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Recent Research Articles from UNTHSC

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Coupling between arterial pressure, cerebral blood velocity, and cerebral tissue oxygenation with spontaneous and forced oscillations.

Wed, 03/25/2015 - 3:29am

Coupling between arterial pressure, cerebral blood velocity, and cerebral tissue oxygenation with spontaneous and forced oscillations.

Physiol Meas. 2015 Mar 23;36(4):785-801

Authors: Rickards CA, Sprick JD, Colby HB, Kay VL, Tzeng YC

Abstract
We tested the hypothesis that transmission of arterial pressure to brain tissue oxygenation is low under conditions of arterial pressure instability. Two experimental models of hemodynamic instability were used in healthy human volunteers; (1) oscillatory lower body negative pressure (OLBNP) (N = 8; 5 male, 3 female), and; (2) maximal LBNP to presyncope (N = 21; 13 male, 8 female). Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2) were measured non-invasively. For the OLBNP protocol, between 0 and -60 mmHg negative pressure was applied for 20 cycles at 0.05 Hz, then 20 cycles at 0.1 Hz. For the maximal LBNP protocol, progressive 5 min stages of chamber decompression were applied until the onset of presyncope. Spectral power of MAP, mean MCAv, and ScO2 were calculated within the VLF (0.04-0.07 Hz), and LF (0.07-0.2 Hz) ranges, and cross-spectral coherence was calculated for MAP-mean MCAv, MAP-ScO2, and mean MCAv-ScO2 at baseline, during each OLBNP protocol, and at the level prior to pre-syncope during maximal LBNP (sub-max). The key findings are (1) both 0.1 Hz OLBNP and sub-max LBNP elicited increases in LF power for MAP, mean MCAv, and ScO2 (p ≤ 0.08); (2) 0.05 Hz OLBNP increased VLF power in MAP and ScO2 only (p ≤ 0.06); (3) coherence between MAP-mean MCAv was consistently higher (≥0.71) compared with MAP-ScO2, and mean MCAv-ScO2 (≤0.43) during both OLBNP protocols, and sub-max LBNP (p ≤ 0.04). These data indicate high linearity between pressure and cerebral blood flow variations, but reduced linearity between cerebral tissue oxygenation and both arterial pressure and cerebral blood flow. Measuring arterial pressure variability may not always provide adequate information about the downstream effects on cerebral tissue oxygenation, the key end-point of interest for neuronal viability.

PMID: 25798890 [PubMed - as supplied by publisher]

Glutaredoxin 1 (Grx1) Protects Human Retinal Pigment Epithelial Cells from Oxidative Damage by Preventing AKT Glutathionylation.

Tue, 03/24/2015 - 3:30am

Glutaredoxin 1 (Grx1) Protects Human Retinal Pigment Epithelial Cells from Oxidative Damage by Preventing AKT Glutathionylation.

Invest Ophthalmol Vis Sci. 2015 Mar 18;

Authors: Liu X, Jann J, Xavier C, Wu H

Abstract
PURPOSE: Glutaredoxin 1 (Grx1) belongs to the oxidoreductase family and is a component of the endogenous antioxidant defense system. However its physiological function remains largely unknown. In this study, we investigated whether and how Grx1 overexpression protects the retinal pigment epithelial (RPE) cells against H2O2-induced apoptosis.
METHODS: Human retinal pigment epithelial (ARPE-19) cells were transfected with either a Grx1-containing plasmid or an empty vector. Primary human RPE cells were transfected with Grx1 siRNA or scrambled siRNA. Cell viability was measured with the WST8 assay. Apoptosis was quantitatively measured by annexin V/propidium iodide (PI) double staining. The level of protein glutathionylation (PSSG) was measured by immunoblotting using anti-PSSG antibody. AKT activation was examined by Western blot. AKT glutathionylation was detected by immunoprecipitation followed by immunoblotting with anti-PSSG antibody.
RESULTS: Grx1 overexpression protected ARPE-19 cells from H2O2-induced cell viability loss. Conversely, Grx1 gene knockdown sensitized primary human RPE cells to H2O2. Assessment of apoptosis indicated that cells transfected with the Grx1-containing plasmid were more resistant to H2O2 with fewer cells undergoing apoptosis as compared to empty vector transfected cells. H2O2-induced PSSG accumulation was also attenuated by Grx1 enrichment. Furthermore, Grx1 overexpression prevented H2O2-induced AKT glutathionylation, resulting in a sustained phospho-AKT elevation in RPE cells.
CONCLUSIONS: Grx1 can protect RPE cells against oxidative stress-induced apoptosis. The mechanism of this protection is associated with its ability to stimulate the phosphorylation of AKT by preventing AKT glutathionylation. Considering Grx1's protective abilities in RPE cells, Grx1 could be a potential pharmacological target for retinal degenerative diseases.

PMID: 25788646 [PubMed - as supplied by publisher]

Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

Tue, 03/24/2015 - 3:30am

Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

J Am Soc Nephrol. 2015 Mar 18;

Authors: Wu P, Wang Y, Davis ME, Zuckerman JE, Chaudhari S, Begg M, Ma R

Abstract
Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca(2+) signals mediated by store-operated Ca(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release-activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose- and TGF-β1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.

