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Massively parallel sequencing of 68 insertion/deletion markers identifies novel microhaplotypes for utility in human identity testing.

Recent Research Articles from UNTHSC - Thu, 06/15/2017 - 10:35
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Massively parallel sequencing of 68 insertion/deletion markers identifies novel microhaplotypes for utility in human identity testing.

Forensic Sci Int Genet. 2016 Nov;25:198-209

Authors: Wendt FR, Warshauer DH, Zeng X, Churchill JD, Novroski NM, Song B, King JL, LaRue BL, Budowle B

Abstract
Short tandem repeat (STR) loci are the traditional markers used for kinship, missing persons, and direct comparison human identity testing. These markers hold considerable value due to their highly polymorphic nature, amplicon size, and ability to be multiplexed. However, many STRs are still too large for use in analysis of highly degraded DNA. Small bi-allelic polymorphisms, such as insertions/deletions (INDELs), may be better suited for analyzing compromised samples, and their allele size differences are amenable to analysis by capillary electrophoresis. The INDEL marker allelic states range in size from 2 to 6 base pairs, enabling small amplicon size. In addition, heterozygote balance may be increased by minimizing preferential amplification of the smaller allele, as is more common with STR markers. Multiplexing a large number of INDELs allows for generating panels with high discrimination power. The Nextera™ Rapid Capture Custom Enrichment Kit (Illumina, Inc., San Diego, CA) and massively parallel sequencing (MPS) on the Illumina MiSeq were used to sequence 68 well-characterized INDELs in four major US population groups. In addition, the STR Allele Identification Tool: Razor (STRait Razor) was used in a novel way to analyze INDEL sequences and detect adjacent single nucleotide polymorphisms (SNPs) and other polymorphisms. This application enabled the discovery of unique allelic variants, which increased the discrimination power and decreased the single-locus random match probabilities (RMPs) of 22 of these well-characterized INDELs which can be considered as microhaplotypes. These findings suggest that additional microhaplotypes containing human identification (HID) INDELs may exist elsewhere in the genome.

PMID: 27685342 [PubMed - indexed for MEDLINE]

Native American population data based on the Globalfiler(®) autosomal STR loci.

Recent Research Articles from UNTHSC - Thu, 06/15/2017 - 10:35
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Native American population data based on the Globalfiler(®) autosomal STR loci.

Forensic Sci Int Genet. 2016 Sep;24:e12-3

Authors: Ng J, Oldt RF, McCulloh KL, Weise JA, Viray J, Budowle B, Smith DG, Kanthaswamy S

Abstract
Native American population data are limited and thus impact computing accurate statistical parameters for forensic investigations. Thus, additional information should be generated from geographically representative tribes in North America, particularly from those that are not included in existing population databases for forensic use. The Globafiler(®) PCR Amplification kit was used to produce STR genotypic data for 533 individuals who represent 31 Native American tribal populations derived from eight geographically diverse regions in North America. Population genetic estimates from 21 autosomal STRs are reported.

PMID: 27421760 [PubMed - indexed for MEDLINE]

Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Recent Research Articles from UNTHSC - Thu, 06/15/2017 - 10:35
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Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Forensic Sci Int Genet. 2016 Sep;24:18-23

Authors: Wendt FR, Churchill JD, Novroski NM, King JL, Ng J, Oldt RF, McCulloh KL, Weise JA, Smith DG, Kanthaswamy S, Budowle B

