Gibson D. Lewis Library

Recent Research Articles from UNTHSC

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Updated: 33 min 48 sec ago

Molecular Detection of Rickettsia Species Within Ticks (Acari: Ixodidae) Collected from Arkansas United States.

33 min 48 sec ago
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Molecular Detection of Rickettsia Species Within Ticks (Acari: Ixodidae) Collected from Arkansas United States.

J Med Entomol. 2015 May;52(3):500-508

Authors: Trout Fryxell RT, Steelman CD, Szalanski AL, Billingsley PM, Williamson PC

Abstract
Rocky Mountain spotted fever (RMSF), caused by the etiological agent Rickettsia rickettsii, is the most severe and frequently reported rickettsial illness in the United States, and is commonly diagnosed throughout the southeast. With the discoveries of Rickettsia parkeri and other spotted fever group rickettsiae (SFGR) in ticks, it remains inconclusive if the cases reported as RMSF are truly caused by R. rickettsii or other SFGR. Arkansas reports one of the highest incidence rates of RMSF in the country; consequently, to identify the rickettsiae in Arkansas, 1,731 ticks, 250 white-tailed deer, and 189 canines were screened by polymerase chain reaction (PCR) for the rickettsial genes gltA, rompB, and ompA. None of the white-tailed deer were positive, while two of the canines (1.1%) and 502 (29.0%) of the ticks were PCR positive. Five different tick species were PCR positive: 244 (37%) Amblyomma americanum L., 130 (38%) Ixodes scapularis Say, 65 (39%) Amblyomma maculatum (Koch), 30 (9%) Rhipicephalus sanguineus Latreille, 7 (4%) Dermacentor variabilis Say, and 26 (44%) unidentified Amblyomma ticks. None of the sequenced products were homologous to R. rickettsii. The most common Rickettsia via rompB amplification was Rickettsia montanensis and nonpathogenic Candidatus Rickettsia amblyommii, whereas with ompA amplification the most common Rickettsia was Ca. R. amblyommii. Many tick specimens collected in northwest Arkansas were PCR positive and these were commonly A. americanum harboring Ca. R. amblyommii, a currently nonpathogenic Rickettsia. Data reported here indicate that pathogenic R. rickettsii was absent from these ticks and suggest by extension that other SFGR are likely the causative agents for Arkansas diagnosed RMSF cases.

PMID: 26334827 [PubMed - as supplied by publisher]

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

12 hours 34 min ago
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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]

Association Between Plantar Temperatures and Triaxial Stresses in Individuals with Diabetes.

Wed, 09/02/2015 - 11:33am
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Association Between Plantar Temperatures and Triaxial Stresses in Individuals with Diabetes.

Diabetes Care. 2015 Aug 27;

Authors: Yavuz M, Brem RW, Glaros AG, Garrett A, Flyzik M, Lavery L, Davis BL, Hilario H, Adams LS

PMID: 26316629 [PubMed - as supplied by publisher]

Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

Wed, 09/02/2015 - 11:33am
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Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

PLoS One. 2014;9(12):e115506

Authors: Hobbs CV, Dixit S, Penzak SR, Sahu T, Orr-Gonzalez S, Lambert L, Zeleski K, Chen J, Neal J, Borkowsky W, Wu Y, Duffy PE

Abstract
Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

PMID: 25541998 [PubMed - indexed for MEDLINE]

Temperature as a predictive tool for plantar triaxial loading.

Wed, 09/02/2015 - 11:33am
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Temperature as a predictive tool for plantar triaxial loading.

