Recent Research Articles from UNTHSC

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Challenges in the development of glaucoma neuroprotection therapy.

Thu, 03/13/2014 - 3:24pm
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Challenges in the development of glaucoma neuroprotection therapy.

Cell Tissue Res. 2013 Aug;353(2):253-60

Authors: Liu Y, Pang IH

Abstract
Glaucoma, a disease of the optic nerve and retina, causes blindness in millions of people worldwide. Currently available therapies for this disease only attempt to reduce intraocular pressure, the major risk factor, without addressing the associated optic neuropathy and retinopathy. Development of glaucoma neuroprotective treatment is therefore a pressing unmet medical need. Unfortunately, many challenges hinder this effort, including an incomplete understanding of the mechanism of pathogenesis, leading to uncertain therapeutic targets and confounded by not yet validated preclinical models. Most importantly, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy, expensive and, to many, prohibitive. No easy solution is available to overcome these challenges. Increased commitment to basic mechanistic research is an essential foundation for dealing with this problem. Innovations in clinical trials with novel surrogate endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budgetary hurdle for the development of new therapies.

PMID: 23474740 [PubMed - indexed for MEDLINE]

17β-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma.

Thu, 03/13/2014 - 3:24pm
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17β-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma.

Mol Pharm. 2013 Aug 5;10(8):3253-61

Authors: Prokai-Tatrai K, Xin H, Nguyen V, Szarka S, Blazics B, Prokai L, Koulen P

Abstract
Neuroprotection in glaucoma as a curative strategy complementary to current therapies to lower intraocular pressure (IOP) is highly desirable. This study was designed to investigate neuroprotection by 17β-estradiol (E2) to prevent retinal ganglion cell (RGC) death in a glaucoma model of surgically elevated IOP in rats. We found that daily treatment with E2-containing eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP. The number of apoptotic cells in the RGC layer was significantly decreased in the E2-treated group, when compared to the vehicle-treated controls. Deterioration in visual acuity in these animals was also markedly prevented. Using mass spectrometry-based proteomics, beneficial changes in the expression of several proteins implicated in the maintenance of retinal health were also found in the retina of E2-treated animals. On the other hand, systemic side effects could not be avoided with the eye drops, as confirmed by the measured high circulating estrogen levels and through the assessment of the uterus representing a typical hormone-sensitive peripheral organ. Collectively, the demonstrated significant neuroprotective effect of topical E2 in the selected animal model of glaucoma provides a clear rationale for further studies aiming at targeting E2 into the eye while avoiding systemic E2 exposure to diminish undesirable off-target side effects.

PMID: 23841874 [PubMed - indexed for MEDLINE]

Assessment and management of back pain.

Fri, 03/07/2014 - 2:32pm

Assessment and management of back pain.

JAMA Intern Med. 2014 Mar 1;174(3):478-9

Authors: Licciardone JC, Gatchel R, Dagenais S

PMID: 24590092 [PubMed - in process]

Impact of a Community Based Implementation of REACH II Program for Caregivers of Alzheimer's Patients.

Wed, 03/05/2014 - 4:47am

Impact of a Community Based Implementation of REACH II Program for Caregivers of Alzheimer's Patients.

PLoS One. 2014;9(2):e89290

Authors: Lykens K, Moayad N, Biswas S, Reyes-Ortiz C, Singh KP

Abstract
BACKGROUND: In 2009 an estimated 5.3 million people in the United States were afflicted with Alzheimer's disease, a degenerative form of dementia. The impact of this disease is not limited to the patient but also has significant impact on the lives and health of their family caregivers. The Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program was developed and tested in clinical studies. The REACH II program is now being delivered by community agencies in several locations. This study examines the impact of the REACH II program on caregiver lives and health in a city in north Texas.
STUDY DESIGN: Family caregivers of Alzheimer's patients were assessed using an instrument covering the multi-item domains of Caregiver Burden, Depression, Self-Care, and Social Support upon enrollment in the program and at the completion of the 6 month intervention. The domain scores were analyzed using a multivariate paired t-test and Bonferroni confidence interval for the differences in pre- and post-service domain scores.
RESULTS: A total of 494 families were enrolled in the program during the period January 1, 2011 through June 30, 2012. Of these families 177 completed the 6 month program and have pre - and post service domain scores. The median age for the caregivers was 62 years. The domain scores for Depression and Caregiver Burden demonstrated statistically significant improvements upon program completion.
CONCLUSION: The REACH II intervention was successfully implemented by a community agency with comparable impacts to those of the clinical trial warranting wider scale implementation.