Abstract
Forensically-relevant genetic markers were typed for sixty-two Yavapai Native Americans using the ForenSeq™ DNA Signature Prep Kit.These data are invaluable to the human identity community due to the greater genetic differentiation among Native American tribes than among other subdivisions within major populations of the United States. Autosomal, X-chromosomal, and Y-chromosomal short tandem repeat (STR) and identity-informative (iSNPs), ancestry-informative (aSNPs), and phenotype-informative (pSNPs) single nucleotide polymorphism (SNP) allele frequencies are reported. Sequence-based allelic variants were observed in 13 autosomal, 3 X, and 3 Y STRs. These observations increased observed and expected heterozygosities for autosomal STRs by 0.081±0.068 and 0.073±0.063, respectively, and decreased single-locus random match probabilities by 0.051±0.043 for 13 autosomal STRs. The autosomal random match probabilities (RMPs) were 2.37×10-26 and 2.81×10-29 for length-based and sequence-based alleles, respectively. There were 22 and 25 unique Y-STR haplotypes among 26 males, generating haplotype diversities of 0.95 and 0.96, for length-based and sequencebased alleles, respectively. Of the 26 haplotypes generated, 17 were assigned to haplogroup Q, three to haplogroup R1b, two each to haplogroups E1b1b and L, and one each to haplogroups R1a and I1. Male and female sequence-based X-STR random match probabilities were 3.28×10-7 and 1.22×10-6, respectively. The average observed and expected heterozygosities for 94 iSNPs were 0.39±0.12 and 0.39±0.13, respectively, and the combined iSNP RMP was 1.08×10-32. The combined STR and iSNP RMPs were 2.55×10-58 and 3.02×10-61 for length-based and sequence-based STR alleles, respectively. Ancestry and phenotypic SNP information, performed using the ForenSeq™ Universal Analysis Software, predicted black hair, brown eyes, and some probability of East Asian ancestry for all but one sample that clustered between European and Admixed American ancestry on a principal components analysis. These data serve as the first population assessment using the ForenSeq™ panel and highlight the value of employing sequence-based alleles for forensic DNA typing to increase heterozygosity, which is beneficial for identity testing in populations with reduced genetic diversity.

PMID: 27243782 [PubMed - indexed for MEDLINE]

D5S2500 is an ambiguously characterized STR: Identification and description of forensic microsatellites in the genomics age.

Recent Research Articles from UNTHSC - Thu, 06/15/2017 - 10:35
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D5S2500 is an ambiguously characterized STR: Identification and description of forensic microsatellites in the genomics age.

Forensic Sci Int Genet. 2016 Jul;23:19-24

Authors: Phillips C, Parson W, Amigo J, King JL, Coble MD, Steffen CR, Vallone PM, Gettings KB, Butler JM, Budowle B

Abstract
In the process of establishing short tandem repeat (STR) sequence variant nomenclature guidelines in anticipation of expanded forensic multiplexes for massively parallel sequencing (MPS), it was discovered that the STR D5S2500 has multiple positions and genomic characteristics reported. This ambiguity is because the marker named D5S2500 consists of two different microsatellites forming separate components in the capillary electrophoresis multiplexes of Qiagen's HDplex (Hilden, Germany) and AGCU ScienTech's non-CODIS STR 21plex (Wuxi, Jiangsu, China). This study outlines the genomic details used to identify each microsatellite and reveals the D5S2500 marker in HDplex has the correctly assigned STR name, while the D5S2500 marker in the AGCU 21plex, closely positioned a further 1643 nucleotides in the human reference sequence, is an unnamed microsatellite. The fact that the D5S2500 marker has existed as two distinct STR loci undetected for almost ten years, even with reported discordant genotypes for the standard control DNA, underlines the need for careful scrutiny of the genomic properties of forensic STRs, as they become adapted for sequence analysis with MPS systems. We make the recommendation that precise chromosome location data must be reported for any forensic marker under development but not in common use, so that the genomic characteristics of the locus are validated to the same level of accuracy as its allelic variation and forensic performance. To clearly differentiate each microsatellite, we propose the name D5S2800 be used to identify the Chromosome-5 STR in the AGCU 21plex.

PMID: 26974236 [PubMed - indexed for MEDLINE]

Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Recent Research Articles from UNTHSC - Wed, 06/14/2017 - 07:35
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Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Am J Phys Anthropol. 2016 Oct;161(2):309-20