J Biomech. 2014 Nov 28;47(15):3767-70

Authors: Yavuz M, Brem RW, Davis BL, Patel J, Osbourne A, Matassini MR, Wood DA, Nwokolo IO

Abstract
Diabetic foot ulcers are caused by moderate repetitive plantar stresses in the presence of peripheral neuropathy. In severe cases, the development of these foot ulcers can lead to lower extremity amputations. Plantar pressure measurements have been considered a capable predictor of ulceration sites in the past, but some investigations have pointed out inconsistencies when solely relying on this method. The other component of ground reaction forces/stresses, shear, has been understudied due to a lack of adequate equipment. Recent articles reported the potential clinical significance of shear in diabetic ulcer etiology. With the lack of adequate tools, plantar temperature has been used as an alternative method for determining plantar triaxial loading and/or shear. However, this method has not been previously validated. The purpose of this study was to analyze the potential association between exercise-induced plantar temperature increase and plantar stresses. Thirteen healthy individuals walked on a treadmill for 10 minutes at 3.2km/h. Pre and post-exercise temperature profiles were obtained with a thermal camera. Plantar triaxial stresses were quantified with a custom-built stress plate. A statistically significant correlation was observed between peak shear stress (PSS) and temperature increase (r=0.78), but not between peak resultant stress (PRS) and temperature increase (r=0.46). Plantar temperature increase could predict the location of PSS and PRS in 23% and 39% of the subjects, respectively. Only a moderate linear relationship was established between triaxial plantar stresses and walking-induced temperature increase. Future research will investigate the value of nonlinear models in predicting plantar loading through foot temperature.

PMID: 25446272 [PubMed - indexed for MEDLINE]

The role of charity care and primary care physician assignment on ED use in homeless patients.

Wed, 09/02/2015 - 11:33am
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The role of charity care and primary care physician assignment on ED use in homeless patients.

Am J Emerg Med. 2015 Aug;33(8):1006-11

Authors: Wang H, Nejtek VA, Zieger D, Robinson RD, Schrader CD, Phariss C, Ku J, Zenarosa NR

Abstract
OBJECTIVE: Homeless patients are a vulnerable population with a higher incidence of using the emergency department (ED) for noncrisis care. Multiple charity programs target their outreach toward improving the health of homeless patients, but few data are available on the effectiveness of reducing ED recidivism. The aim of this study is to determine whether inappropriate ED use for nonemergency care may be reduced by providing charity insurance and assigning homeless patients to a primary care physician (PCP) in an outpatient clinic setting.
METHODS: A retrospective medical records review of homeless patients presenting to the ED and receiving treatment between July 2013 and June 2014 was completed. Appropriate vs inappropriate use of the ED was determined using the New York University ED Algorithm. The association between patients with charity care coverage, PCP assignment status, and appropriate vs inappropriate ED use was analyzed and compared.
RESULTS: Following New York University ED Algorithm standards, 76% of all ED visits were deemed inappropriate with approximately 77% of homeless patients receiving charity care and 74% of patients with no insurance seeking noncrisis health care in the ED (P=.112). About 50% of inappropriate ED visits and 43.84% of appropriate ED visits occurred in patients with a PCP assignment (P=.019).
CONCLUSIONS: Both charity care homeless patients and those without insurance coverage tend to use the ED for noncrisis care resulting in high rates of inappropriate ED use. Simply providing charity care and/or PCP assignment does not seem to sufficiently reduce inappropriate ED use in homeless patients.

PMID: 26001738 [PubMed - indexed for MEDLINE]

Effect of an acute increase in central blood volume on cerebral hemodynamics.

Tue, 09/01/2015 - 3:30am
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Effect of an acute increase in central blood volume on cerebral hemodynamics.

Am J Physiol Regul Integr Comp Physiol. 2015 Aug 26;:ajpregu.00137.2015

Authors: Ogoh S, Hirasawa A, Raven PB, Rebuffat T, Denise P, Lericollais R, Sugawara J, Normand H