PMID: 24586664 [PubMed - in process]

A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats.

Wed, 03/05/2014 - 4:47am
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A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats.

PLoS One. 2013;8(8):e73581

Authors: Sun F, Jin K, Uteshev VV

Abstract
In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.

PMID: 23951360 [PubMed - indexed for MEDLINE]

Glial scar formation occurs in the human brain after ischemic stroke.

Tue, 03/04/2014 - 5:21am

Glial scar formation occurs in the human brain after ischemic stroke.

Int J Med Sci. 2014;11(4):344-8

Authors: Huang L, Wu ZB, Zhuge Q, Zheng W, Shao B, Wang B, Sun F, Jin K

Abstract
Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.

PMID: 24578611 [PubMed - in process]

The Impact of APOE Status on Relationship of Biomarkers of Vascular Risk and Systemic Inflammation to Neuropsychiatric Symptoms in Alzheimer's Disease.

Tue, 03/04/2014 - 5:21am

The Impact of APOE Status on Relationship of Biomarkers of Vascular Risk and Systemic Inflammation to Neuropsychiatric Symptoms in Alzheimer's Disease.

J Alzheimers Dis. 2014 Feb 20;

Authors: Hall JR, Wiechmann AR, Johnson LA, Edwards M, Barber RC, Cunningham R, Singh M, O'Bryant SE

Abstract
Research on the link between APOEε4 and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) has been inconsistent. Previous work has shown a relationship between serum biomarkers of vascular risk and inflammation and NPS in AD. The current study investigated the impact of APOEε4 status on the relationship between biomarkers of cardiovascular risk, systemic inflammation, and NPS. The sample was drawn from the TARCC Longitudinal Research Cohort; the final sample of 190 consisted of 124 females and 66 males meeting the diagnostic criteria for mild to moderate AD. 115 individuals were APOEε4 carriers and 75 were non-carriers. Serum-based clinical biomarkers of vascular risk and biomarkers of inflammation related to AD were analyzed. NPS data was gathered from caretakers/family members using the Neuropsychiatric Inventory. The significant biomarkers differed for carriers and non-carriers with IL15 being a negative biomarker of total NPS accounting for 12% of the variance for carriers and IL18 and TNFα negative predictors for non-carriers (18% of variance). Patterns related to specific symptoms were similar. Stratification by gender revealed significant biomarkers of total NPS for female carriers were negative IL15 and IL1ra (18% of variance) and for female non-carriers were negative IL18 and positive homocysteine. Total cholesterol was a positive biomarker of total NPS for both male carriers (36% of variance) and non-carriers (negative TNFα and total cholesterol, 32% of variance). These findings suggest that dysregulation of inflammatory activity is related to NPS, that cholesterol is a significant factor in the occurrence of NPS, and that gender and APOE status need to be considered.

PMID: 24577461 [PubMed - as supplied by publisher]

Label-free LC-MS/MS identification of phosphatidylglycerol-regulated proteins in Synechocystis sp. PCC6803.

Sat, 03/01/2014 - 5:23am

Label-free LC-MS/MS identification of phosphatidylglycerol-regulated proteins in Synechocystis sp. PCC6803.