Authors: Maddux SD, Yokley TR, Svoma BM, Franciscus RG

Abstract
OBJECTIVES: Investigations into the selective role of climate on human nasal variation commonly divide climates into four broad adaptive zones (hot-dry, hot-wet, cold-dry, and cold-wet) based on temperature and relative humidity. Yet, absolute humidity-not relative humidity-is physiologically more important during respiration. Here, we investigate the global distribution of absolute humidity to better clarify ecogeographic demands on nasal physiology.
METHODS: We use monthly observations from the Climatic Research Unit Timeseries 3 (CRU TS3) database to construct global maps of average annual temperature, relative humidity and absolute humidity. Further, using data collected by Thomson and Buxton (1923) for over 15,000 globally-distributed individuals, we calculate the actual amount of heat and water that must be transferred to inspired air in different climatic regimes to maintain homeostasis, and investigate the influence of these factors on the nasal index.
RESULTS: Our results show that absolute humidity, like temperature, generally decreases with latitude. Furthermore, our results demonstrate that environments typically characterized as "cold-wet" actually exhibit low absolute humidities, with values virtually identical to cold-dry environments and significantly lower than hot-wet and even hot-dry environments. Our results also indicate that strong associations between the nasal index and absolute humidity are, potentially erroneously, predicated on individuals from hot-dry environments possessing intermediate (mesorrhine) nasal indices.
DISCUSSION: We suggest that differentially allocating populations to cold-dry or cold-wet climates is unlikely to reflect different selective pressures on respiratory physiology and nasal morphology-it is cold-dry, and to a lesser degree hot-dry environments, that stress respiratory function. Our study also supports assertions that demands for inspiratory modification are reduced in hot-wet environments, and that expiratory heat elimination for thermoregulation is a greater selective pressure in such environments.

PMID: 27374937 [PubMed - indexed for MEDLINE]

Allostery: An Overview of Its History, Concepts, Methods, and Applications.

Recent Research Articles from UNTHSC - Wed, 06/14/2017 - 07:35
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Allostery: An Overview of Its History, Concepts, Methods, and Applications.

PLoS Comput Biol. 2016 Jun;12(6):e1004966

Authors: Liu J, Nussinov R

Abstract
The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.

PMID: 27253437 [PubMed - indexed for MEDLINE]

Fast STR allele identification with STRait Razor 3.0.

Recent Research Articles from UNTHSC - Tue, 06/13/2017 - 07:37

Fast STR allele identification with STRait Razor 3.0.

Forensic Sci Int Genet. 2017 Jun 01;30:18-23

Authors: Woerner AE, King JL, Budowle B

Abstract
The short tandem repeat allele identification tool (STRait Razor), a program used to characterize the haplotypes of short tandem repeats (STRs) in massively parallel sequencing (MPS) data, was redesigned. STRait Razor v3.0 performs ∼660× faster allele identification than its previous version (v2s), a speedup that is largely due to a novel indexing strategy used to perform "fuzzy" (approximate) string matching of anchor sequences. Written in a portable compiled language, C++, STRait Razor v3.0 functions on all major operating systems including Microsoft Windows, and it has cross-platform multithreading support. In silico estimates of precision and accuracy of STRait Razor v3.0 were 100% in this evaluation and results were highly concordant with those of Strait Razor v2s. STRait Razor v3.0 adds several key features that simplify the haplotype reporting process, including simple filters to remove low frequency haplotypes as well as merging haplotypes within a locus encoded on opposite strands of the DNA molecule.

PMID: 28605651 [PubMed - as supplied by publisher]

Estimated blood alcohol concentrations achieved by consuming supersized alcopops.

Recent Research Articles from UNTHSC - Tue, 06/13/2017 - 07:37

Estimated blood alcohol concentrations achieved by consuming supersized alcopops.

Am J Drug Alcohol Abuse. 2017 Jun 12;:1-4

Authors: Rossheim ME, Thombs DL

Abstract
BACKGROUND: Producers of supersized alcopops have ignored requests from a number of state attorneys general to reduce the alcohol concentration in these products. To the contrary, new flavor options have since been released that contain even greater alcohol content so that some alcopop products now contain 5.5 standard alcoholic drinks in a single-serving can. Though alcohol content of supersized alcopops has risen, little attention has been paid to the blood alcohol concentration (BAC) level consumers can expect to achieve from drinking these products.
OBJECTIVES: To estimate BAC levels expected from consuming one or two cans of supersized alcopop, relative to beer.
METHODS: Median weight data from the National Health and Nutrition Examination Survey were used in Matthews and Miller's (1979) BAC estimation formula.
RESULTS: Consuming a single supersized alcopop over the course of 2 hours can put youth and young adults well over the legal per se driving limit of 0.08 g/dL. Consuming two cans puts them at risk of alcohol poisoning.
CONCLUSIONS: Estimates provided here show that supersized alcopop consumers obtain dangerously high BAC levels. Reductions in the alcohol content of supersized alcopops should be an urgent priority for public health policy and law.