PMID: 25788524 [PubMed - as supplied by publisher]

Impairment of HNF4α Binding to stim1 Promoter Contributes to High Glucose-induced Upregulation of STIM1 Expression in Glomerular Mesangial Cells.

Tue, 03/24/2015 - 3:30am

Impairment of HNF4α Binding to stim1 Promoter Contributes to High Glucose-induced Upregulation of STIM1 Expression in Glomerular Mesangial Cells.

Am J Physiol Renal Physiol. 2015 Mar 18;:ajprenal.00563.2014

Authors: Wang Y, Chaudhari S, Ren Y, Ma R

Abstract
The present study was carried out to investigate if hepatic nuclear factor 4α (HNF4α) contributed to high glucose-induced increase in STIM1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence studies showed HNF4α expression in MCs. Knockdown of HNF4α using siRNA approach significantly increased mRNA expression levels of both STIM1 and Orai1, and protein expression level of STIM1 in cultured human MCs. Consistently, over expression of HNF4α reduced expressed STIM1 protein expression in HEK293 cells. Furthermore, high glucose treatment did not significantly change abundance of HNF4α protein in MCs, but significantly attenuated HNF4α binding activity to stim1 promoter. Moreover, knockdown of HNF4α significantly augmented store-operated Ca2+ entry that is known to be gated by STIM1 and was recently found to be anti-fibrotic in MCs. In agreement with those results, knockdown of HNF4α significantly attenuated the fibrotic response of high glucose. These results suggest that HNF4α negatively regulates STIM1 transcription in MCs. High glucose increases STIM1 expression level by impairing HNF4α binding activity to stim1 promoter, which subsequently releases stim1 transcription from HNF4α repression. Since the STIM1-gated store-operated Ca(2+) entry pathway in MCs has anti-fibrotic effect, inhibition of HNF4α in MCs might be a potential therapeutic option for diabetic kidney disease.

PMID: 25786776 [PubMed - as supplied by publisher]

Transcription Factor Brn-3b Overexpression Enhances Neurite Outgrowth in PC12 Cells Under Condition of Hypoxia.

Tue, 03/24/2015 - 3:30am

Transcription Factor Brn-3b Overexpression Enhances Neurite Outgrowth in PC12 Cells Under Condition of Hypoxia.

Cell Mol Neurobiol. 2015 Mar 19;

Authors: Phatak NR, Stankowska DL, Krishnamoorthy RR

Abstract
Transcription factor Brn-3b plays a key role in retinal ganglion cell differentiation, survival, and axon outgrowth during development. However, the precise role of Brn-3b in the normal adult retina as well as during neurodegeneration is unclear. In the current study, the effect of overexpression of Brn-3b was assessed in vitro, in PC12 cells under conditions of normoxia and hypoxia. Immunoblot analysis showed that overexpression of Brn-3b in PC12 cells as well as 661W cells produced significant increase in the growth cone marker, growth-associated protein-43 (GAP-43), and acetylated-tubulin (ac-TUBA). In addition, an increased immunostaining for GAP-43 and ac-TUBA was observed in PC12 cells overexpressing Brn-3b, which was accompanied by a marked increase in neurite outgrowth, compared to PC12 cells overexpressing the empty vector. In separate experiments, one set of PC12 cells transfected either with a Brn-3b expression vector or an empty vector was subjected to conditions of hypoxia for 2 h, while another set of similarly transfected PC12 cells was maintained in normoxic conditions. It was found that the upregulation of GAP-43 and ac-TUBA in PC12 cells overexpressing Brn-3b under conditions of normoxia was sustained under conditions of hypoxia. Immunocytochemical analysis revealed not only an upregulation of GAP-43 and ac-TUBA, but also increased neurite outgrowth in PC12 cells transfected with Brn-3b as compared to PC12 cells transfected with empty vector in both normoxia and hypoxia. The findings have implications for a potential role of Brn-3b in neurodegenerative diseases in which hypoxia/ischemia contribute to pathophysiology of the disease.

PMID: 25786379 [PubMed - as supplied by publisher]

A novel Alzheimer disease locus located near the gene encoding tau protein.

Fri, 03/20/2015 - 3:29am

A novel Alzheimer disease locus located near the gene encoding tau protein.

