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"Youth Are More Aware and Intelligent than Imagined": The Mountain Air Youth Photovoice Project.

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"Youth Are More Aware and Intelligent than Imagined": The Mountain Air Youth Photovoice Project.

Int J Environ Res Public Health. 2019 10 11;16(20):

Authors: Cardarelli KM, Paul M, May B, Dunfee M, Browning S, Schoenberg N

Abstract
Appalachian Kentucky reports some of the highest rates of respiratory illness in the United States, including chronic obstructive pulmonary disease and asthma. While smoking rates are high in the region, unexplained variation remains, and community-engaged research approaches are warranted to identify contributing factors. The Mountain Air Project's community advisory board recommended that investigators invite youth to provide their perspectives on possible contributing factors to respiratory illness, and we undertook an exploratory study to determine the utility of photovoice to elicit such perspectives with this population. While photovoice has been employed for other youth-focused health studies in Appalachia, to our knowledge, this work represents the region's first environmental study using photovoice among youth. Over eight weeks, ten participants (age 12-18) represented their perspectives through photographs and accompanying narratives. A brief thematic content analysis of the youth narratives that accompanied the photos revealed three primary themes of environmental determinants of respiratory illness. These themes included compromises community members make regarding respiratory health in order to secure a livelihood; tension between cultural legacies and respiratory health; and consequences of geographic forces. This study demonstrates the value of incorporating youth perspectives in environmental health research, and that photovoice was a valuable approach to elicit such perspectives.

PMID: 31614429 [PubMed - indexed for MEDLINE]

In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection.

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In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection.

Antimicrob Agents Chemother. 2019 04;63(4):

Authors: Weiss WJ, Pulse ME, Nguyen P, Growcott EJ

Abstract
LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in kidney, urine, and bladder. The successful treatment of murine infection models established with carbapenem-resistant K. pneumoniae further supports the clinical development of LYS228.

PMID: 30642927 [PubMed - indexed for MEDLINE]

Models of poststroke depression and assessments of core depressive symptoms in rodents: How to choose?

Recent Research Articles from UNTHSC - Tue, 02/25/2020 - 07:43
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Models of poststroke depression and assessments of core depressive symptoms in rodents: How to choose?

Exp Neurol. 2019 12;322:113060

Authors: Tao X, Yang W, Zhu S, Que R, Liu C, Fan T, Wang J, Mo D, Zhang Z, Tan J, Jin K, Yenari MA, Song T, Wang Q

Abstract
Our previous studies have indicated that depression and declined cognition have been involved in some neurodegenerative diseases including Stroke, Parkinson's diseases and Vascular Parkinsonism. Post-stroke depression (PSD) is the most common psychiatric disorder following a stroke and has high morbidity and mortality. Studies on PSD are increasingly common, but the specific mechanisms remain unknown. Current research mainly includes clinical and animal aspects. Questionnaires and peripheral blood examination are two of the most common methods used to study clinical PSD. The results of questionnaires are influenced by multiple factors such as disease history, education background, occupation, economic status, family relationships and social support. There are certain limitations to blood sample testing; for example, it is influenced by cerebrovascular diseases and some other disruptions of the internal environment. It is difficult for either method to fully clarify the pathophysiological mechanism of PSD. Animal models provide alternative methods to further understand the pathophysiological mechanisms of PSD, such as the involvement of neuronal circuits and cytokines. More than ten animal models of PSD have been developed, and new models are constantly being introduced. Therefore, it is important to choose the appropriate model for any given study. In this paper, we will discuss the characteristics of the different models of PSD and comment on the advantages and disadvantages of each model, drawing from research on model innovation. Finally, we briefly describe the current assessment methods for the core symptoms of PSD models, point out the shortcomings, and present the improved sucrose preference test as a rational evaluation of anhedonia.

PMID: 31505162 [PubMed - indexed for MEDLINE]

Acne vulgaris and risk of depression and anxiety: A meta-analytic review.