PMID: 28605266 [PubMed - as supplied by publisher]

Rapid repeatable in vivo detection of retinal reactive oxygen species.

Recent Research Articles from UNTHSC - Tue, 06/13/2017 - 07:37
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Rapid repeatable in vivo detection of retinal reactive oxygen species.

Exp Eye Res. 2017 Jun 08;:

Authors: Fan N, Silverman SM, Liu Y, Wang X, Kim BJ, Tang L, Clark AF, Liu X, Pang IH

Abstract
Oxidative injuries, such as those related to reactive oxygen species (ROS), have been implicated in various retinal and optic nerve disorders. Many ROS detection methods have been developed. Although widely utilized, many of these methods are useful only in post mortem tissues, or require relatively expensive equipment, or involve intraocular injection. In the present study, we demonstrated and characterized a chemiluminescent probe L-012 as a noninvasive, in vivo ROS detection agent in the mouse retina. Using optic nerve crush (ONC) and retinal ischemia/reperfusion (I/R) as mouse injury models, we show that L-012 produced intensive luminescent signals specifically in the injured eyes. Histological examination showed that L-012 administration was safe to the retina. Additionally, compounds that reduce tissue superoxide levels, apocynin and TEMPOL, decreased injury-induced L-012 chemiluminescence. The decrease in L-012 signals correlated with their protective effects against retinal I/R-induced morphological and functional changes in the retina. Together, these data demonstrate the feasibility of a fast, simple, reproducible, and non-invasive detection method to monitor in vivo ROS in the retina. Furthermore, the results also show that reduction of ROS is a potential therapeutic approach for protection from these retinal injuries.

PMID: 28603016 [PubMed - as supplied by publisher]

The efficacy of novel anatomical sites for the assessment of muscle oxygenation during central hypovolemia.

Recent Research Articles from UNTHSC - Fri, 06/09/2017 - 07:35
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The efficacy of novel anatomical sites for the assessment of muscle oxygenation during central hypovolemia.

Exp Biol Med (Maywood). 2016 Nov;241(17):2007-2013

Authors: Sprick JD, Soller BR, Rickards CA

Abstract
Muscle tissue oxygenation (SmO2) can track central blood volume loss associated with hemorrhage. Traditional peripheral measurement sites (e.g., forearm) may not be practical due to excessive movement or injury (e.g., amputation). The aim of this study was to evaluate the efficacy of three novel anatomical sites for the assessment of SmO2 under progressive central hypovolemia. 10 male volunteers were exposed to stepwise prone lower body negative pressure to decrease central blood volume, while SmO2 was assessed at four sites-the traditional site of the flexor carpi ulnaris (ARM), and three novel sites not previously investigated during lower body negative pressure, the deltoid, latissimus dorsi, and trapezius. SmO2 at the novel sites was compared to the ARM sensor and to stroke volume responses. A reduction in SmO2 was detected by the ARM sensor at the first level of lower body negative pressure (-15 mmHg; P = 0.007), and at -30 (the deltoid), -45 (latissimus dorsi), and -60 mmHg lower body negative pressure (trapezius) at the novel sites (P ≤ 0.04). SmO2 responses at all novel sites were correlated with responses at the ARM (R ≥ 0.89), and tracked the reduction in stroke volume (R ≥ 0.87); the latissimus dorsi site exhibited the strongest linear correlations (R ≥ 0.96). Of the novel sensor sites, the latissimus dorsi exhibited the strongest linear associations with SmO2 at the ARM, and with reductions in central blood volume. These findings have important implications for detection of hemorrhage in austere environments (e.g., combat) when use of a peripheral sensor may not be ideal, and may facilitate incorporation of these sensors into uniforms.

PMID: 27439541 [PubMed - indexed for MEDLINE]

Using an exercise program to improve activity tolerance in a female with postural orthostatic tachycardia syndrome: A case report.

