Recent Research Articles from UNTHSC

Syndicate content NCBI pubmed
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 49 min ago

Evidence for the exclusive expression of functional homomeric α7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats.

1 hour 49 min ago
Related Articles

Evidence for the exclusive expression of functional homomeric α7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats.

Neurosci Lett. 2014 Mar 20;563:107-11

Authors: Tischkau S, Mhaskar Y, Uteshev VV

Abstract
Hypothalamic histaminergic tuberomammillary (TM) neurons in rats express high densities of nicotinic acetylcholine receptors (nAChRs) whose Ca(2+) permeability, kinetic and pharmacological properties are similar to those of heterologous homomeric α7 nAChRs. However, native α7 nAChR subunits can co-assemble with β or α5 nAChR subunits to form functional heteromeric α7-containing α7β or α7α5 nAChRs with kinetics and pharmacology similar to those of α7 homomers. Therefore, although TM nAChRs have been used as an ex vivo model of functional α7 homomers, the molecular makeup of TM nAChRs has not been determined and the expression of functional α7-containing heteromers in TM neurons has not been excluded. To determine the profile of TM nAChR subunit transcripts, we have conducted single-cell qRT-PCR experiments using acutely dissociated TM neurons in rats. TM neurons were found to express transcripts of only principal α3, α6 and α7 nAChR subunits. Transcripts of other known mammalian neuronal subunits (α2, α4-5, α9-10, β2-4) were not detected. In the absence of β and α5 subunits, the expression of functional α7-containing heteromers in TM neurons is highly unlikely because principal α3, α6 and α7 nAChR subunits alone are not known to form functional heteromeric nAChRs. These results support the exclusive expression of native functional α7 homomers in rat TM neurons and introduce these neurons as a unique reliable source of native functional homomeric α7 nAChRs suitable for ex vivo and in vitro pharmacological assays in developing selective α7 nAChR agents.

PMID: 24486841 [PubMed - indexed for MEDLINE]

Methylene blue promotes quiescence of rat neural progenitor cells.

17 hours 47 min ago
Related Articles

Methylene blue promotes quiescence of rat neural progenitor cells.

Front Cell Neurosci. 2014;8:315

Authors: Xie L, Choudhury GR, Wang J, Park Y, Liu R, Yuan F, Zhang CL, Yorio T, Jin K, Yang SH

Abstract
Neural stem cell-based treatment holds a new therapeutic opportunity for neurodegenerative disorders. Here, we investigated the effect of methylene blue on proliferation and differentiation of rat neural progenitor cells (NPCs) both in vitro and in vivo. We found that methylene blue inhibited proliferation and promoted quiescence of NPCs in vitro without affecting committed neuronal differentiation. Consistently, intracerebroventricular infusion of methylene blue significantly inhibited NPC proliferation at the subventricular zone (SVZ). Methylene blue inhibited mTOR signaling along with down-regulation of cyclins in NPCs in vitro and in vivo. In summary, our study indicates that methylene blue may delay NPC senescence through enhancing NPCs quiescence.

PMID: 25339866 [PubMed]

Validation of a self-administered computerized system to detect cognitive impairment in older adults.

Fri, 10/24/2014 - 4:05am
Related Articles

Validation of a self-administered computerized system to detect cognitive impairment in older adults.

J Appl Gerontol. 2014 Dec;33(8):942-62

Authors: Brinkman SD, Reese RJ, Norsworthy LA, Dellaria DK, Kinkade JW, Benge J, Brown K, Ratka A, Simpkins JW

Abstract
There is increasing interest in the development of economical and accurate approaches to identifying persons in the community who have mild, undetected cognitive impairments. Computerized assessment systems have been suggested as a viable approach to identifying these persons. The validity of a computerized assessment system for identification of memory and executive deficits in older individuals was evaluated in the current study. Volunteers (N = 235) completed a 3-hr battery of neuropsychological tests and a computerized cognitive assessment system. Participants were classified as impaired (n = 78) or unimpaired (n = 157) on the basis of the Mini Mental State Exam, Wechsler Memory Scale-III and the Trail Making Test (TMT), Part B. All six variables (three memory variables and three executive variables) derived from the computerized assessment differed significantly between groups in the expected direction. There was also evidence of temporal stability and concurrent validity. Application of computerized assessment systems for clinical practice and for identification of research participants is discussed in this article.