Recent Research Articles from UNTHSC - Mon, 02/24/2020 - 07:30
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Acne vulgaris and risk of depression and anxiety: A meta-analytic review.

J Am Acad Dermatol. 2020 Feb 20;:

Authors: Samuels DV, Rosenthal R, Lin R, Chaudhari S, Natsuaki MN

Abstract
BACKGROUND: Several studies have shown an association of acne vulgaris with depression and anxiety but a quantitative review has not yet been conducted.
OBJECTIVE: To conduct a systematic review and meta-analysis that elucidates the association of acne vulgaris with depression and anxiety.
METHOD: A systematic review and meta-analysis of literature published prior to October 1, 2019 from PubMed, PsycINFO, MEDLINE, and Cochrane databases was conducted. We used a meta-analytic approach to perform a random effects analysis comparing individuals with and without acne. Subgroup analyses between studies included age, study setting, and geographic region.
RESULTS: In all, 42 studies were included. We found a significant association of acne vulgaris with depression, r = 0.22 (95% CI: 0.17-0.26, p < .00001), and anxiety, r = 0.25 (95% CI: 0.19-0.31, p < .00001). Subgroup analyses and comparisons showed moderating influences based on factors including age, study setting, and geographic region.
LIMITATIONS: Inconsistency between publications regarding acne and outcome ascertainment, data reporting, and studies with no control group posed considerable barriers to synthesizing all available literature.
CONCLUSION: Because of increased risk for depression and anxiety, clinicians should pursue aggressive treatment of acne and consider psychiatric screening or referrals.

PMID: 32088269 [PubMed - as supplied by publisher]

The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?

Recent Research Articles from UNTHSC - Sun, 02/23/2020 - 07:09
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The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?

Int J Epidemiol. 2020 Feb 22;:

Authors: Peeri NC, Shrestha N, Rahman MS, Zaki R, Tan Z, Bibi S, Baghbanzadeh M, Aghamohammadi N, Zhang W, Haque U

Abstract
OBJECTIVES: To provide an overview of the three major deadly coronaviruses and identify areas for improvement of future preparedness plans, as well as provide a critical assessment of the risk factors and actionable items for stopping their spread, utilizing lessons learned from the first two deadly coronavirus outbreaks, as well as initial reports from the current novel coronavirus (COVID-19) epidemic in Wuhan, China.
METHODS: Utilizing the Centers for Disease Control and Prevention (CDC, USA) website, and a comprehensive review of PubMed literature, we obtained information regarding clinical signs and symptoms, treatment and diagnosis, transmission methods, protection methods and risk factors for Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and COVID-19. Comparisons between the viruses were made.
RESULTS: Inadequate risk assessment regarding the urgency of the situation, and limited reporting on the virus within China has, in part, led to the rapid spread of COVID-19 throughout mainland China and into proximal and distant countries. Compared with SARS and MERS, COVID-19 has spread more rapidly, due in part to increased globalization and the focus of the epidemic. Wuhan, China is a large hub connecting the North, South, East and West of China via railways and a major international airport. The availability of connecting flights, the timing of the outbreak during the Chinese (Lunar) New Year, and the massive rail transit hub located in Wuhan has enabled the virus to perforate throughout China, and eventually, globally.
CONCLUSIONS: We conclude that we did not learn from the two prior epidemics of coronavirus and were ill-prepared to deal with the challenges the COVID-19 epidemic has posed. Future research should attempt to address the uses and implications of internet of things (IoT) technologies for mapping the spread of infection.

PMID: 32086938 [PubMed - as supplied by publisher]

Ancestry inference and admixture component estimations of Chinese Kazak group based on 165 AIM-SNPs via NGS platform.

Recent Research Articles from UNTHSC - Sat, 02/22/2020 - 13:00

Ancestry inference and admixture component estimations of Chinese Kazak group based on 165 AIM-SNPs via NGS platform.