Recent Research Articles from UNTHSC - Thu, 06/08/2017 - 07:43
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Using an exercise program to improve activity tolerance in a female with postural orthostatic tachycardia syndrome: A case report.

Physiother Theory Pract. 2017 Jun 07;:1-10

Authors: Richardson MV, Nordon-Craft A, Carrothers L

Abstract
INTRODUCTION: The incidence of postural orthostatic tachycardia syndrome (POTS) is estimated to be at least 500,000 in the United States and is most commonly found in premenopausal females. This syndrome shares clinical features with orthostatic hypotension (OH); however, the inclusion criteria and clinical features for POTS are not well known. The purposes of this case report are to: 1) describe the common clinical features of POTS and highlight the differences to orthostatic hypotension and 2) discuss physical therapy management of patients with POTS using exercise.
CASE PRESENTATION: A 34-year-old female with a POTS exacerbation completed a 4-week physical therapy endurance and strengthening 'reconditioning' program. Initial symptoms included the following: dyspnea with mild exertion, light-headedness, fatigue, leg "heaviness," and the inability to perform normal work duties.
OUTCOMES: One-mile track walk test (1-MWT) estimated VO2max improved from the 45-50th percentile to the 65-70th percentile at 8 weeks post-discharge. She returned to work full-time and resumed all previous fitness activities.
CONCLUSION: The patient demonstrated clinically meaningful improvements in estimated VO2max after the "reconditioning" training. Physical therapists should be able to recognize the clinical features and inclusion criteria for POTS as part of a differential diagnosing process for patients complaining of orthostatic symptoms.

PMID: 28590791 [PubMed - as supplied by publisher]

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease.

Recent Research Articles from UNTHSC - Wed, 06/07/2017 - 07:34
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Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease.

Exp Biol Med (Maywood). 2016 Jun;241(12):1351-63

Authors: Manukhina EB, Downey HF, Shi X, Mallet RT

Abstract
Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

PMID: 27190276 [PubMed - indexed for MEDLINE]

Crosstalk between TGFβ and Wnt signaling pathways in the human trabecular meshwork.

Recent Research Articles from UNTHSC - Wed, 06/07/2017 - 07:34
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Crosstalk between TGFβ and Wnt signaling pathways in the human trabecular meshwork.

Exp Eye Res. 2016 Jul;148:97-102

Authors: Webber HC, Bermudez JY, Sethi A, Clark AF, Mao W

Abstract
Primary Open Angle Glaucoma (POAG) is an irreversible, vision-threatening disease that affects millions worldwide. The principal risk factor of POAG is increased intraocular pressure (IOP) due to pathological changes in the trabecular meshwork (TM). The TGFβ signaling pathway activator TGFβ2 and the Wnt signaling pathway inhibitor secreted frizzled-related protein 1 (sFRP1) are elevated in the POAG TM. In this study, we determined whether there is a crosstalk between the TGFβ/Smad pathway and the canonical Wnt pathway using luciferase reporter assays. Lentiviral luciferase reporter vectors for studying the TGFβ/Smad pathway or the canonical Wnt pathway were transduced into primary human non-glaucomatous TM (NTM) cells. Cells were treated with or without a combination of 5 μg/ml TGFβ2 and/or 100 ng/ml Wnt3a recombinant proteins, and luciferase levels were measured using a plate reader. We found that TGFβ2 inhibited Wnt3a-induced canonical Wnt pathway activation, while Wnt3a inhibited TGFβ2-induced TGFβ/Smad pathway activation (n = 6, p < 0.05) in 3 NTM cell strains. We also found that knocking down of Smad4 or β-catenin using siRNA in HTM5 cells transfected with similar luciferase reporter plasmids abolished the inhibitory effect of TGFβ2 and/or Wnt3a on the other pathway (n = 6). Our results suggest the existence of a cross-inhibition between the TGFβ/Smad and canonical Wnt pathways in the TM, and this cross-inhibition may be mediated by Smad4 and β-catenin.

PMID: 27091054 [PubMed - indexed for MEDLINE]

A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus.