Abstract
Systemic blood distribution is an important factor involved in regulating cerebral blood flow (CBF). However, the effect of an acute change in central blood volume (CBV) on CBF regulation remains unclear. To address our question, we sought to examine the CBF and systemic hemodynamic responses to microgravity during parabolic flight. Twelve healthy subjects were seated upright and exposed to microgravity during parabolic flight. During the brief periods of microgravity mean arterial pressure was decreased (-26 ± 1%, P<0.001) despite an increase in cardiac output (+21 ± 6%, P<0.001). During microgravity central arterial pulse pressure and estimated carotid sinus pressure increased rapidly. In addition, this increase in central arterial pulse pressure was associated with an arterial baroreflex-mediated decrease in heart rate (r=-0.888, P<0.0001) and an increase in total vascular conductance (r=0.711, P<0.001). The middle cerebral artery mean blood velocity (MCA Vmean) remained unchanged throughout parabolic flight (P=0.30). During microgravity the contribution of cardiac output to MCA Vmean was gradually reduced (P<0.05) and its contribution was negatively correlated with an increase in total vascular conductance (r=-0.683, P<0.0001). These findings suggest that the acute loading of the arterial and cardiopulmonary baroreceptors by increases in CBV during microgravity results in acute and marked systemic vasodilation. Furthermore, we conclude that this marked systemic vasodilation decreases the contribution of cardiac output to CBF. These findings suggest that the arterial and cardiopulmonary baroreflex mediated peripheral vasodilation along with dynamic cerebral autoregulation counteracts a cerebral over-perfusion, that otherwise would occur during acute increases in CBV.

PMID: 26310936 [PubMed - as supplied by publisher]

Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells.

Tue, 09/01/2015 - 3:30am
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Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells.

Immunobiology. 2015 Aug 15;

Authors: Kim JR, Mathew SO, Mathew PA

Abstract
CS1 (CRACC/CD319/SLAMF7) is a member of SLAM (Signaling Lymphocyte Activation Molecule) family receptors and is expressed on NK cells, a subset of CD8(+) T lymphocytes, activated monocytes, mature dendritic cells and activated B cells. In NK cells, CS1 signaling induces cytolytic function of NK cells against targets whereas in B cells CS1 induces proliferation and autocrine cytokine production. CS1 is upregulated in multiple myeloma cells and contributes to clonogenic growth and tumorigenicity. However, the mechanism of CS1 upregulation is unknown. In this study, we analyzed the transcriptional regulation of human CS1 gene in NK and B cells. The promoter region of CS1 contains a Blimp-1/PRDM1 binding site and relative luciferase activities of successive deletion mutants of CS1 promoter were different between Blimp-1/PRDM1-positive and Blimp-1/PRDM1-negative cells. Proximal region of CS1 promoter contains a CAAT box and atypical TATA-box that might result in common transcription initiation at -29 nucleotides upstream of the ATG translation start codon. Electrophoretic Mobility Shift Assay (EMSA) and Chromatin Immunoprecipitation (ChIP) assays revealed Blimp-1/PRDM1 binds to the CS1 promoter region. Mutating the Blimp-1/PRDM1 site at -750 to -746 decreased the transcriptional activity of CS1 promoter implicating a trans-activating function of Blimp-1/PRDM1 in human CS1 gene regulation. The finding that Blimp-1/PRDM1 enhances transcription of CS1 gene in multiple myeloma cells may help in developing novel strategies for therapeutic intervention in multiple myeloma.

PMID: 26310579 [PubMed - as supplied by publisher]

Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

Fri, 08/28/2015 - 3:29am
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Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