J Hum Genet. 2020 Feb 21;:

Authors: Xie T, Shen C, Liu C, Fang Y, Guo Y, Lan Q, Wang L, Ge J, Zhou Y, Wen S, Yang Q, Zhu B

Abstract
Predicting the biogeographical ancestries of populations and unknown individuals based on ancestry-informative markers (AIMs) has been widely applied in providing DNA clues to criminal investigations, correcting the factor of population stratification in genome-wide association studies (GWAS), and working as the basis of predicting the externally visible characteristics (EVCs) of individuals. The present study chose Chinese Xinjiang Kazak (XJK) group as research object using a 165 AIM-SNPs panel via next generation sequencing (NGS) technology to reveal its ancestral information and genetic background by referencing the populations' data from 1000 Genomes Phase 3. After the Bonferroni correction, there were no significant deviations at the 165 AIM-SNP loci except two loci with homozygote in the studied XJK group. Ancestry information inference and populations genetic analyses were conducted basing on multiplex statistical methods such as forensic statistical parameter analyses, estimation of the success ratios with cross-validation, population tree, principal component analysis (PCA), and genetic structure analysis. The present results revealed that XJK group had the admixed ancestral components of East Asian and European populations with the ratio of about 62:37.

PMID: 32081902 [PubMed - as supplied by publisher]

Increasing body temperature with dynamic exercise and/or by wallowing/bathing in hot water or saunas: effects on cerebral blood flow.

Recent Research Articles from UNTHSC - Sat, 02/22/2020 - 13:00
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Increasing body temperature with dynamic exercise and/or by wallowing/bathing in hot water or saunas: effects on cerebral blood flow.

J Physiol. 2020 Feb 21;:

Authors: Raven PB, Romero SA

PMID: 32080850 [PubMed - as supplied by publisher]

Effects of TAK-639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice.

Recent Research Articles from UNTHSC - Sat, 02/22/2020 - 13:00
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Effects of TAK-639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice.

Exp Eye Res. 2019 11;188:107763

Authors: Millar JC, Savinainen A, Josiah S, Pang IH

Abstract
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, and individuals with ocular hypertension are at risk to develop POAG. Currently, the only modifiable risk factor for glaucoma progression is lowering of intraocular pressure (IOP). A novel mechanism for lowering IOP involves activation of the type B natriuretic peptide receptor (NPR-B), the naturally occurring agonist of which is C-type natriuretic peptide (CNP). Being a cyclic peptide of 22 amino acids, CNP does not readily penetrate the cornea and its ocular hypotensive effect requires intraocular injection. TAK-639 is a synthetic, cornea-permeable, 9-amino acid CNP analog has been studied for the treatment of ocular hypertension and POAG. We assessed TAK-639 in a receptor binding profile and the effects of TAK-639 on NPR-B-mediated cyclic GMP production in cultured transformed human trabecular meshwork (TM) cells (GTM-3). We also evaluated the effects of topical ocular administration of TAK-639 on mouse IOP and aqueous humor dynamics. Among 89 non-natriuretic peptide receptors, transporters, and channels evaluated, TAK-639 at 10 μM displaced ligand binding by more than 50% to only two receptors: the type 2 angiotensin receptor (IC50 = 8.2 μM) and the cholecystokinin A receptor (IC50 = 25.8 μM). In vitro, TAK-639 selectively activates NPR-B (EC50 = 61 ± 11 nM; GTM-3 cells) relative to NPR-A (EC50 = 2179 ± 670 nM; 293T cells). In vivo, TAK-639 lowered mouse IOP by three mechanisms: increase in aqueous humor outflow facility (C), reduction in the aqueous humor formation rate (Fin), and reduction in episcleral venous pressure (Pe). The maximum mean IOP decreases from baseline were -12.1%, -21.0%, and -36.1% for 0.1%, 0.3%, and 0.6% doses of TAK-639, respectively. Maximum IOP-lowering effect was seen at 2 h, and the duration of action was >6 h. With TAK-639 0.6%, at 2 h post-dose, aqueous outflow facility (C) increased by 155.8%, Fin decreased by 41.0%, the uveoscleral outflow rate (Fu) decreased by 52.6%, and Pe decreased by 31.5% (all p < 0.05). No ocular adverse effects were observed. TAK-639 is an efficacious IOP-lowering agent, with a unique combination of mechanisms of action on both aqueous formation and aqueous outflow facility. Further study of this mechanism of treatment may optimize pharmacologic outcomes and provide disease management in patients with POAG and ocular hypertension.