Recent Research Articles from UNTHSC - Tue, 06/06/2017 - 13:37

A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus.

Aging Dis. 2017 May;8(3):277-286

Authors: Xu M, Sizova O, Wang L, Su DM

Abstract
Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3'UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.

PMID: 28580184 [PubMed]

mGlu5 negative allosteric modulators: a patent review (2013 - 2016).

Recent Research Articles from UNTHSC - Tue, 06/06/2017 - 13:37
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mGlu5 negative allosteric modulators: a patent review (2013 - 2016).

Expert Opin Ther Pat. 2017 Jun;27(6):691-706

Authors: Emmitte KA

Abstract
INTRODUCTION: The pursuit of small molecule mGlu5 NAMs as treatments for a variety of psychiatric and neurodegenerative disorders has developed into a mature field. In addition to extensive preclinical studies, multiple compounds have advanced into clinical trials with the most advanced studies occurring in patients with FXS, PD-LID, and MDD. Areas covered: This review begins with an update of the clinical activity with mGlu5 NAMs, and then moves into a summary of patent applications filed since 2013. The summaries are organized into three separate sections: (1) inventions centered on improvements to existing clinical compounds; (2) new small molecules that maintain the prototypical disubstituted alkyne chemotype found in many mGlu5 NAM compounds; and (3) new small molecules that are not from a disubstituted alkyne chemotype. Expert opinion: It is a critical moment for mGlu5 NAM research as recent reports from clinical trials have included some significant disappointments that have blunted prior optimism. Still, research in this area remains active, and recent years have added several more attractive small molecules to this field. There is now an arsenal of diverse chemotypes available to continue to probe this target in the hopes that a drug may yet emerge.

PMID: 28067079 [PubMed - indexed for MEDLINE]

Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line.

Recent Research Articles from UNTHSC - Tue, 06/06/2017 - 13:37
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Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line.

Endocrinology. 2016 Jul;157(7):2824-35

Authors: Holmes S, Singh M, Su C, Cunningham RL

Abstract
Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress-induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress-induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.

PMID: 27167771 [PubMed - indexed for MEDLINE]

Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk.

Recent Research Articles from UNTHSC - Tue, 06/06/2017 - 13:37
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Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk.

Endocrinology. 2016 May;157(5):2067-79

Authors: Sun F, Nguyen T, Jin X, Huang R, Chen Z, Cunningham RL, Singh M, Su C

Abstract
Progesterone (P4) exerts robust cytoprotection in brain slice cultures (containing both neurons and glia), yet such protection is not as evident in neuron-enriched cultures, suggesting that glia may play an indispensable role in P4's neuroprotection. We previously reported that a membrane-associated P4 receptor, P4 receptor membrane component 1, mediates P4-induced brain-derived neurotrophic factor (BDNF) release from glia. Here, we sought to determine whether glia are required for P4's neuroprotection and whether glia's roles are mediated, at least partially, via releasing soluble factors to act on neighboring neurons. Our data demonstrate that P4 increased the level of mature BDNF (neuroprotective) while decreasing pro-BDNF (potentially neurotoxic) in the conditioned media (CMs) of cultured C6 astrocytes. We examined the effects of CMs derived from P4-treated astrocytes (P4-CMs) on 2 neuronal models: 1) all-trans retinoid acid-differentiated SH-SY5Y cells and 2) mouse primary hippocampal neurons. P4-CM increased synaptic marker expression and promoted neuronal survival against H2O2. These effects were attenuated by Y1036 (an inhibitor of neurotrophin receptor [tropomysin-related kinase] signaling), as well as tropomysin-related kinase B-IgG (a more specific inhibitor to block BDNF signaling), which pointed to BDNF as the key protective component within P4-CM. These findings suggest that P4 may exert its maximal protection by triggering a glia-neuron cross talk, in which P4 promotes mature BDNF release from glia to enhance synaptogenesis as well as survival of neurons. This recognition of the importance of glia in mediating P4's neuroprotection may also inform the design of effective therapeutic methods for treating diseases wherein neuronal death and/or synaptic deficits are noted.

PMID: 26990062 [PubMed - indexed for MEDLINE]

An approach to understanding sleep and depressed mood in adolescents: person-centred sleep classification.