Mol Neurodegener. 2015;10(1):40

Authors: Choudhury S, Liu Y, Clark AF, Pang IH

Abstract
BACKGROUND: Axonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Caspases have been implicated in RGC pathogenesis. However, the role of caspase-7, a functionally unique caspase, in ON injury and RGC apoptosis has not been reported previously. The purpose of this study is to evaluate the role of caspase-7 in ON injury-induced RGC apoptosis.
RESULTS: C57BL/6 (wildtype, WT) and caspase-7 knockout (Casp7 (-/-) ) mice were used. We show that ON crush activated caspase-7 and calpain-1, an upstream activator of caspase-7, in mouse RGCs, as well as hydrolysis of kinectin and co-chaperone P23, specific substrates of caspase-7. ON crush caused a progressive loss of RGCs to 28 days after injury. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7 (-/-) mice was approximately twice of that in WT ON injured retinas. Consistent with changes in RGC counts, spectral-domain optical coherence tomography analysis revealed that ON crush significantly reduced the in vivo thickness of the ganglion cell complex layer (including ganglion cell layer, nerve fiber layer, and inner plexiform layer) in the retina. The ON crush-induced thinning of retinal layer was significantly ameliorated in Casp7 (-/-) mice when compared to WT mice. Moreover, electroretinography analysis demonstrated a decline in the positive component of scotopic threshold response amplitude in ON crushed eyes of the WT mice, whereas this RGC functional response was significantly higher in Casp7 (-/-) mice at 28 days post injury.
CONCLUSION: Altogether, our findings indicate that caspase-7 plays a critical role in ON injury-induced RGC death, and inhibition of caspase-7 activity may be a novel therapeutic strategy for glaucoma and other neurodegenerative diseases of the retina.

PMID: 26306916 [PubMed - in process]

Glycosyltransferase ST6GAL1 contributes to the regulation of pluripotency in human pluripotent stem cells.

Thu, 08/27/2015 - 3:30am
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Glycosyltransferase ST6GAL1 contributes to the regulation of pluripotency in human pluripotent stem cells.

Sci Rep. 2015;5:13317

Authors: Wang YC, Stein JW, Lynch CL, Tran HT, Lee CY, Coleman R, Hatch A, Antontsev VG, Chy HS, O'Brien CM, Murthy SK, Laslett AL, Peterson SE, Loring JF

Abstract
Many studies have suggested the significance of glycosyltransferase-mediated macromolecule glycosylation in the regulation of pluripotent states in human pluripotent stem cells (hPSCs). Here, we observed that the sialyltransferase ST6GAL1 was preferentially expressed in undifferentiated hPSCs compared to non-pluripotent cells. A lectin which preferentially recognizes α-2,6 sialylated galactosides showed strong binding reactivity with undifferentiated hPSCs and their glycoproteins, and did so to a much lesser extent with differentiated cells. In addition, downregulation of ST6GAL1 in undifferentiated hPSCs led to a decrease in POU5F1 (also known as OCT4) protein and significantly altered the expression of many genes that orchestrate cell morphogenesis during differentiation. The induction of cellular pluripotency in somatic cells was substantially impeded by the shRNA-mediated suppression of ST6GAL1, partially through interference with the expression of endogenous POU5F1 and SOX2. Targeting ST6GAL1 activity with a sialyltransferase inhibitor during cell reprogramming resulted in a dose-dependent reduction in the generation of human induced pluripotent stem cells (hiPSCs). Collectively, our data indicate that ST6GAL1 plays an important role in the regulation of pluripotency and differentiation in hPSCs, and the pluripotent state in human cells can be modulated using pharmacological tools to target sialyltransferase activity.

PMID: 26304831 [PubMed - in process]

Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans.

Wed, 08/26/2015 - 3:30am
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Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans.

Auton Neurosci. 2015 Aug 7;

Authors: White DW, Shoemaker JK, Raven PB

Abstract
The technique of microneurography and the assessment of muscle sympathetic nerve activity (MSNA) are used in laboratories throughout the world. The variables used to describe MSNA, and the criteria by which these variables are quantified from the integrated neurogram, vary among studies and laboratories and, therefore, can become confusing to those starting to learn the technique. Therefore, the purpose of this educational review is to discuss guidelines and standards for the assessment of sympathetic nervous activity through the collection and analysis of MSNA. This review will reiterate common practices in the collection of MSNA, but will also introduce considerations for the evaluation and physiological inference using MSNA.

PMID: 26299824 [PubMed - as supplied by publisher]

Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation.

Tue, 08/25/2015 - 3:30am
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Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation.