PMID: 31421135 [PubMed - indexed for MEDLINE]

Assessment of Longitudinal Clinical Outcome Measures for Chronic Low Back Pain over 12 Months.

Recent Research Articles from UNTHSC - Fri, 02/21/2020 - 12:51
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Assessment of Longitudinal Clinical Outcome Measures for Chronic Low Back Pain over 12 Months.

J Gen Intern Med. 2020 Feb 19;:

Authors: Licciardone JC

PMID: 32076968 [PubMed - as supplied by publisher]

The Role of Phylogenetically Conserved Elements in Shaping Patterns of Human Genomic Diversity.

Recent Research Articles from UNTHSC - Fri, 02/21/2020 - 12:51
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The Role of Phylogenetically Conserved Elements in Shaping Patterns of Human Genomic Diversity.

Mol Biol Evol. 2018 09 01;35(9):2284-2295

Authors: Woerner AE, Veeramah KR, Watkins JC, Hammer MF

Abstract
Evolutionary genetic studies have shown a positive correlation between levels of nucleotide diversity and either rates of recombination or genetic distance to genes. Both positive-directional and purifying selection have been offered as the source of these correlations via genetic hitchhiking and background selection, respectively. Phylogenetically conserved elements (CEs) are short (∼100 bp), widely distributed (comprising ∼5% of genome), sequences that are often found far from genes. While the function of many CEs is unknown, CEs also are associated with reduced diversity at linked sites. Using high coverage (>80×) whole genome data from two human populations, the Yoruba and the CEU, we perform fine scale evaluations of diversity, rates of recombination, and linkage to genes. We find that the local rate of recombination has a stronger effect on levels of diversity than linkage to genes, and that these effects of recombination persist even in regions far from genes. Our whole genome modeling demonstrates that, rather than recombination or GC-biased gene conversion, selection on sites within or linked to CEs better explains the observed genomic diversity patterns. A major implication is that very few sites in the human genome are predicted to be free of the effects of selection. These sites, which we refer to as the human "neutralome," comprise only 1.2% of the autosomes and 5.1% of the X chromosome. Demographic analysis of the neutralome reveals larger population sizes and lower rates of growth for ancestral human populations than inferred by previous analyses.

PMID: 30113695 [PubMed - indexed for MEDLINE]

Allosteric regulation of CRISPR-Cas9 for DNA-targeting and cleavage.

Recent Research Articles from UNTHSC - Thu, 02/20/2020 - 06:38
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Allosteric regulation of CRISPR-Cas9 for DNA-targeting and cleavage.

Curr Opin Struct Biol. 2020 Feb 15;62:166-174

Authors: Zuo Z, Liu J

Abstract
The CRISPR-Cas9 system from Streptococcus pyogenes has been exploited as a programmable RNA-guided DNA-targeting and DNA-editing platform. This evolutionary tool enables diverse genetic manipulations with unprecedented precision and ease. Cas9 is an allosteric enzyme, which is allosterically regulated in conformational activation, target recognition, and DNA cleavage. Here, we outline the underlying allosteric control over the Cas9 complex assembly and targeting specificity. We further review the strategies for mitigating intrinsic Cas9 off-target effects through allosteric modulations and the advances in engineering controllable Cas9 systems that are responsive to external allosteric signals. Future development of highly specific, tunable CRISPR-Cas9 systems through allosteric modulations would greatly benefit applications that require both conditional control and high precision.