Recent Research Articles from UNTHSC - Sat, 06/03/2017 - 07:37
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An approach to understanding sleep and depressed mood in adolescents: person-centred sleep classification.

J Sleep Res. 2017 Jun 02;:

Authors: Shochat T, Barker DH, Sharkey KM, Van Reen E, Roane BM, Carskadon MA

Abstract
Depressive mood in youth has been associated with distinct sleep dimensions, such as timing, duration and quality. To identify discrete sleep phenotypes, we applied person-centred analysis (latent class mixture models) based on self-reported sleep patterns and quality, and examined associations between phenotypes and mood in high-school seniors. Students (n = 1451; mean age = 18.4 ± 0.3 years; 648 M) completed a survey near the end of high-school. Indicators used for classification included school night bed- and rise-times, differences between non-school night and school night bed- and rise-times, sleep-onset latency, number of awakenings, naps, and sleep quality and disturbance. Mood was measured using the total score on the Center for Epidemiologic Studies-Depression Scale. One-way anova tested differences between phenotype for mood. Fit indexes were split between 3-, 4- and 5-phenotype solutions. For all solutions, between phenotype differences were shown for all indicators: bedtime showed the largest difference; thus, classes were labelled from earliest to latest bedtime as 'A' (n = 751), 'B' (n = 428) and 'C' (n = 272) in the 3-class solution. Class B showed the lowest sleep disturbances and remained stable, whereas classes C and A each split in the 4- and 5-class solutions, respectively. Associations with mood were consistent, albeit small, with class B showing the lowest scores. Person-centred analysis identified sleep phenotypes that differed in mood, such that those with the fewest depressive symptoms had moderate sleep timing, shorter sleep-onset latencies and fewer arousals. Sleep characteristics in these groups may add to our understanding of how sleep and depressed mood associate in teens.

PMID: 28573658 [PubMed - as supplied by publisher]

Preparation and Characterization of Novel HDL-mimicking Nanoparticles for Nerve Growth Factor Encapsulation.

Recent Research Articles from UNTHSC - Fri, 06/02/2017 - 07:35
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Preparation and Characterization of Novel HDL-mimicking Nanoparticles for Nerve Growth Factor Encapsulation.

J Vis Exp. 2017 May 22;(123):

Authors: Zhu J, Dong X

Abstract
The objective of this article is to introduce preparation and characterization methods for nerve growth factor (NGF)-loaded, high-density, lipoprotein (HDL)-mimicking nanoparticles (NPs). HDLs are endogenous NPs and have been explored as vehicles for the delivery of therapeutic agents. Various methods have been developed to prepare HDL-mimicking NPs. However, they are generally complicated, time consuming, and difficult for industrial scale-up. In this study, one-step homogenization was used to mix the excipients and form the prototype NPs. NGF is a water-soluble protein of 26 kDa. To facilitate the encapsulation of NGF into the lipid environment of HDL-mimicking NPs, protamine USP was used to form an ion-pair complex with NGF to neutralize the charges on the NGF surface. The NGF/protamine complex was then introduced into the prototype NPs. Apolipoprotein A-I was finally coated on the surface of the NPs. NGF HDL-mimicking NPs showed preferable properties in terms of particle size, size distribution, entrapment efficiency, in vitro release, bioactivity, and biodistribution. With the careful design and exploration of homogenization in HDL-mimicking NPs, the procedure was greatly simplified, and the NPs were made scalable. Moreover, various challenges, such as separating unloaded NGF from the NPs, conducting reliable in vitro release studies, and measuring the bioactivity of the NPs, were overcome.

PMID: 28570541 [PubMed - in process]

Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units.

Recent Research Articles from UNTHSC - Fri, 06/02/2017 - 07:35
Related Articles

Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units.

Cell Death Dis. 2017 Jun 01;8(6):e2854

Authors: Zou J, Chen Z, Wei X, Chen Z, Fu Y, Yang X, Chen D, Wang R, Jenner P, Lu JH, Li M, Zhang Z, Tang B, Jin K, Wang Q

Abstract
Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

PMID: 28569795 [PubMed - in process]

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