitiligo: A Case Report of a 23-Year-Old with Stable Congenital Vitiligo.

Case Rep Dermatol Med. 2017;2017:5172140

Authors: Casey C, Weis SE

Abstract
Vitiligo is a disorder of skin pigmentation. It affects approximately 1% of the world's population. Vitiligo occurs equally between the sexes with no racial predilections. The majority of cases are acquired and arise between the second and third decades of life. Acquired vitiligo has an unpredictable clinical course. Congenital vitiligo is rare with few reported cases. Due to the rarity of congenital vitiligo, little is known about the clinical course. For patients with acquired or congenital vitiligo, the psychosocial burden can have a profound impact on quality of life. The unknown course of congenital vitiligo can exacerbate the feelings of distress and embarrassment. We report of a case of congenital vitiligo that has been stable for 23 years. The patient had no associated autoimmune disease. The pathogenesis of congenital vitiligo is unknown. This case may be useful to assist clinicians caring for newborns with congenital vitiligo in reassuring parents.

PMID: 28884030 [PubMed]

Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2.

Fri, 09/08/2017 - 07:45
Related Articles

Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2.

PLoS One. 2017;12(3):e0173854

Authors: Basu A, Sridharan S

Abstract
The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin complex 1 (mTORC1), enhanced breast cancer cell death by apoptotic stimuli. The increase in cell death by S6K2 depletion was partly due to inactivation of Akt. In the present study, we investigated if S6K2 regulates Mcl-1, which acts downstream of Akt. Silencing of S6K2 but not S6K1 in T47D cells decreased Mcl-1 level, and potentiated apoptosis induced by TRAIL and doxorubicin. Knockdown of S6K2 also decreased the level of anti-apoptotic Bcl-xl. Depletion of the tumor suppressor protein PDCD4 (programmed cell death 4), which regulates translation of several anti-apoptotic proteins, reversed downregulation of Bcl-xl but not Mcl-1 and failed to reverse the effect of S6K2 knockdown on potentiation of doxorubicin-induced apoptosis. Downregulation of Mcl-1 by S6K2 knockdown was partly restored by the proteasome inhibitor MG132. Overexpression of catalytically-active Akt or knockdown of glycogen synthase kinase-3 (GSK3)-β, a substrate for Akt, had little effect on Mcl-1 downregulation caused by S6K2 deficiency. Silencing of S6K2 increased the level of c-Jun N-terminal kinase (JNK) and knockdown of JNK1 increased basal Mcl-1 level and partly reversed the effect of S6K2 knockdown on Mcl-1 downregulation. JNK1 knockdown also had a modest effect in attenuating the increase in doxorubicin-induced apoptosis caused by S6K2 deficiency. These results suggest that S6K2 regulates apoptosis via multiple mechanisms, and involves both Akt and JNK.

PMID: 28301598 [PubMed - indexed for MEDLINE]

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease.

Fri, 09/08/2017 - 07:45
Related Articles

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease.

Horm Behav. 2016 Jul;83:39-44

Authors: Tschiffely AE, Schuh RA, Prokai-Tatrai K, Prokai L, Ottinger MA

Abstract
Estrogens are neuroprotective and, thus, potentially useful for the therapy of Alzheimer's disease; however, clinical use of hormone therapy remains controversial due to adverse peripheral effects. The goal of this study was to investigate the benefits of treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, in comparison with the parent hormone using APPswe/PS1dE9 double transgenic mice to model the pathology of the disease. Ovariectomized and intact females were continuously treated with vehicle, 17β-estradiol, or DHED via subcutaneous osmotic pumps from 6 to 8months of age. We confirmed that this prolonged treatment with DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment increased uterine weight. Amyloid precursor protein decreased in both treatment groups of intact, but not in ovariectomized double transgenic females in which ovariectomy already decreased the expression of this protein significantly. However, reduced brain amyloid-β peptide levels could be observed for both treatments. Consequently, double-transgenic ovariectomized and intact mice had higher cognitive performance compared to untreated control animals in response to both estradiol and DHED administrations. Overall, the tested brain-selective 17β-estradiol prodrug proved to be an effective early-stage intervention in an Alzheimer's disease-relevant mouse model without showing systemic impact and, thus, warrants further evaluation as a potential therapeutic candidate.