PMID: 32070859 [PubMed - as supplied by publisher]

Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension.

Recent Research Articles from UNTHSC - Thu, 02/20/2020 - 06:38
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Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension.

Am J Physiol Regul Integr Comp Physiol. 2019 05 01;316(5):R651-R665

Authors: Shell B, Farmer GE, Nedungadi TP, Wang LA, Marciante AB, Snyder B, Cunningham RL, Cunningham JT

Abstract
Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

PMID: 30892911 [PubMed - indexed for MEDLINE]

A free-choice high-fat, high-sucrose diet induces hyperphagia, obesity, and cardiovascular dysfunction in female cycling and pregnant rats.

Recent Research Articles from UNTHSC - Thu, 02/20/2020 - 06:38
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A free-choice high-fat, high-sucrose diet induces hyperphagia, obesity, and cardiovascular dysfunction in female cycling and pregnant rats.

Am J Physiol Regul Integr Comp Physiol. 2019 05 01;316(5):R472-R485

Authors: Ahmed H, Hannan JL, Apolzan JW, Osikoya O, Cushen SC, Romero SA, Goulopoulou S

Abstract
The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female cycling and pregnant rats. In the nonpregnant state, female Sprague-Dawley rats offered a 3-wk free-choice high-fat, high-sucrose diet had greater energy intake, adiposity, serum leptin, and triglyceride concentrations compared with rats fed with standard chow and developed glucose intolerance. In addition, choice-diet-fed rats had larger cardiac ventricular weights, smaller kidney and pancreas weights, and higher blood pressure than chow-fed rats, but they did not exhibit resistance artery endothelial dysfunction. When the free-choice diet continued throughout pregnancy, rats remained hyperphagic, hyperleptinemic, and obese. Choice pregnant rats exhibited uterine artery endothelial dysfunction and had smaller fetuses compared with chow pregnant rats. Pregnancy normalized mean arterial blood pressure and pancreas weights in choice rats. These studies are the first to provide a comprehensive evaluation of free-choice high-fat, high-sucrose diet on metabolic and cardiovascular functions in female rats, extending the previous studies in males to female cycling and pregnant rodents. Free-choice diet may provide a new model of preconceptual maternal obesity to study the role of increased energy intake, individual food components, and preexisting maternal obesity on maternal and offspring physiological responses during pregnancy and after birth.

PMID: 30758976 [PubMed - indexed for MEDLINE]

Corticotropin-releasing hormone projections from the paraventricular nucleus of the hypothalamus to the nucleus of the solitary tract increase blood pressure.

Recent Research Articles from UNTHSC - Wed, 02/19/2020 - 09:22
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Corticotropin-releasing hormone projections from the paraventricular nucleus of the hypothalamus to the nucleus of the solitary tract increase blood pressure.

J Neurophysiol. 2019 02 01;121(2):602-608

Authors: Wang LA, Nguyen DH, Mifflin SW

Abstract
Activation of corticotropin-releasing hormone (CRH) type 2 receptors (CRHR2) in the nucleus of the solitary tract (NTS) contributes to the development of hypertension, but the source of CRH inputs to the NTS that increases blood pressure remains unknown. This study tested the hypothesis that activation of CRH-containing projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS increase blood pressure. We expressed channelrhodopsin 2 (ChR2), a light-sensitive ion channel, into CRH-containing neurons in the PVN. This was achieved by injecting Cre-inducible virus expressing ChR2 into the PVN of CRH-Cre mice. CRH-Cre mice are genetically modified mice expressing Cre recombinase only in neurons producing CRH. We found that optogenetic stimulation of CRH-containing somas in the PVN or CRH-containing fibers in the NTS originating from the PVN significantly increased blood pressure and heart rate. Microinjection of K-41498 (CRHR2 antagonist) into the NTS attenuated the pressor and tachycardiac responses induced by optogenetic stimulation of CRH-containing somas in the PVN. In vitro loose-patch recordings revealed that optogenetic stimulation of CRH-containing fibers in the NTS originating from the PVN significantly increased the discharge frequency of NTS neurons. This effect was attenuated by pretreatment of K-41498 and was abolished by pretreatment of kynurenic acid (nonselective glutamate receptor antagonist). These results suggest that activation of PVN-NTS CRH-containing projections increases blood pressure and heart rate. The cardiovascular responses may be mediated at least in part by the corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN. NEW & NOTEWORTHY Optogenetic stimulation of paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH)-containing somas or nucleus of the solitary tract (NTS) CRH-containing fibers originating from the PVN increased blood pressure and heart rate. Corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN may contribute to the pressor and tachycardiac responses elicited by optogenetic stimulation of PVN CRH-containing somas.