Proteomics. 2014 Feb 26;

Authors: Talamantes T, Ughy B, Domonkos I, Kis M, Gombos Z, Prokai L

Abstract
We present a proteomics dataset combining SDS-PAGE prefractionation and data-dependent LC-MS/MS that enables the identification of phosphatidylglycerol-regulated proteins in the pgsA(-) mutant of Synechocystis sp. PCC6803, a cyanobacterium strain that grows with this indispensable phospholipid added exogenously. We searched the acquired raw data against a composite protein sequence database of Synechocystis using Mascot, and employed Progenesis LC-MS software for label-free quantification based on extracted peptide intensitiesto detect changes in protein abundances upon phospholipid withdrawal. Protein identifications were validated using rigorous criteria, and our analysis of the dataset revealed 80 phosphatidylglycerol-regulated proteins involved in various cellular processes including photosynthesis, respiration, metabolism, transport, transcription, and translation. The data have been deposited to the ProteomeXchange with identifier PXD000363. This article is protected by copyright. All rights reserved.

PMID: 24574175 [PubMed - as supplied by publisher]

Investigation of the bacterial retting community of kenaf (Hibiscus cannabinus) under different conditions using next-generation semiconductor sequencing.

Sat, 03/01/2014 - 5:23am
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Investigation of the bacterial retting community of kenaf (Hibiscus cannabinus) under different conditions using next-generation semiconductor sequencing.

J Ind Microbiol Biotechnol. 2013 May;40(5):465-75

Authors: Visi DK, D'Souza N, Ayre BG, Webber Iii CL, Allen MS

Abstract
The microbial communities associated with kenaf (Hibiscus cannabinus) plant fibers during retting were determined in an effort to identify possible means of accelerating this process for industrial scale-up. Microbial communities were identified by semiconductor sequencing of 16S rRNA gene amplicons from DNA harvested from plant-surface associated samples and analyzed using an Ion Torrent PGM. The communities were sampled after 96 h from each of three different conditions, including amendments with pond water, sterilized pond water, or with a mixture of pectinolytic bacterial isolates. Additionally, plants from two different sources and having different pretreatment conditions were compared. We report that the best retting communities are dominated by members of the order Clostridiales. These bacteria appear to be naturally associated with the plant material, although slight variations between source materials were found. Additionally, heavy inoculations of pectinolytic bacteria established themselves and in addition their presence facilitated the rapid dominance of the original plant-associated Clostridiales. These data suggest that members of the order Clostridiales dominate the community and are most closely associated with efficient and effective retting. The results further suggest that establishment of the community structure is first driven by the switch to anaerobic conditions, and subsequently by possible competition for nitrogen. These findings reveal important bacterial groups involved in fiber retting, and suggest mechanisms for the manipulation of the community and retting efficiency by modifying nutrient availability.

PMID: 23475284 [PubMed - indexed for MEDLINE]

Mineralocorticoid receptor in the NTS stimulates saline intake during fourth ventricular infusions of aldosterone.

Fri, 02/28/2014 - 5:18am
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Mineralocorticoid receptor in the NTS stimulates saline intake during fourth ventricular infusions of aldosterone.

Am J Physiol Regul Integr Comp Physiol. 2014 Jan 1;306(1):R61-6

Authors: Koneru B, Bathina CS, Cherry BH, Mifflin SW

Abstract
The purpose of this study was to determine whether neurons within the nucleus tractus solitarius (NTS) that express the mineralocorticoid receptor (MR) play a role in aldosterone stimulation of salt intake. Adult Wistar-Kyoto (WKY) rats received microinjections into the NTS of a short-hairpin RNA (shRNA) for the MR, to site specifically reduce levels of the MR by RNA interference (shRNA; n = 9) or scrambled RNA as a control (scRNA; n = 8). After injection of the viral construct, aldosterone-filled osmotic minipumps were implanted subcutaneously and connected to a cannula extending into the fourth ventricle to infuse aldosterone at a rate of 25 ng/h. Before and after surgeries, rats had ad libitum access to normal sodium (0.26%) rat chow and two graduated drinking bottles filled with either distilled water or 0.3 M NaCl. Before the surgeries, basal saline intake was 1.6 ± 0.6 ml in the scRNA group and 1.56 ± 0.6 ml in the shRNA group. Twenty-four days postsurgery, saline intake was elevated to a greater extent in the scRNA group (5.9 ± 1.07 ml) than in the shRNA group (2.41 ± 0.6 ml). Post mortem immunohistochemistry revealed a significant reduction in the number of NTS neurons exhibiting immunoreactivity for MR in shRNA-injected rats (23 ± 1 cells/section) versus scRNA-injected rats (33 ± 2 cells/section; P = 0.008). shRNA did not alter the level of 11-β-hydroxysteroid dehydrogenase type II (HSD2) protein in the NTS as judged by the number of HSD2 immunoreactive neurons. These results suggest that fourth ventricular infusions of aldosterone stimulate saline intake, and that this stimulation is at least in part mediated by hindbrain NTS neurons that express MR.