PMID: 27210479 [PubMed - indexed for MEDLINE]

Ceruloplasmin, a Potential Therapeutic Agent for Alzheimer's Disease.

Thu, 09/07/2017 - 07:37
Related Articles

Ceruloplasmin, a Potential Therapeutic Agent for Alzheimer's Disease.

Antioxid Redox Signal. 2017 Sep 06;:

Authors: Zhao YS, Zhang LH, Yu PP, Gou YJ, Zhao J, You LH, Wang ZY, Zheng X, Yan LJ, Yu P, Chang YZ

Abstract
AIMS: Ceruloplasmin (CP), as a ferrous oxidase enzyme, plays an important role in regulating iron metabolism and redox reactions. Previous studies showed that CP deficiency contributes to Parkinson's disease by increasing iron accumulation and oxidative stress in the substantia nigra. However, the role of CP in Alzheimer's disease (AD) is unclear. We hypothesized that the lack of CP gene expression would affect the pathogenesis and damage of AD by promoting abnormal iron levels and oxidative stress.
RESULTS: AD mouse models were induced in CP knock-out mouse either by injection of Aβ25-35 into the lateral ventricle of the brain or transgenic APP expression. CP levels were decreased significantly in the hippocampus of AD patients, as well as Aβ-CP+/+ and APP-CP+/+ mice. Compared to control AD mice, Aβ-CP-/- and APP-CP-/- mice had increases in memory impairment and iron accumulation, which could be associated with elevated reactive oxygen species (ROS) levels and lead to cell apoptosis mediated through the Bcl-2/Bax and Erk/p38 signaling pathways. In contrast, the restoration of CP expression to CP-/- mice through injection of an exogenous expression plasmid into the brain ventricle alleviated Aβ-induced neuronal damage in the hippocampus.
INNOVATION: CP alterations in iron contents were mediated through DMT1(-IRE) and changes in ROS levels, which in turn attenuated the progression of AD through the Erk/p38 and Bcl-2/Bax signaling pathways.
CONCLUSION: Our results show a protective role of CP in AD, and suggest that regulating CP expression in the hippocampus may provide a new neuroprotective strategy for AD.

PMID: 28874056 [PubMed - as supplied by publisher]

The dual modulatory effects of efavirenz on GABAA receptors are mediated via two distinct sites.

Thu, 09/07/2017 - 07:37
Related Articles

The dual modulatory effects of efavirenz on GABAA receptors are mediated via two distinct sites.