PMID: 25332303 [PubMed - in process]

Electrophoretic Characterization of the Mammalian Nuclear Matrix Proteome, Nuclear Envelope, Nucleoli and Covalently Bound ADP-Ribose Polymers: Potential Applications to Cancer.

Fri, 10/24/2014 - 4:05am
Related Articles

Electrophoretic Characterization of the Mammalian Nuclear Matrix Proteome, Nuclear Envelope, Nucleoli and Covalently Bound ADP-Ribose Polymers: Potential Applications to Cancer.

Cancer Genomics Proteomics. 2014 09-10;11(5):217-223

Authors: Aranda XG, Racho RG, Pacheco-Rodríguez G, Alvarez-González R

Abstract
Background/Aim: Nucleic acid metabolism is biochemically compartmentalized to the nucleus. Thus, it is necessary to define the proteome of the various macromolecular structures within this organelle. Materials and Methods: We isolated the nuclear matrix (NM) fraction from rat liver by sequential centrifugation steps at 13,000 rpm, staggered between endogenous nuclease treatment for 2 h at 37°C, followed by high-salt (H.S.; 2.0 M NaCl) and non-ionic detergent extractions (0.1%- or 1.0% Triton X-100) to eliminate the bulk of chromosomal DNA/RNA, histone proteins and the nuclear envelope (NE). Results: Integrity of the NM and NE structures was confirmed by electron microscopy. Next, we analyzed the NM proteome on a 20% polyacrylamide gel using the PhastSystem. We observed the absence of histone proteins and the characteristic presence of the lamins by Coomassie blue staining. By contrast, upon silver staining, following electrophoretic separation with a Tris-Borate-EDTA buffer, we observed the NM-associated nucleic RNA and protein-free ADP-ribose polymers. While polymers are found in much lower concentration than RNA in NM, they were purified by affinity chromatography on boronate resin prior to electrophoresis. We observed the electrophoretic resolution of free ADP-ribose chains (5-25 units) by silver staining. Conclusion: The significance of our observations to cancer studies and carcinogenesis is discussed.

PMID: 25331794 [PubMed - as supplied by publisher]

A Weighted U-Statistic for Genetic Association Analyses of Sequencing Data.

Fri, 10/24/2014 - 4:05am
Related Articles

A Weighted U-Statistic for Genetic Association Analyses of Sequencing Data.

Genet Epidemiol. 2014 Oct 20;

Authors: Wei C, Li M, He Z, Vsevolozhskaya O, Schaid DJ, Lu Q

Abstract
With advancements in next-generation sequencing technology, a massive amount of sequencing data is generated, which offers a great opportunity to comprehensively investigate the role of rare variants in the genetic etiology of complex diseases. Nevertheless, the high-dimensional sequencing data poses a great challenge for statistical analysis. The association analyses based on traditional statistical methods suffer substantial power loss because of the low frequency of genetic variants and the extremely high dimensionality of the data. We developed a Weighted U Sequencing test, referred to as WU-SEQ, for the high-dimensional association analysis of sequencing data. Based on a nonparametric U-statistic, WU-SEQ makes no assumption of the underlying disease model and phenotype distribution, and can be applied to a variety of phenotypes. Through simulation studies and an empirical study, we showed that WU-SEQ outperformed a commonly used sequence kernel association test (SKAT) method when the underlying assumptions were violated (e.g., the phenotype followed a heavy-tailed distribution). Even when the assumptions were satisfied, WU-SEQ still attained comparable performance to SKAT. Finally, we applied WU-SEQ to sequencing data from the Dallas Heart Study (DHS), and detected an association between ANGPTL 4 and very low density lipoprotein cholesterol.

PMID: 25331574 [PubMed - as supplied by publisher]

Long lived BSA Au clusters as a time gated intensity imaging probe.

Fri, 10/24/2014 - 4:05am
Related Articles

Long lived BSA Au clusters as a time gated intensity imaging probe.

Nanoscale. 2014 Mar 7;6(5):2594-7

Authors: Raut SL, Fudala R, Rich R, Kokate RA, Chib R, Gryczynski Z, Gryczynski I

Abstract
The work presented here reports the use of long lifetime (>1 μs) BSA Au clusters as a cellular/tissue, time gated, intensity imaging probe. By collecting the emission signal 50 ns post excitation, one can off-gate the intense auto-fluorescence background, thereby greatly enhancing the clarity/specificity in fluorescence imaging.