J Immunol. 2015 Jun 15;194(12):5825-37

Authors: Coder BD, Wang H, Ruan L, Su DM

Abstract
Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNF-α production, and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of Foxn1 conditional knockout mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related regulatory T cell accumulation in naturally aged mice, but not inflammatory infiltration. Taken together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).

PMID: 25957168 [PubMed - indexed for MEDLINE]

COMBINATION OF 13CIS-RETINOIC ACID AND TOLFENAMIC ACID INDUCES APOPTOSIS AND EFFECTIVELY INHIBITS HIGH-RISK NEUROBLASTOMA CELL PROLIFERATION.

Fri, 08/21/2015 - 3:29am

COMBINATION OF 13CIS-RETINOIC ACID AND TOLFENAMIC ACID INDUCES APOPTOSIS AND EFFECTIVELY INHIBITS HIGH-RISK NEUROBLASTOMA CELL PROLIFERATION.

Int J Dev Neurosci. 2015 Aug 10;

Authors: Shelake S, Eslin D, Sutphin RM, Sankpal UT, Wadwani A, Kenyon LE, Tabor-Simecka L, Bowman WP, Vishwanatha JK, Basha R

Abstract
Chemotherapeutic regimens used for the treatment of Neuroblastoma (NB) cause long-term side effects in pediatric patients. NB arises in immature sympathetic nerve cells and primarily affects infants and children.A high rate of relapse in high-risk neuroblastoma (HRNB) necessitates the development of alternative strategies for effective treatment. This study investigated the efficacy of a small molecule, Tolfenamic Acid (TA), for enhancing the anti-proliferative effect of 13 cis-Retinoic Acid (RA) in HRNB cell lines. LA1-55n and SH-SY5Y cells were treated with TA (30μM) or RA (20μM) or both (optimized doses, derived from dose curves) for 48h and tested the effect on cell viability, apoptosis and selected molecular markers (Sp1, survivin, AKT and ERK1/2). Cell viability and caspase activity were measured using the CellTiter-Glo and Caspase-Glo kits. The apoptotic cell population was determined by flow cytometry with Annexin-V staining. The expression of Sp1, survivin, AKT, ERK1/2 and c-PARP were evaluated by Western blots. The combination therapy of TA and RA resulted in significant inhibition of cell viability ( p <0.0001) when compared to individual agents. The anti-proliferative effect is accompanied by a decrease in Sp1 and survivin expression and an increase in apoptotic markers, Annexin-V positive cells, caspase 3/7 activity and c-PARP levels. Notably, TA+RA combination also caused down regulation of AKT and ERK1/2 suggesting a distinct impact on survival and proliferation pathways via signaling cascades. This study demonstrates that the TA mediated inhibition of Sp1 in combination with RA provides a novel therapeutic strategy for the effective treatment of HRNB in children.

PMID: 26287661 [PubMed - as supplied by publisher]

Minimum Information about a Biosynthetic Gene cluster.

Thu, 08/20/2015 - 3:30am

Minimum Information about a Biosynthetic Gene cluster.

Nat Chem Biol. 2015 Aug 18;11(9):625-631

Authors: Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O'Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO

PMID: 26284661 [PubMed - as supplied by publisher]

Tip110 Regulates the Cross Talk between p53 and Hypoxia-Inducible Factor 1α under Hypoxia and Promotes Survival of Cancer Cells.

Thu, 08/20/2015 - 3:30am
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Tip110 Regulates the Cross Talk between p53 and Hypoxia-Inducible Factor 1α under Hypoxia and Promotes Survival of Cancer Cells.