PMID: 24259463 [PubMed - indexed for MEDLINE]

A Pilot Case-Cohort Study of Brain Cancer in Poultry and Control Workers.

Thu, 02/27/2014 - 4:47am

A Pilot Case-Cohort Study of Brain Cancer in Poultry and Control Workers.

Nutr Cancer. 2014 Feb 24;

Authors: Gandhi S, Felini MJ, Ndetan H, Cardarelli K, Jadhav S, Faramawi M, Johnson ES

Abstract
We conducted an exploratory study to investigate which exposures (including poultry oncogenic viruses) are associated with brain cancer in poultry workers. A total of 46,819 workers in poultry and nonpoultry plants from the same union were initially followed for mortality. Brain cancer was observed to be in excess among poultry workers. Here we report on a pilot case-cohort study with cases consisting of 26 (55%) of the 47 brain cancer deaths recorded in the cohort, and controls consisting of a random sample of the cohort (n = 124). Exposure information was obtained from telephone interviews, and brain cancer mortality risk estimated by odds ratios. Increased risk of brain cancer was associated with killing chickens, odds ratio (OR) = 5.8 (95% confidence interval, 1.2-28.3); working in a shell-fish farm, OR = 13.0 (95% CI, 1.9-84.2); and eating uncooked fish, OR = 8.2 (95% CI, 1.8-37.0). Decreased risks were observed for chicken pox illness, OR = 0.2 (95% CI, 0.1-0.6), and measles vaccination, OR = 0.2 (95% CI, 0.1-0.6). Killing chickens, an activity associated with the highest occupational exposure to poultry oncogenic viruses, was associated with brain cancer mortality, as were occupational and dietary shellfish exposures. These findings are novel.

PMID: 24564367 [PubMed - as supplied by publisher]

Toward an improved understanding of the physiology of aqueous humor flow.

Thu, 02/27/2014 - 4:47am
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Toward an improved understanding of the physiology of aqueous humor flow.

Invest Ophthalmol Vis Sci. 2014 Jan;55(1):404

Authors: Millar JC

PMID: 24448440 [PubMed - indexed for MEDLINE]

Comparison of the accuracy of kriging and IDW interpolations in estimating groundwater arsenic concentrations in Texas.

Wed, 02/26/2014 - 5:37am

Comparison of the accuracy of kriging and IDW interpolations in estimating groundwater arsenic concentrations in Texas.

Environ Res. 2014 Feb 19;

Authors: Gong G, Mattevada S, O'Bryant SE

Abstract
Exposure to arsenic causes many diseases. Most Americans in rural areas use groundwater for drinking, which may contain arsenic above the currently allowable level, 10µg/L. It is cost-effective to estimate groundwater arsenic levels based on data from wells with known arsenic concentrations. We compared the accuracy of several commonly used interpolation methods in estimating arsenic concentrations in >8000 wells in Texas by the leave-one-out-cross-validation technique. Correlation coefficient between measured and estimated arsenic levels was greater with inverse distance weighted (IDW) than kriging Gaussian, kriging spherical or cokriging interpolations when analyzing data from wells in the entire Texas (p<0.0001). Correlation coefficient was significantly lower with cokriging than any other methods (p<0.006) for wells in Texas, east Texas or the Edwards aquifer. Correlation coefficient was significantly greater for wells in southwestern Texas Panhandle than in east Texas, and was higher for wells in Ogallala aquifer than in Edwards aquifer (p<0.0001) regardless of interpolation methods. In regression analysis, the best models are when well depth and/or elevation were entered into the model as covariates regardless of area/aquifer or interpolation methods, and models with IDW are better than kriging in any area/aquifer. In conclusion, the accuracy in estimating groundwater arsenic level depends on both interpolation methods and wells' geographic distributions and characteristics in Texas. Taking well depth and elevation into regression analysis as covariates significantly increases the accuracy in estimating groundwater arsenic level in Texas with IDW in particular.