PMID: 24469148 [PubMed - indexed for MEDLINE]

Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10.

Wed, 10/22/2014 - 4:06am

Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10.

Eur J Immunol. 2014 Oct 20;

Authors: Xie L, Choudhury GR, Winters A, Yang SH, Jin K

Abstract
Forkhead box P3 (Foxp3)(+) regulatory T (Treg) cells maintain the immune tolerance and prevent inflammatory responses in the periphery. However, the presence of Treg cells in the central nervous system under steady state has not been studied. Here, for the first time, we show a substantial TCRαβ (+) CD4(+) Foxp3(+) T-cell population (cerebral Treg cells) in the normal rat cerebrum, constituting more than 15% of the cerebral CD4(+) T-cell compartment. Cerebral Treg cells showed an activated/memory phenotype and expressed many Treg-cell signature genes at higher levels than peripheral Treg cells. Consistent with their activated/memory phenotype, cerebral Treg cells robustly restrained the LPS-induced inflammatory responses of brain microglia/macrophages, suggesting a role in maintaining the cerebral homeostasis by inhibiting the neuroinflammation. In addition, brain astrocytes were the helper cells that sustained Foxp3 expression in Treg cells through IL-2/STAT5 signaling, showing that the interaction between astrocytes and Treg cells contributes to the maintenance of Treg-cell identity in the brain. Taken together, our work represents the first study to characterize the phenotypic and functional features of Treg cells in the normal rat cerebrum. Our data have provided a novel insight for the contribution of Treg cells to the immunosurveillance and immunomodulation in the cerebrum under steady state. This article is protected by copyright. All rights reserved.

PMID: 25329858 [PubMed - as supplied by publisher]

Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice.

Tue, 10/21/2014 - 4:06am
Related Articles

Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice.

Behav Pharmacol. 2014 Oct 16;

Authors: Gatch MB, Forster MJ

Abstract
A number of cannabinoid compounds are being sold in the form of incense as 'legal' alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ-tetrahydrocannabinol (Δ-THC), the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201, and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ-THC (3 mg/kg, intraperitoneally). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for 1-2 h. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ-THC, and the effects of three of the compounds lasted substantially longer (JWH-073, JWH-250, and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable with those of Δ-THC, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards among humans.

PMID: 25325289 [PubMed - as supplied by publisher]

Resident Assistant Training Program for Increasing Alcohol, Other Drug, and Mental Health First-Aid Efforts.

Tue, 10/21/2014 - 4:06am
Related Articles

Resident Assistant Training Program for Increasing Alcohol, Other Drug, and Mental Health First-Aid Efforts.

Prev Sci. 2014 Oct 17;

Authors: Thombs DL, Gonzalez JM, Osborn CJ, Rossheim ME, Suzuki S

Abstract
In college and university residence halls, resident assistants (RAs) are expected to serve as first-aid providers to students who may have alcohol, other drug, mental health, and academic problems. Despite this responsibility, evidence-based, first-aid programs have not been developed and tested for the RA workforce. The current study examined effects of an investigational first-aid program designed specifically for RAs. The online Peer Hero Training program is a novel approach to RA training in its use of interactive video dramatizations of incidents involving substance-using or distressed residents. A 9-month randomized trial conducted on eight US campuses compared RAs who participated in the Peer Hero Training program to RAs who received training-as-usual. Participation in the Peer Hero Training program significantly increased RA first-aid efforts for residential students who may have had alcohol, other drug, mental health, or academic problems 6 months after baseline. Compared with those in the training-as-usual condition, RAs in the Peer Hero Training program made more than 10 times as many first-aid efforts for possible alcohol problems, almost 14 times the number of first-aid efforts for possible drug use, almost 3 times the number of first-aid efforts for possible mental health problems, and 3 times the number of first-aid efforts for academic problems. There was no evidence that measured RA attitudes mediated the effects of the intervention. Results of this preliminary evaluation trial suggest that online training using interactive video dramatizations is a viable approach to strengthening RAs' ability to provide alcohol, other drugs, and mental health first-aid to undergraduates.

PMID: 25322950 [PubMed - as supplied by publisher]

Blood pressure regulation XI: overview and future research directions.