Mol Cell Biol. 2015 Jul;35(13):2254-64

Authors: Timani KA, Liu Y, Fan Y, Mohammad KS, He JJ

Abstract
Hypoxia often occurs under various physiological and pathophysiological conditions, including solid tumors; it is linked to malignant transformation, metastatic progression, and treatment failure or resistance. Tip110 protein plays important roles in several known physiological and pathophysiological processes, including cancers. Thus, in the present study we investigated the regulation of Tip110 expression under hypoxia. Hypoxia led to Tip110 protein degradation through the ubiquitin-proteasome system. Under hypoxia, Tip110 stabilized p53, which in return destabilized Tip110. In addition, Tip110 regulated hypoxia-inducible factor 1α (HIF-1α), likely through enhancement of its protein stability. Furthermore, Tip110 upregulated p300, a known coactivator for both p53 and HIF-1α. Expression of a p53(22/23) mutant deficient in p300 binding accelerated Tip110 degradation under hypoxia. Tip110 knockdown resulted in the inhibition of cell proliferation and cell death in the presence of p53. Finally, significantly less Tip110, p53, and HIF-1α was detected in the hypoxic region of bone metastasis tumors in a mouse model of human melanoma cells. Taken together, these results suggest Tip110 is an important mediator in the cross talk between p53 and HIF-1α in response to hypoxic stress.

PMID: 25939381 [PubMed - indexed for MEDLINE]

MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Wed, 08/19/2015 - 3:39am
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MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Mol Cancer. 2015;14:156

Authors: Kpetemey M, Dasgupta S, Rajendiran S, Das S, Gibbs LD, Shetty P, Gryczynski Z, Vishwanatha JK

Abstract
BACKGROUND: Migration and invasion enhancer 1 (MIEN1) is a novel gene found to be abundantly expressed in breast tumor tissues and functions as a critical regulator of tumor cell migration and invasion to promote systemic metastases. Previous studies have identified post-translational modifications by isoprenylation at the C-terminal tail of MIEN1 to favor its translocation to the inner leaflet of plasma membrane and its function as a membrane-bound adapter molecule. However, the exact molecular events at the membrane interface activating the MIEN1-driven tumor cell motility are vaguely understood.
METHODS: MIEN1 was first studied using in-silico analysis on available RNA sequencing data of human breast tissues and its expression was ascertained in breast cells. We performed several assays including co-immunoprecipitation, wound healing, western blotting and immunofluorescence to decipher the molecular events involved in MIEN1-mediated tumor cell migration.
RESULTS: Clinically, MIEN1 is predominantly overexpressed in Her-2 and luminal B subtypes of breast tumors, and its increased expression correlates with poor disease free survival. Molecular studies identified a phosphorylation-dependent activation signal in the immunoreceptor tyrosine based activation motif (ITAM) of MIEN1 and the phosphorylation-deficient MIEN1-mutants (Y39F/50 F) to regulate filopodia generation, migration and invasion. We found that ITAM-phosphorylation of MIEN1 is significantly impaired in isoprenylation-deficient MIEN1 mutants indicating that prenylation of MIEN1 and membrane association is required for cross-phosphorylation of tyrosine residues. Furthermore, we identified MIEN1 as a novel interactor of Annexin A2 (AnxA2), a Ca(2+) -dependent phospholipid binding protein, which serves as an extracellular proteolytic center regulating plasmin generation. Fluorescence resonance energy transfer (FRET) confirmed that MIEN1 physically interacts with AnxA2 and functional studies revealed that they mutually cooperate to accentuate tumor cell motility. Interestingly, our study identified that ectopic overexpression of MIEN1 significantly enhances Tyr23-phosphorylation on AnxA2, thereby stimulating cell surface translocation of AnxA2 and catalyzing the activation of its proteolytic activity.
CONCLUSION: Our data show that the presence and interaction of both MIEN1 and AnxA2 in breast tumors are crucial drivers of cell motility. Our study has now deciphered a novel regulatory network governing the vicious process of breast tumor cell invasion-metastasis, and findings suggest MIEN1-AnxA2 as prospective targets to counter the deadly disease.

PMID: 26272794 [PubMed - in process]

Factors Contributing to 50-ft Walking Speed and Observed Ethnic Differences in Older Community-Dwelling Mexican Americans and European Americans.