PMID: 24559533 [PubMed - as supplied by publisher]

The structural basis of an NADP(+)-independent dithiol oxidase in FK228 biosynthesis.

Tue, 02/25/2014 - 5:28am

The structural basis of an NADP(+)-independent dithiol oxidase in FK228 biosynthesis.

Sci Rep. 2014;4:4145

Authors: Li J, Wang C, Zhang ZM, Cheng YQ, Zhou J

Abstract
The disulfide bond is unusual in natural products and critical for thermal stability, cell permeability and bioactivity. DepH from Chromobacterium violaceum No. 968 is an FAD-dependent enzyme responsible for catalyzing the disulfide bond formation of FK228, an anticancer prodrug approved for the treatment of cutaneous T-cell lymphoma. Here we report the crystal structures of DepH and DepH complexed with a substrate analogue S,S'-dimethyl FK228 at 1.82 Å and 2.00 Å, respectively. Structural and biochemical analyses revealed that DepH, in contrast to the well characterized low molecular weight thioredoxin reductases (LMW TrxRs), is an NADP(+)-independent dithiol oxidase. DepH not only lacks a conserved GGGDXAXE motif necessary for NADP(+) binding in the canonical LMW TrxRs, but also contains a 11-residue sequence which physically impedes the binding of NADP(+). These observations explain the difference between NADP(+)-independent small molecule dithiol oxidases and NADP(+)-dependent thioredoxin reductases and provide insights for understanding the catalytic mechanism of dithiol oxidases involved in natural product biosynthesis.

PMID: 24553401 [PubMed - as supplied by publisher]

Internal validation of the GlobalFiler™ Express PCR Amplification Kit for the direct amplification of reference DNA samples on a high-throughput automated workflow.

Tue, 02/25/2014 - 5:28am

Internal validation of the GlobalFiler™ Express PCR Amplification Kit for the direct amplification of reference DNA samples on a high-throughput automated workflow.

Forensic Sci Int Genet. 2014 Jan 28;10C:33-39

Authors: Flores S, Sun J, King J, Budowle B

Abstract
The GlobalFiler™ Express PCR Amplification Kit uses 6-dye fluorescent chemistry to enable multiplexing of 21 autosomal STRs, 1 Y-STR, 1 Y-indel and the sex-determining marker amelogenin. The kit is specifically designed for processing reference DNA samples in a high throughput manner. Validation studies were conducted to assess the performance and define the limitations of this direct amplification kit for typing blood and buccal reference DNA samples on various punchable collection media. Studies included thermal cycling sensitivity, reproducibility, precision, sensitivity of detection, minimum detection threshold, system contamination, stochastic threshold and concordance. Results showed that optimal amplification and injection parameters for a 1.2mm punch from blood and buccal samples were 27 and 28 cycles, respectively, combined with a 12s injection on an ABI 3500xL Genetic Analyzer. Minimum detection thresholds were set at 100 and 120RFUs for 27 and 28 cycles, respectively, and it was suggested that data from positive amplification controls provided a better threshold representation. Stochastic thresholds were set at 250 and 400RFUs for 27 and 28 cycles, respectively, as stochastic effects increased with cycle number. The minimum amount of input DNA resulting in a full profile was 0.5ng, however, the optimum range determined was 2.5-10ng. Profile quality from the GlobalFiler™ Express Kit and the previously validated AmpFlSTR(®) Identifiler(®) Direct Kit was comparable. The validation data support that reliable DNA typing results from reference DNA samples can be obtained using the GlobalFiler™ Express PCR Amplification Kit.