Tue, 10/21/2014 - 4:06am
Related Articles

Blood pressure regulation XI: overview and future research directions.

Eur J Appl Physiol. 2014 Mar;114(3):579-86

Authors: Raven PB, Chapleau MW

Abstract
While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

PMID: 24463603 [PubMed - indexed for MEDLINE]

Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies.

Sat, 10/18/2014 - 4:08am
Related Articles

Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies.

Br J Cancer. 2014 Oct 16;

Authors: Chaudhary P, Thamake SI, Shetty P, Vishwanatha JK

Abstract
Background:Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting this role is still unknown.Methods:The membrane function of AnxA2 was blocked by incubating cells with anti-AnxA2 antibodies. Western blotting, immunoprecipitation, immunofluorescence, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic, and wound-healing assays were performed in this study.Results:We demonstrate that AnxA2 interacts with epidermal growth factor receptor (EGFR) at the cell surface and has an important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalisation by blocking its homodimerisation. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR-dependent PI3K-AKT and Raf-MEK-ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and migration.Conclusions:These findings suggest that cell-surface AnxA2 has an important regulatory role in EGFR-mediated oncogenic processes by keeping EGFR signalling events in an activated state. Therefore, AnxA2 could potentially be used as a therapeutic target in triple-negative and Herceptin-resistant breast cancers.British Journal of Cancer advance online publication 16 October 2014; doi:10.1038/bjc.2014.542 www.bjcancer.com.

PMID: 25321192 [PubMed - as supplied by publisher]

HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China.

Sat, 10/18/2014 - 4:08am
Related Articles

HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China.

BMJ Open. 2014;4(10):e005886

Authors: Leng X, Liang S, Ma Y, Dong Y, Kan W, Goan D, Hsi JH, Liao L, Wang J, He C, Zhang H, Xing H, Ruan Y, Shao Y

Abstract
OBJECTIVE: To explore HIV virological failure and drug resistance among injecting drug users (IDUs) receiving first-line antiretroviral treatment (ART) in China.
DESIGN: A series of cross-sectional surveys from 2003 to 2012 from the Chinese National HIV Drug Resistance (HIVDR) Surveillance and Monitoring Network.
SETTING: China.
PARTICIPANTS: Data were analysed by the Chinese National (HIVDR) Surveillance and Monitoring Network from 2003 to 2012. Demographic, ART and laboratory data (CD4+ cell count, viral load and drug resistance) were included. Factors associated with virological failure were identified by logistic regression analysis.
RESULTS: 929 of the 8556 individuals in the Chinese HIVDR database were IDUs receiving first-line ART. For these 929 IDUs, the median duration of treatment was 14 months (IQR 6.0-17.8). 193 of the 929 IDUs (20.8%) experienced virological failure (HIV viral load ≥1000 copies/mL). The prevalence of HIVDR among patients with virological failure was 38.9% (68/175). The proportion of patients with drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs), nucleoside reverse transcriptase inhibitor (NRTIs) and protease inhibitors (PIs) was 52.9%, 76.5% and 4.4%, respectively. Factors independently associated with virological failure include: ethnic minorities, junior high school education or less, farmers, self-reported missing doses in the past month, CD4 cell count at survey from 200 to 349 cells/mm(3) or from 0 to 199 cells/mm(3), and residence of Guangxi and Yunnan provinces.
CONCLUSIONS: The proportion of virological failure was high among IDUs receiving first-line ART in China. However, better treatment outcomes were observed in Guangxi and Yunnan, which indicates the importance of ART education and adherence to intervention, especially for patients who are farmers, minorities or have a poor educational background.

PMID: 25319999 [PubMed - in process]

Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke.

Fri, 10/17/2014 - 12:05pm
Related Articles

Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke.

