Recent Research Articles from UNTHSC

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

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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: 1 hour 51 min ago

Fluorescence properties of doxorubicin in PBS buffer and PVA films.

Thu, 09/21/2017 - 07:33
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Fluorescence properties of doxorubicin in PBS buffer and PVA films.

J Photochem Photobiol B. 2017 May;170:65-69

Authors: Shah S, Chandra A, Kaur A, Sabnis N, Lacko A, Gryczynski Z, Fudala R, Gryczynski I

Abstract
We studied steady-state and time-resolved fluorescence properties of an anticancer drug Doxorubicin in a saline buffer and poly-vinyl alcohol (PVA) film. Absorption of Doxorubicin, located at blue-green spectral region, allows a convenient excitation with visible light emitting diodes or laser diodes. Emission of Doxorubicin with maximum near 600nm can be easily detected with photomultipliers and CCD cameras. Both, absorption and fluorescence spectra in polymeric matrix show more pronounced vibronic structures than in solution. Also, the steady-state anisotropy in the polymer film is significantly higher than in the saline solution. In PVA film the fluorescence anisotropy is about 0.30 whereas in the saline buffer only 0.07. Quantum efficiencies of Doxorubicin were compared to a known standard Rhodamine 101 which has fluorescence emission in a similar spectral region. The quantum yield of Doxorubicin in PVA film is more than 10% and about twice higher than in the saline solution. Similarly, the lifetime of doxorubicin in PVA film is about 2ns whereas in the saline solution only about 1ns. The fluorescence anisotropy decays show that Doxorubicin molecules are freely rotating in the saline buffer with a correlation time of about 290ps, and are almost completely immobilized in the PVA film. The spectroscopic investigations presented in this manuscript are important, as they provide answers to changes in molecular properties of Doxorubicin depending changes in the local environment, which is useful when synthesizing nanoparticles for Doxorubicin entrapment.

PMID: 28390260 [PubMed - indexed for MEDLINE]

Hormone-Related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization.

Wed, 09/20/2017 - 07:34
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Hormone-Related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization.

Pharmacotherapy. 2017 Jan;37(1):120-128

Authors: Warnock JK, Cohen LJ, Blumenthal H, Hammond JE

Abstract
Because estrogens and the trigeminal system are inherently linked, prescribers who are treating a woman with a hormonally related mood disorder and migraine headaches should consider hormonal options to optimize the patient's treatment. This article discusses the interrelationships of estrogen, serotonin, and the trigeminal system as they relate to menstrual migraine occurrence and hormone-related mood symptoms. In addition, clinical examples are provided to facilitate the prescribers treating women during reproductive transitions in which declining estrogens are related to their suffering.

PMID: 27888528 [PubMed - indexed for MEDLINE]

New perspectives on healthy aging.

Tue, 09/19/2017 - 07:33
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New perspectives on healthy aging.

Prog Neurobiol. 2017 Oct;157:1

Authors: Jin K

PMID: 28918824 [PubMed - in process]

Research data management in academic institutions: A scoping review.

Tue, 09/19/2017 - 07:33
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Research data management in academic institutions: A scoping review.

PLoS One. 2017;12(5):e0178261

Authors: Perrier L, Blondal E, Ayala AP, Dearborn D, Kenny T, Lightfoot D, Reka R, Thuna M, Trimble L, MacDonald H

Abstract
OBJECTIVE: The purpose of this study is to describe the volume, topics, and methodological nature of the existing research literature on research data management in academic institutions.
MATERIALS AND METHODS: We conducted a scoping review by searching forty literature databases encompassing a broad range of disciplines from inception to April 2016. We included all study types and data extracted on study design, discipline, data collection tools, and phase of the research data lifecycle.
RESULTS: We included 301 articles plus 10 companion reports after screening 13,002 titles and abstracts and 654 full-text articles. Most articles (85%) were published from 2010 onwards and conducted within the sciences (86%). More than three-quarters of the articles (78%) reported methods that included interviews, cross-sectional, or case studies. Most articles (68%) included the Giving Access to Data phase of the UK Data Archive Research Data Lifecycle that examines activities such as sharing data. When studies were grouped into five dominant groupings (Stakeholder, Data, Library, Tool/Device, and Publication), data quality emerged as an integral element.
CONCLUSION: Most studies relied on self-reports (interviews, surveys) or accounts from an observer (case studies) and we found few studies that collected empirical evidence on activities amongst data producers, particularly those examining the impact of research data management interventions. As well, fewer studies examined research data management at the early phases of research projects. The quality of all research outputs needs attention, from the application of best practices in research data management studies, to data producers depositing data in repositories for long-term use.

PMID: 28542450 [PubMed - indexed for MEDLINE]

Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

Tue, 09/19/2017 - 07:33
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Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

BMC Neurosci. 2017 Mar 01;18(1):27

Authors: McGrady NR, Minton AZ, Stankowska DL, He S, Jefferies HB, Krishnamoorthy RR

Abstract
BACKGROUND: Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro.
RESULTS: IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs.
CONCLUSIONS: Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.

PMID: 28249604 [PubMed - indexed for MEDLINE]

M2b macrophage polarization accompanied with reduction of long noncoding RNA GAS5.

Mon, 09/18/2017 - 07:34
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M2b macrophage polarization accompanied with reduction of long noncoding RNA GAS5.

Biochem Biophys Res Commun. 2017 Sep 13;:

Authors: Ito I, Asai A, Suzuki S, Kobayashi M, Suzuki F

Abstract
Macrophages (Mϕ) are highly plastic and change their functional phenotypes depending on microenvironmental signals. Recent studies have shown that microRNAs are involved in the polarization of Mϕ. In this study, we demonstrated that the phenotype of M2bMϕ [CCL1(+) IL-10(+) LIGHT(+)] switches to other phenotypes with interchangeability attained through the increased expression of growth arrest-specific 5 RNA (GAS5 RNA), a long non-coding RNA. GAS5 RNA has been described as a silencer of the CCL1 gene. Various phenotypes of Mϕ were prepared from bone marrow-derived Mϕ (BMDMϕ) after stimulation with IFNγ [M(IFNγ)]/M1Mϕ, IL-4 [M(IL-4)]/M2aMϕ, LPS and immobilized IgG [M(LPS + IC)]/M2bMϕ, and IL-10 [M(IL-10)/M2cMϕ]. BMDMϕ cultured with medium, [M(no)]/quiescent Mϕ, were used as a control. As compared to Μ(no), M(IFNγ), M(IL-4) and M(IL-10), the reduced level of GAS5 RNA was shown in M(LPS + IC). CCL1 and LIGHT mRNAs (typical biomarkers of M2bMϕ) were not expressed by M(LPS + IC) transduced with a GAS5 gene using lentiviral vector. The reduction of GAS5 RNA in M(LPS + IC) was mediated by the activation of nonsense-mediated RNA decay (NMD pathway). BMDMϕ overexpressed with GAS5 RNA after GAS5 gene transduction did not polarize to M2bMϕ even though they were stimulated with LPS and IC in combination. These results indicate that the reduction of GAS5 RNA influenced by the NMD pathway activation leads to the Mϕ polarization stimulated with LPS and IC in combination.

PMID: 28917839 [PubMed - as supplied by publisher]

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

Sat, 09/16/2017 - 07:44
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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]

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