Neuropharmacology. 2017 Jul 15;121:167-178

Authors: Huang R, Chen Z, Dolan S, Schetz JA, Dillon GH

Abstract
Efavirenz is a widely prescribed medicine used to treat type 1 human immunodeficiency virus (HIV-1), the most prevalent pathogenic strain of the virus responsible for the acquired immune deficiency syndrome (AIDS) pandemic. Under prescribed dosing conditions, either alone or in combination therapy, efavirenz-induced CNS disturbances are frequently reported. Efavirenz was recently reported to interact in a similar concentration range with a number of receptors, transporters and ion channels including recombinant rat α1β2γ2 GABAA receptors whose actions were potentiated (Gatch et al., 2013; Dalwadi et al., 2016). Now we report on the molecular mechanism of efavirenz on GABAA receptors as a function of concentration and subunit composition via whole-cell recordings of GABA-activated currents from HEK293 cells expressing varying subunit configurations of GABAA receptors. Efavirenz elicited dual effects on the GABA response; it allosterically potentiated currents at low concentrations, whereas it inhibited currents at higher concentrations. The allosteric potentiating action on GABAA receptors was pronounced in the α1β2γ2, α2β2γ2 and α4β2γ2 configurations, greatly diminished in the α6β2γ2 configuration, and completely absent in the α3β2γ2 or α5β2γ2 configuration. In stark contrast, the inhibitory modulation of efavirenz at higher concentrations was evident in all subunit configurations examined. Moreover, efavirenz-induced modulatory effects were dependent on GABA concentration ([GABA]), with a pronounced impact on currents activated by low [GABA] but little effect at saturating [GABA]. Mutation of a highly-conserved threonine to phenylalanine in transmembrane domain 2 of the α1 subunit abolished the inhibitory effect of efavirenz in α1β2 receptors. Finally, mutations of any of the three conserved extracellular residues in α1/2/4 subunits to the conserved residues at the corresponding positions in α3/5 subunits (i.e., R84P, M89L or I120L) completely eliminated the potentiating effect of efavirenz in α1β2γ2 configuration. These findings demonstrate that efavirenz's positive allosteric modulation of the GABAA receptor is mediated via a novel allosteric site associated with the extracellular domain of the receptor.

PMID: 28456686 [PubMed - indexed for MEDLINE]

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Thu, 09/07/2017 - 07:37
Related Articles

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Int J Legal Med. 2016 Sep;130(5):1169-80

Authors: Churchill JD, King JL, Chakraborty R, Budowle B

Abstract
Massively parallel sequencing (MPS) offers substantial improvements over current forensic DNA typing methodologies such as increased resolution, scalability, and throughput. The Ion PGM™ is a promising MPS platform for analysis of forensic biological evidence. The system employs a sequencing-by-synthesis chemistry on a semiconductor chip that measures a pH change due to the release of hydrogen ions as nucleotides are incorporated into the growing DNA strands. However, implementation of MPS into forensic laboratories requires a robust chemistry. Ion Torrent's Hi-Q™ Sequencing Chemistry was evaluated to determine if it could improve on the quality of the generated sequence data in association with selected genetic marker targets. The whole mitochondrial genome and the HID-Ion STR 10-plex panel were sequenced on the Ion PGM™ system with the Ion PGM™ Sequencing 400 Kit and the Ion PGM™ Hi-Q™ Sequencing Kit. Concordance, coverage, strand balance, noise, and deletion ratios were assessed in evaluating the performance of the Ion PGM™ Hi-Q™ Sequencing Kit. The results indicate that reliable, accurate data are generated and that sequencing through homopolymeric regions can be improved with the use of Ion Torrent's Hi-Q™ Sequencing Chemistry. Overall, the quality of the generated sequencing data supports the potential for use of the Ion PGM™ in forensic genetic laboratories.

PMID: 27025714 [PubMed - indexed for MEDLINE]

Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.

Tue, 09/05/2017 - 07:34
Related Articles

Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.

Biochem Biophys Rep. 2017 Sep;11:119-129

Authors: Wu J, Luo X, Thangthaeng N, Sumien N, Chen Z, Rutledge MA, Jing S, Forster MJ, Yan LJ

Abstract
It is well established that NADH/NAD(+) redox balance is heavily perturbed in diabetes, and the NADH/NAD(+) redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD(+) regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD(+) redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and β cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.

PMID: 28868496 [PubMed]

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Sun, 09/03/2017 - 07:36

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Drug Alcohol Depend. 2017 Aug 24;180:39-45