Brain Res. 2014 Mar 10;1551:45-58

Authors: Roy Choudhury G, Ryou MG, Poteet E, Wen Y, He R, Sun F, Yuan F, Jin K, Yang SH

Abstract
Reactive astrogliosis is an essential feature of astrocytic response to all forms of central nervous system (CNS) injury and disease, which may benefit or harm surrounding neural and non-neural cells. Despite extensive study, its molecular triggers remain largely unknown in term of ischemic stroke. In the current study we investigated the role p38 mitogen-activated protein kinase (MAPK) in astrogliosis both in vitro and in vivo. In a mouse model of middle cerebral artery occlusion (MCAO), p38 MAPK activation was observed in the glia scar area, along with increased glial fibrillary acidic protein (GFAP) expression. In primary astrocyte cultures, hypoxia and scratch injury-induced astrogliosis was attenuated by both p38 inhibition and knockout of p38 MAPK. In addition, both knockout and inhibition of p38 MAPK also reduced astrocyte migration, but did not affect astrocyte proliferation. In a mouse model of permanent MCAO, no significant difference in motor function recovery and lesion volume was observed between conditional GFAP/p38 MAPK knockout mice and littermates. While a significant reduction of astrogliosis was observed in the GFAP/p38 knockout mice compared with the littermates. Our findings suggest that p38 MAPK signaling pathway plays an important role in the ischemic stroke-induced astrogliosis and thus may serve as a novel target to control glial scar formation.

PMID: 24440774 [PubMed - indexed for MEDLINE]

Ancient human genomes suggest three ancestral populations for present-day Europeans.

Thu, 10/16/2014 - 4:04am
Related Articles

Ancient human genomes suggest three ancestral populations for present-day Europeans.

Nature. 2014 Sep 18;513(7518):409-13

Authors: Lazaridis I, Patterson N, Mittnik A, Renaud G, Mallick S, Kirsanow K, Sudmant PH, Schraiber JG, Castellano S, Lipson M, Berger B, Economou C, Bollongino R, Fu Q, Bos KI, Nordenfelt S, Li H, de Filippo C, Prüfer K, Sawyer S, Posth C, Haak W, Hallgren F, Fornander E, Rohland N, Delsate D, Francken M, Guinet JM, Wahl J, Ayodo G, Babiker HA, Bailliet G, Balanovska E, Balanovsky O, Barrantes R, Bedoya G, Ben-Ami H, Bene J, Berrada F, Bravi CM, Brisighelli F, Busby GB, Cali F, Churnosov M, Cole DE, Corach D, Damba L, van Driem G, Dryomov S, Dugoujon JM, Fedorova SA, Gallego Romero I, Gubina M, Hammer M, Henn BM, Hervig T, Hodoglugil U, Jha AR, Karachanak-Yankova S, Khusainova R, Khusnutdinova E, Kittles R, Kivisild T, Klitz W, Kučinskas V, Kushniarevich A, Laredj L, Litvinov S, Loukidis T, Mahley RW, Melegh B, Metspalu E, Molina J, Mountain J, Näkkäläjärvi K, Nesheva D, Nyambo T, Osipova L, Parik J, Platonov F, Posukh O, Romano V, Rothhammer F, Rudan I, Ruizbakiev R, Sahakyan H, Sajantila A, Salas A, Starikovskaya EB, Tarekegn A, Toncheva D, Turdikulova S, Uktveryte I, Utevska O, Vasquez R, Villena M, Voevoda M, Winkler CA, Yepiskoposyan L, Zalloua P, Zemunik T, Cooper A, Capelli C, Thomas MG, Ruiz-Linares A, Tishkoff SA, Singh L, Thangaraj K, Villems R, Comas D, Sukernik R, Metspalu M, Meyer M, Eichler EE, Burger J, Slatkin M, Pääbo S, Kelso J, Reich D, Krause J

Abstract
We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.

PMID: 25230663 [PubMed - indexed for MEDLINE]

A useful mouse model of glucocorticoid-induced ocular hypertension.

Thu, 10/16/2014 - 4:04am
Related Articles

A useful mouse model of glucocorticoid-induced ocular hypertension.

Invest Ophthalmol Vis Sci. 2014 Aug;55(8):4934

Authors: Clark AF

PMID: 25108005 [PubMed - indexed for MEDLINE]

Differentially expressed wound healing-related microRNAs in the human diabetic cornea.

Wed, 10/15/2014 - 4:05am
Related Articles

Differentially expressed wound healing-related microRNAs in the human diabetic cornea.