Mol Psychiatry. 2015 Mar 17;

Authors: Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, Kunkle BW, Wang LS, Bis JC, Bellenguez C, Harold D, Lunetta KL, Destefano AL, Grenier-Boley B, Sims R, Beecham GW, Smith AV, Chouraki V, Hamilton-Nelson KL, Ikram MA, Fievet N, Denning N, Martin ER, Schmidt H, Kamatani Y, Dunstan ML, Valladares O, Laza AR, Zelenika D, Ramirez A, Foroud TM, Choi SH, Boland A, Becker T, Kukull WA, van der Lee SJ, Pasquier F, Cruchaga C, Beekly D, Fitzpatrick AL, Hanon O, Gill M, Barber R, Gudnason V, Campion D, Love S, Bennett DA, Amin N, Berr C, Tsolaki M, Buxbaum JD, Lopez OL, Deramecourt V, Fox NC, Cantwell LB, Tárraga L, Dufouil C, Hardy J, Crane PK, Eiriksdottir G, Hannequin D, Clarke R, Evans D, Mosley TH, Letenneur L, Brayne C, Maier W, De Jager P, Emilsson V, Dartigues JF, Hampel H, Kamboh MI, de Bruijn RF, Tzourio C, Pastor P, Larson EB, Rotter JI, O'Donovan MC, Montine TJ, Nalls MA, Mead S, Reiman EM, Jonsson PV, Holmes C, St George-Hyslop PH, Boada M, Passmore P, Wendland JR, Schmidt R, Morgan K, Winslow AR, Powell JF, Carasquillo M, Younkin SG, Jakobsdóttir J, Kauwe JS, Wilhelmsen KC, Rujescu D, Nöthen MM, Hofman A, Jones L, IGAP Consortium, Haines JL, Psaty BM, Van Broeckhoven C, Holmans P, Launer LJ, Mayeux R, Lathrop M, Goate AM, Escott-Price V, Seshadri S, Pericak-Vance MA, Amouyel P, Williams J, van Duijn CM, Schellenberg GD, Farrer LA

Abstract
APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.

PMID: 25778476 [PubMed - as supplied by publisher]

Underlying Data for Sequencing the Mitochondrial Genome with the Massively Parallel Sequencing Platform Ion Torrent(™) PGM (™).

Fri, 03/20/2015 - 3:29am

Underlying Data for Sequencing the Mitochondrial Genome with the Massively Parallel Sequencing Platform Ion Torrent(™) PGM (™).

BMC Genomics. 2015 Dec;16(1):6938

Authors: Seo SB, Zeng X, King JL, Larue BL, Assidi M, Al-Qahtani MH, Sajantila A, Budowle B

Abstract
BACKGROUND: Massively parallel sequencing (MPS) technologies have the capacity to sequence targeted regions or whole genomes of multiple nucleic acid samples with high coverage by sequencing millions of DNA fragments simultaneously. Compared with Sanger sequencing, MPS also can reduce labor and cost on a per nucleotide basis and indeed on a per sample basis. In this study, whole genomes of human mitochondria (mtGenome) were sequenced on the Personal Genome Machine (PGM(TM)) (Life Technologies, San Francisco, CA), the out data were assessed, and the results were compared with data previously generated on the MiSeq(TM) (Illumina, San Diego, CA). The objectives of this paper were to determine the feasibility, accuracy, and reliability of sequence data obtained from the PGM.
RESULTS: 24 samples were multiplexed (in groups of six) and sequenced on the at least 10 megabase throughput 314 chip. The depth of coverage pattern was similar among all 24 samples; however the coverage across the genome varied. For strand bias, the average ratio of coverage between the forward and reverse strands at each nucleotide position indicated that two-thirds of the positions of the genome had ratios that were greater than 0.5. A few sites had more extreme strand bias. Another observation was that 156 positions had a false deletion rate greater than 0.15 in one or more individuals. There were 31-98 (SNP) mtGenome variants observed per sample for the 24 samples analyzed. The total 1237 (SNP) variants were concordant between the results from the PGM and MiSeq. The quality scores for haplogroup assignment for all 24 samples ranged between 88.8%-100%.
CONCLUSIONS: In this study, mtDNA sequence data generated from the PGM were analyzed and the output evaluated. Depth of coverage variation and strand bias were identified but generally were infrequent and did not impact reliability of variant calls. Multiplexing of samples was demonstrated which can improve throughput and reduce cost per sample analyzed. Overall, the results of this study, based on orthogonal concordance testing and phylogenetic scrutiny, supported that whole mtGenome sequence data with high accuracy can be obtained using the PGM platform.

PMID: 25776722 [PubMed - in process]

Treatment of acute pulmonary embolism: update on newer pharmacologic and interventional strategies.

Wed, 03/18/2015 - 3:29am
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Treatment of acute pulmonary embolism: update on newer pharmacologic and interventional strategies.

Biomed Res Int. 2014;2014:410341

Authors: Pelliccia F, Schiariti M, Terzano C, Keylani AM, D'Agostino DC, Speziale G, Greco C, Gaudio C

Abstract
Acute pulmonary embolism (PE) is a common complication in hospitalized patients, spanning multiple patient populations and crossing various therapeutic disciplines. Current treatment paradigm in patients with massive PE mandates prompt risk stratification with aggressive therapeutic strategies. With the advent of endovascular technologies, various catheter-based thrombectomy and thrombolytic devices are available to treat patients with massive or submassive PE. In this paper, a variety of newer treatment strategies for PE are analyzed, with special emphasis on various interventional treatment strategies. Clinical evidence for utilizing endovascular treatment modalities, based on our institutional experience as well as a literature review, is provided.

PMID: 25025049 [PubMed - indexed for MEDLINE]

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