Sat, 08/15/2015 - 3:34am
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Factors Contributing to 50-ft Walking Speed and Observed Ethnic Differences in Older Community-Dwelling Mexican Americans and European Americans.

Phys Ther. 2015 Jun;95(6):871-83

Authors: Quiben MU, Hazuda HP

Abstract
BACKGROUND: Mexican Americans comprise the most rapidly growing segment of the older US population and are reported to have poorer functional health than European Americans, but few studies have examined factors contributing to ethnic differences in walking speed between Mexican Americans and European Americans.
OBJECTIVE: The purpose of this study was to examine factors that contribute to walking speed and observed ethnic differences in walking speed in older Mexican Americans and European Americans using the disablement process model (DPM) as a guide.
DESIGN: This was an observational, cross-sectional study.
METHODS: Participants were 703 Mexican American and European American older adults (aged 65 years and older) who completed the baseline examination of the San Antonio Longitudinal Study of Aging (SALSA). Hierarchical regression models were performed to identify the contribution of contextual, lifestyle/anthropometric, disease, and impairment variables to walking speed and to ethnic differences in walking speed.
RESULTS: The ethic difference in unadjusted mean walking speed (Mexican Americans=1.17 m/s, European Americans=1.29 m/s) was fully explained by adjustment for contextual (ie, age, sex, education, income) and lifestyle/anthropometric (ie, body mass index, height, physical activity) variables; adjusted mean walking speed in both ethnic groups was 1.23 m/s. Contextual variables explained 20.3% of the variance in walking speed, and lifestyle/anthropometric variables explained an additional 8.4%. Diseases (ie, diabetes, stroke, chronic obstructive pulmonary disease) explained an additional 1.9% of the variance in walking speed; impairments (ie, FEV1, upper leg pain, and lower extremity strength and range of motion) contributed an additional 5.5%. Thus, both nonmodifiable (ie, contextual, height) and modifiable (ie, impairments, body mass index, physical activity) factors contributed to walking speed in older Mexican Americans and European Americans.
LIMITATIONS: The study was conducted in a single geographic area and included only Mexican American Hispanic individuals.
CONCLUSIONS: Walking speed in older Mexican Americans and European Americans is influenced by modifiable and nonmodifiable factors, underscoring the importance of the DPM framework, which incorporates both factors into the physical therapist patient/client management process.

PMID: 25592187 [PubMed - indexed for MEDLINE]

Randomized trial of a dry-powder, fibrin sealant in vascular procedures.

Tue, 08/11/2015 - 3:30am

Randomized trial of a dry-powder, fibrin sealant in vascular procedures.

J Vasc Surg. 2015 Aug 4;

Authors: Gupta N, Chetter I, Hayes P, O-Yurvati AH, Moneta GL, Shenoy S, Pribble JP, Zuckerman LA

Abstract
OBJECTIVE: Topical hemostats are important adjuncts for stopping surgical bleeding. The safety and efficacy of Fibrocaps, a dry-powder, fibrin sealant containing human plasma-derived thrombin and fibrinogen, was evaluated in patients undergoing vascular surgical procedures.
METHODS: In this single-blind trial (clinicaltrials.gov: NCT01527357), adult patients were randomized 2:1 to Fibrocaps plus gelatin sponge (Fibrocaps) vs gelatin sponge alone. Results are presented for the patient subset undergoing vascular procedures with suture hole bleeding. The primary efficacy endpoint compared time to hemostasis (TTH) over 5 minutes. Safety follow-up continued to day 29.
RESULTS: A total of 175 patients were randomized and treated (Fibrocaps, 117; gelatin sponge, 58). Patients were predominately male (69%) and underwent arterial bypass (81%), arteriovenous graft formation (9%), or carotid endarterectomy (9%). Fibrocaps significantly reduced TTH compared with gelatin sponge (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.5-3.1; median TTH, 2 minutes; 95% CI, 1.5-2.5 vs 4 minutes; 95% CI, 3.0-5.0; P < .002). Significant reductions were also observed in patients receiving concomitant antiplatelet agents alone (HR, 2.8; 95% CI, 1.0-7.4; P = .03; n = 33), anticoagulants alone (HR, 2.0; 95% CI, 1.0-4.0; P = .04; n = 43), or both antiplatelet agents and anticoagulants (Fibrocaps vs gelatin sponge, HR, 2.3; 95% CI, 1.2-4.3; P = .008; n = 65). Incidences of common adverse events (procedural pain, nausea, constipation) were generally comparable between treatment arms. Anti-thrombin antibodies developed in 2% of Fibrocaps-treated patients and no-gelatin-sponge patients.
CONCLUSIONS: Fibrocaps, a ready-to-use, dry-powder fibrin sealant, was well-tolerated and reduced TTH in patients undergoing vascular procedures, including those receiving antiplatelet agents and/or anticoagulants, demonstrating its safety and usefulness as an adjunct to hemostasis.