PLoS One. 2013;8(12):e84425

Authors: Funari VA, Winkler M, Brown J, Dimitrijevich SD, Ljubimov AV, Saghizadeh M

Abstract
MicroRNAs are powerful gene expression regulators, but their corneal repertoire and potential changes in corneal diseases remain unknown. Our purpose was to identify miRNAs altered in the human diabetic cornea by microarray analysis, and to examine their effects on wound healing in cultured telomerase-immortalized human corneal epithelial cells (HCEC) in vitro. Total RNA was extracted from age-matched human autopsy normal (n=6) and diabetic (n=6) central corneas, Flash Tag end-labeled, and hybridized to Affymetrix® GeneChip® miRNA Arrays. Select miRNAs associated with diabetic cornea were validated by quantitative RT-PCR (Q-PCR) and by in situ hybridization (ISH) in independent samples. HCEC were transfected with human pre-miR™miRNA precursors (h-miR) or their inhibitors (antagomirs) using Lipofectamine 2000. Confluent transfected cultures were scratch-wounded with P200 pipette tip. Wound closure was monitored by digital photography. Expression of signaling proteins was detected by immunostaining and Western blot. Using microarrays, 29 miRNAs were identified as differentially expressed in diabetic samples. Two miRNA candidates showing the highest fold increased in expression in the diabetic cornea were confirmed by Q-PCR and further characterized. HCEC transfection with h-miR-146a or h-miR-424 significantly retarded wound closure, but their respective antagomirs significantly enhanced wound healing vs. controls. Cells treated with h-miR-146a or h-miR-424 had decreased p-p38 and p-EGFR staining, but these increased over control levels close to the wound edge upon antagomir treatment. In conclusion, several miRNAs with increased expression in human diabetic central corneas were found. Two such miRNAs inhibited cultured corneal epithelial cell wound healing. Dysregulation of miRNA expression in human diabetic cornea may be an important mediator of abnormal wound healing.

PMID: 24376808 [PubMed - indexed for MEDLINE]

Sigma-1 Receptor Stimulation Protects Retinal Ganglion Cells from Ischemia-Like Insult through the Activation of Extracellular-Signal-Regulated Kinases1/2.

Tue, 10/14/2014 - 4:05am
Related Articles

Sigma-1 Receptor Stimulation Protects Retinal Ganglion Cells from Ischemia-Like Insult through the Activation of Extracellular-Signal-Regulated Kinases1/2.

Exp Eye Res. 2014 Oct 8;

Authors: Mueller BH, Park Y, Ma HY, Dibas A, Ellis DZ, Clark AF, Yorio T

Abstract
Sigma-1 receptor (σ-1) activation and mitogen-activated protein kinases (MAPKs) have been shown to protect retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if σ-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of an ischemia-like insult (oxygen glucose deprivation (OGD)) through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using Thy 1.1 antibodies. RGCs were cultured for 7 days before subjecting the cells to an OGD insult (0.5% oxygen in glucose-free medium) for 6 hours. During the OGD, RGCs were treated with pentazocine (σ-1 receptor agonist) with or without BD 1047 (σ-1 receptor antagonist). In other experiments, primary RGCs were treated with pentazocine in the presence or absence of an MEK1/2 inhibitor, PD098059. Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined by immunoblotting and immunofluorescence staining. RGCs subjected to OGD for 6 hours induced 50% cell death in primary RGCs (p<0.001) and inhibited pERK1/2 expression by 65% (p<0.001). Cell death was attenuated when RGCs were treated with pentazocine under OGD (p<0.001) and pERK1/2 expression was increased by 1.6 fold (p<0.05) compared to OGD treated RGCs without pentazocine treatment. The co-treatment of PD098059 (MEK 1/2 inhibitor) with pentazocine significantly abolished the protective effects of pentazocine on the RGCs during this OGD insult. Activation of the σ-1 receptor is a neuroprotective target that can protect RGCs from an ischemia-like insult. These results also established a direct relationship between σ-1 receptor stimulation and the neuroprotective effects of the ERK1/2 pathway in purified RGCs subjected to OGD. These findings suggest that activation of the σ-1 receptor may be a therapeutic target for neuroprotection particularly relevant to ocular neurodegenerative diseases that effect RGCs..

PMID: 25305575 [PubMed - as supplied by publisher]

Coding ill-defined and unknown cause of death is 13 times more frequent in Denmark than in Finland.

Sun, 10/12/2014 - 4:04am
Related Articles

Coding ill-defined and unknown cause of death is 13 times more frequent in Denmark than in Finland.