PMID: 24552885 [PubMed - as supplied by publisher]

Lens specific RLIP76 transgenic mice show a phenotype similar to microphthalmia.

Fri, 02/21/2014 - 5:24am
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Lens specific RLIP76 transgenic mice show a phenotype similar to microphthalmia.

Exp Eye Res. 2014 Jan;118:125-34

Authors: Sahu M, Sharma R, Yadav S, Wakamiya M, Chaudhary P, Awasthi S, Awasthi YC

Abstract
RALBP1/RLIP76 is a ubiquitously expressed protein, involved in promotion and regulation of functions initiated by Ral and R-Ras small GTPases. Presence of multiple domains in its structure enables RLIP76 to be involved in a number of physiological processes such as endocytosis, exocytosis, mitochondrial fission, actin cytoskeleton remodeling, and transport of exogenous and endogenous toxicants. Previously, we have established that RLIP76 provides protection to ocular tissues against oxidative stress by transporting the glutathione-conjugates of the toxic, electrophilic products of lipid peroxidation generated during oxidative stress. Therefore, we developed lens specific RLIP76 transgenic mice (lensRLIP76 Tg) to elucidate the role of RLIP76 in protection against oxidative stress, but these transgenic mice showed impaired lens development and a phenotype with small eyes similar to that observed in microphthalmia. These findings prompted us to investigate the mechanisms via which RLIP76 affects lens and eye development. In the present study, we report engineering of lensRLIP76 Tg mice, characterization of the associated phenotype, and the possible molecular mechanisms that lead to the impaired development of eye and lens in these mice. The results of microarray array analysis indicate that the genes involved in pathways for G-Protein signaling, actin cytoskeleton reorganization, endocytosis, and apoptosis are affected in these transgenic mice. The expression of transcription factors, Pax6, Hsf1, and Hsf4b known to be involved in lens development is down regulated in the lens of these Tg mice. However, the expression of heat shock proteins (Hsps), the downstream targets of Hsfs, is differentially affected in the lens showing down regulation of Hsp27, Hsp40, up regulation of Hsp60, and no effect on Hsp70 and Hsp90 expression. The disruption in the organization of actin cytoskeleton of these Tg mice was associated with the inhibition of the activation of Cdc42 and down regulation of cofilin phosphorylation. These mice may provide useful animal model for elucidating the mechanisms of lens development, and etiology of microphthalmia.

PMID: 24188744 [PubMed - indexed for MEDLINE]

The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Wed, 02/19/2014 - 5:20am

The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Eur J Pharmacol. 2014 Feb 11;

Authors: Uteshev VV

Abstract
In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, the nicotinic-PAM-based treatments are expected to be highly efficacious with fewer side effects as compared to a more indiscriminate action of exogenous orthosteric agonists. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

PMID: 24530419 [PubMed - as supplied by publisher]

Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Wed, 02/19/2014 - 5:20am

Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Forensic Sci Int Genet. 2014 Mar;9C:33-41