Authors: Dolan SB, Forster MJ, Gatch MB

Abstract
Novel psychoactive substances have maintained a prominent role in the global drug culture, despite increased regulation by governing bodies. Novel compounds continue to become available on the market, often in "Ecstasy" or "Molly" formulations in lieu of MDMA, at a much faster rate than they can be properly characterized. The current study aimed to investigate the discriminative stimulus and locomotor effects of three putatively entactogenic compounds that have become increasingly prevalent on the drug market: 5-(2-aminopropyl)-benzofuran (5-APB), 6-(2-aminopropryl)-2,3-dihydrobenzofuran (6-APDB), and 4-fluoroamphetamine (4-FA). Locomotor stimulant effects were assessed in an open-field assay for locomotor activity using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine, DOM, or MDMA from vehicle. The benzofuran compounds produced locomotor stimulation whereas 4-FA depressed locomotor activity. The benzofurans substituted for the discriminative stimulus effects of MDMA, but only partially or not at all for methamphetamine, cocaine, and DOM, whereas 4-FA fully substituted for MDMA, methamphetamine and cocaine, but not DOM. These results indicate an MDMA-like pattern of abuse might be expected for the benzofurans, whereas 4-FA may be substituted for psychostimulants and MDMA.

PMID: 28865391 [PubMed - as supplied by publisher]

Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape?

Sat, 09/02/2017 - 07:34
Related Articles

Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape?

Am J Med. 2017 Aug;130(8):900-906

Authors: Gibson CM, Finks SW

Abstract
Edoxaban is the most recently approved factor Xa inhibitor within the class of direct oral anticoagulants (DOACs). Like other DOACs, edoxaban was approved by the US Food and Drug Administration for treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Similar to other DOACs, edoxaban has fewer drug-drug interactions than warfarin and does not require routine laboratory monitoring. Unlike other DOACs, edoxaban has yet to be approved for secondary or postoperative venous thromboembolism thromboprophylaxis. Currently no antidote for edoxaban is available. To optimally prescribe agents in the DOAC class, it is critical that providers 1) understand how the agents compare; and 2) identify specific settings in which one agent may be preferred over another.

PMID: 28390791 [PubMed - indexed for MEDLINE]

The Third International Genomic Medicine Conference (3rd IGMC, 2015): overall activities and outcome highlights.

Sat, 09/02/2017 - 07:34
Related Articles

The Third International Genomic Medicine Conference (3rd IGMC, 2015): overall activities and outcome highlights.

BMC Genomics. 2016 Oct 17;17(Suppl 9):747

Authors: Abu-Elmagd M, Assidi M, Dallol A, Buhmeida A, Pushparaj PN, Kalamegam G, Al-Hamzi E, Shay JW, Scherer SW, Agarwal A, Budowle B, Gari M, Chaudhary A, Abuzenadah A, Al-Qahtani M

Abstract
The Third International Genomic Medicine Conference (3(rd) IGMC) was organised by the Centre of Excellence in Genomic Medicine Research (CEGMR) at the King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia (KSA). This conference is a continuation of a series of meetings, which began with the first International Genomic Medicine Conference (1(st) IGMC, 2011) followed by the second International Genomic Medicine Conference (2(nd) IGMC, 2013). The 3(rd) IGMC meeting presented as a timely opportunity to bring scientists from across the world to gather, discuss, and exchange recent advances in the field of genomics and genetics in general as well as practical information on using these new technologies in different basic and clinical applications. The meeting undoubtedly inspired young male and female Saudi researchers, who attended the conference in large numbers, as evidenced by the oversubscribed oral and poster presentations. The conference also witnessed the launch of the first content for npj Genomic Medicine, a high quality new journal was established in partnership by CEGMR with Springer Nature and published as part of the Nature Partner Journal series. Here, we present a brief summary report of the 2-day meeting including highlights from the oral presentations, poster presentations, workshops, poster prize-winners and comments from the distinguished scientists.

PMID: 27766952 [PubMed - indexed for MEDLINE]

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

Sat, 09/02/2017 - 07:34
Related Articles

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

Leukemia. 2017 Feb;31(2):333-339

Authors: Pui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, Sandlund JT, Ribeiro RC, Rubnitz JE, Inaba H, Gruber TA, Leung WH, Yang JJ, Downing JR, Evans WE, Relling MV, Campana D

Abstract
To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

PMID: 27560110 [PubMed - indexed for MEDLINE]

Pages