Forensic Sci Int. 2014 Sep 28;244C:289-294

Authors: Ylijoki-Sørensen S, Sajantila A, Lalu K, Bøggild H, Boldsen JL, Boel LW

Abstract
Exact cause and manner of death determination improves legislative safety for the individual and for society and guides aspects of national public health. In the International Classification of Diseases, codes R00-R99 are used for "symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified" designated as "ill-defined" or "with unknown etiology". The World Health Organisation recommends avoiding the use of ill-defined and unknown causes of death in the death certificate as this terminology does not give any information concerning the possible conditions that led to the death. Thus, the aim of the study was, firstly, to analyse the frequencies of R00-R99-coded deaths in mortality statistics in Finland and in Denmark and, secondly, to compare these and the methods used to investigate the cause of death. To do so, we extracted a random 90% sample of the Finnish death certificates and 100% of the Danish certificates from the national mortality registries for 2000, 2005 and 2010. Subsequently, we analysed the frequencies of forensic and medical autopsies and external clinical examinations of the bodies in R00-R99-coded deaths. The use of R00-R99 codes was significantly higher in Denmark than in Finland; OR 18.6 (95% CI 15.3-22.4; p<0.001) for 2000, OR 9.5 (95% CI 8.0-11.3; p<0.001) for 2005 and OR 13.2 (95% CI 11.1-15.7; p<0.001) for 2010. More than 80% of Danish deaths with R00-R99 codes were over 70 years of age at the time of death. Forensic autopsy was performed in 88.3% of Finnish R00-R99-coded deaths, whereas only 3.5% of Danish R00-R99-coded deaths were investigated with forensic or medical autopsy. The codes that were most used in both countries were R96-R99, meaning "unknown cause of death". In Finland, all of these deaths were investigated with a forensic autopsy. Our study suggests that if all deaths in all age groups with unclear cause of death were systematically investigated with a forensic autopsy, only 2-3/1000 deaths per year would be coded as an ill-defined and unknown cause of death in national mortality statistics. At the same time the risk to overlook unnatural deaths is decreased to a minimum. To achieve this in Denmark requires that the existing legislation on cause of death investigation would need to be changed to ensure that all deaths with unknown cause of death are investigated with a forensic autopsy.

PMID: 25300069 [PubMed - as supplied by publisher]

Longevity loss among cured tuberculosis patients and the potential value of prevention.

Sun, 10/12/2014 - 4:04am
Related Articles

Longevity loss among cured tuberculosis patients and the potential value of prevention.

Int J Tuberc Lung Dis. 2014 Nov;18(11):1347-1352

Authors: Hoger S, Lykens K, Beavers SF, Katz D, Miller TL

Abstract
BACKGROUND: Evidence of substantial, quantifiable and preventable burdens of mortality hazard even after anti-tuberculosis treatment and cure would be a compelling, concrete, and useful measure of the value of prevention.
METHODS: We compared years of potential life lost between a cohort of 3 933 cured tuberculosis (TB) patients and 9 166 persons with latent tuberculous infection. We constructed a regression model to predict the expected years of potential life lost in each cohort and for demographic subgroups.
RESULTS: Among decedents, a history of fully treated TB is associated with a predicted average 3.6 more years of potential life loss than a comparable population without active TB. Greater longevity losses were predicted among those identified as White and Hispanic than among Black and Asian counterparts.
CONCLUSION: We found significant differences in predicted longevity of treated TB survivors relative to a similar group without active TB. These excess losses are substantial: a total of 14 158 life-years or the equivalent of more than 188 75-year lifespans. These findings illustrate an important opportunity cost associated with each preventable TB case - an average of 3.6 potential years of life. We conclude that substantial preventable mortality burdens remain despite adequate anti-tuberculosis treatment, a compelling rationale for more widespread and systematic use of prevention.

PMID: 25299869 [PubMed - as supplied by publisher]

Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.

Sun, 10/12/2014 - 4:04am
Related Articles

Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.

Cell Death Dis. 2014;5:e1457

Authors: Ruan L, Zhang Z, Mu L, Burnley P, Wang L, Coder B, Zhuge Q, Su DM

Abstract
FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOP(flox)-FoxN1 mice, in which over- and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOP(flox) in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOP(flox) mediated by progressive uCreER(T) leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreER(T)-mediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreER(T) activation in juveniles adversely influenced total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Over- and ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development.

PMID: 25299782 [PubMed - as supplied by publisher]