Authors: Ambers A, Gill-King H, Dirkmaat D, Benjamin R, King J, Budowle B

Abstract
The 120-year-old skeletal remains of Confederate Civil War soldier Captain Ezekiel "Zeke" Harper were exhumed by court order in January 2011 for DNA analysis. The goal of the DNA testing was to support or refute whether Captain Harper had fathered a son (Earl J. Maxwell) with his Native American maid prior to his murder in 1892. Bones with adequate structural integrity (left tibia, right tibia, right femur, mandible, four teeth) were retrieved from the burial site and sent to the Institute of Applied Genetics in Fort Worth, Texas for analysis. Given the age and condition of the remains, three different extraction methods were used to maximize the probability of DNA recovery. The majority of the DNA isolates from over fifty separate bone sections yielded partial autosomal STR genotypes and partial Y-STR haplotypes. After comparing the partial results for concordance, consensus profiles were generated for comparison to reference samples from alleged family members. Considering the genetic recombination that occurs in autosomal DNA over the generations within a family, Y-STR analysis was determined to be the most appropriate and informative approach for determining potential kinship. Two of Earl J. Maxwell's grandsons submitted buccal samples for comparison. The Y-STR haplotypes obtained from both of these reference samples were identical to each other and to the alleles in Ezekiel Harper's consensus profile at all 17 loci examined. This Y-STR haplotype was not found in either of two major Y-STR population databases (U.S. Y-STR database and YHRD). The fact that the Y-STR haplotype obtained from Ezekiel's skeletal remains and Earl's grandsons is not found in either population database demonstrates its rarity and further supports a paternal lineage relationship among them. Results of the genetic analyses are consistent with the hypothesis that Earl J. Maxwell is the son of Ezekiel Harper.

PMID: 24528577 [PubMed - as supplied by publisher]

Age estimation via quantification of signal-joint T cell receptor excision circles in Koreans.

Tue, 02/18/2014 - 5:22am

Age estimation via quantification of signal-joint T cell receptor excision circles in Koreans.

Leg Med (Tokyo). 2014 Jan 31;

Authors: Cho S, Ge J, Seo SB, Kim K, Lee HY, Lee SD

Abstract
The estimation of age from biological samples (i.e., remains) at crime scenes could provide useful information about both victims and other persons related to criminal activities. Signal-joint T cell receptor excision circle (sjTREC) levels in peripheral blood decline with age, and negative correlations between sjTREC levels and age have been demonstrated in several ethnic groups. To validate the utility of sjTREC for age estimation in Koreans, Taqman qPCR was used to quantify the sjTREC level in samples obtained from 172 individuals ranging from 16 to 65years old. We modified the previously reported method by using a shorter amplicon and confirmed the efficiency and utility of this method in this report. Our results showed that the linear negative regression curve between sjTREC levels and age was characterized by r=-0.807 and a standard error of 8.49years. These results indicate that sjTREC level is an effective age estimation method in Koreans. The value of the standard error of quantification was not different from previous reports for other population groups.

PMID: 24524944 [PubMed - as supplied by publisher]

The Role of TGF-β2 and Bone Morphogenetic Proteins in the Trabecular Meshwork and Glaucoma.

Sat, 02/15/2014 - 5:42am

The Role of TGF-β2 and Bone Morphogenetic Proteins in the Trabecular Meshwork and Glaucoma.

J Ocul Pharmacol Ther. 2014 Feb 11;

Authors: Wordinger RJ, Sharma T, Clark AF

Abstract
Abstract Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a primary risk factor associated with POAG. Increased aqueous humor (AH) outflow resistance through the trabecular meshwork (TM) results in elevated IOP in POAG patients. Resistance to AH outflow is associated with increased accumulation of extracellular matrix (ECM) proteins in the TM. In addition, levels of transforming growth factor-beta2 (TGF-β2) are elevated in the AH and TM tissue of POAG patients. Elevated levels of TGF-β2 in other tissues have been associated with fibrosis and increased tissue stiffness. However, locally produced effectors that maintain homeostatic relationships must also be present. Bone morphogenetic proteins (BMPs) serve this purpose in the TM as they inhibit TGF-β2-induced ECM changes in TM cells. This review article first describes the TGF-β superfamily of growth factors including BMPs and their canonical and noncanonical signaling pathways. The article then addresses the role of TGF-β2 in the pathophysiology of POAG as related to the ECM and ECM crosslinking enzymes. This is followed by a discussion of potential homeostatic control mechanisms of TGF-β2 signaling in the TM including the inhibitory role of BMP-4 and BMP-7. We then describe the relationship of TGF-β2 and BMPs in TM fibrosis including the role of antagonists. Lastly, in future directions, we identify potential future studies that explore new and unique cellular interactions within the TM for potential therapeutic interventions.

PMID: 24517218 [PubMed - as supplied by publisher]