PMID: 26254451 [PubMed - as supplied by publisher]

Eyebrow restoration: the approach, considerations, and technique in follicular unit transplantation.

Sun, 08/09/2015 - 3:29am
Related Articles

Eyebrow restoration: the approach, considerations, and technique in follicular unit transplantation.

J Cosmet Dermatol. 2015 Aug 6;

Authors: Tomc CM, Malouf PJ

Abstract
BACKGROUND: Eyebrows serve a key role in eye protection, communication, and self-expression. Trends in eyebrow grooming are constantly evolving, often requiring plucking, waxing, or laser hair removal to style. When combined with the natural thinning of the brow with aging, the result can be a sparse or even absent eyebrow hair over time. Follicular unit transplantation provides a means of restoring eyebrow fullness and architecture. With careful attention and augmentation of follicle transfer techniques, a natural end result is possible.

PMID: 26248542 [PubMed - as supplied by publisher]

Downregulation of Aquaporin 4 Expression through Extracellular Signal-regulated Kinases1/2 Activation in Cultured Astrocytes Following Scratch-injury.

Sun, 08/09/2015 - 3:29am
Related Articles

Downregulation of Aquaporin 4 Expression through Extracellular Signal-regulated Kinases1/2 Activation in Cultured Astrocytes Following Scratch-injury.

Biomed Environ Sci. 2015 Mar;28(3):199-205

Authors: Shi ZF, Zhao WJ, Xu LX, Dong LP, Yang SH, Yuan F

Abstract
OBJECTIVE: To investigate the role of extracellular signal-regulated kinase1/2 (ERK1/2) pathway in the regulation of aquaporin 4 (AQP4) expression in cultured astrocytes after scratch-injury.
METHODS: The scratch-injury model was produced in cultured astrocytes of rat by a 10-μL plastic pipette tip. The morphological changes of astrocytes and lactate dehydrogenase (LDH) leakages were observed to assess the degree of scratch-injury. AQP4 expression was detected by immunofluorescence staining and Western blot, and phosphorylated-ERK1/2 (p-ERK1/2) expression was determined by Western blot. To explore the effect of ERK1/2 pathway on AQP4 expression in scratch-injured astrocytes, 10 µmol/L U0126 (ERK1/2 inhibitor) was incubated in the medium at 30 min before the scratch-injury in some groups.
RESULTS: Increases in LDH leakage were observed at 1, 12, and 24 h after scratch-injury, and AQP4 expression was reduced simultaneously. Decrease in AQP4 expression was associated with a significant increase in ERK1/2 activation. Furthermore, pretreatment with U0126 blocked both ERK1/2 activation and decrease in AQP4 expression induced by scratch-injury.
CONCLUSION: These results indicate that ERK1/2 pathway down-regulates AQP4 expression in scratch-injured astrocytes, and ERK1/2 pathway might be a novel therapeutic target in reversing the effects of astrocytes that contribute to traumatic brain edema.

PMID: 25800444 [PubMed - indexed for MEDLINE]

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