PMID: 30565964 [PubMed - indexed for MEDLINE]

A Protective Role of Translocator Protein in Alzheimer's Disease Brain.

Recent Research Articles from UNTHSC - Tue, 02/18/2020 - 18:12

A Protective Role of Translocator Protein in Alzheimer's Disease Brain.

Curr Alzheimer Res. 2020 Feb 16;:

Authors: Jung ME

Abstract
Translocator protein (18 kDa) (TSPO) is a mitochondrial protein that locates cytosol cholesterol to mitochondrial membranes to begin the synthesis of steroids including neurotrophic neurosteroids. TSPO is abundantly present in glial cells that support neurons and respond to neuroinflammation. Located at the outer membrane of mitochondria, TSPO regulates the opening of mitochondrial permeability transition pore (mPTP) that controls the entry of molecules necessary for mitochondrial function. TSPO is linked to neurodegenerative Alzheimer's disease (AD) such that TSPO is upregulated in the brain of AD patients and signals AD-induced adverse changes in brain. The initial increase in TSPO in response to brain insults remains elevated to repair cellular damages and perhaps to prevent further neuronal degeneration as AD progresses. To exert such protective activities, TSPO increases the synthesis of neuroprotective steroids, decreases neuroinflammation, limits the opening of mPTP, and reduces the generation of reactive oxygen species. The beneficial effects of TSPO on AD brain are manifested as the attenuation of neurotoxic amyloid β and mitochondrial dysfunction accompanied by the improvement of memory and cognition. However, the protective activities of TSPO appear to be temporary and eventually diminish as the severity of AD becomes profound. Timely treatment with TSPO agonists/ligands before the loss of endogenous TSPO's activity may promote the protective functions and may extend neuronal survival.

PMID: 32065102 [PubMed - as supplied by publisher]

Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity.

Recent Research Articles from UNTHSC - Tue, 02/18/2020 - 18:12
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Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity.

Toxicol Lett. 2020 Apr 01;322:66-76

Authors: Yang X, Sun X, Wu J, Ma J, Si P, Yin L, Zhang Y, Yan LJ, Zhang C

Abstract
Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, contributes to the neuroprotective effect. However, intracellular signaling pathways that affect SIRT1 function remain unknown. It is well known that N-methyl-D-aspartate (NMDA) receptor activation induces calcium influx which then activates PKC, and SIRT1 is a mRNA target for HuR protein. We hypothesize that Ca2+-PKC-HuR-SIRT1 pathway modulates SIRT1 function. The present study is to investigate the potential pathway of SIRT1 in the SH-SY5Y cell line as an in vitro model of NMDA-induced neurotoxicity. The results showed that: (1) SIRT1 levels were downregulated in NMDA model; (2) NMDA induced an increase in serine phosphorylation of HuR, while inhibition of serine phosphorylation of HuR increased SIRT1 levels, promoting cell survival; (3) PKC inhibitor (Gö 6976) reversed NMDA insults and also suppressed serine phosphorylation of HuR; (4) 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, fully reversed NMDA insults and also inhibited PKC activity evoked by NMDA. These results indicate that intracellular elevated Ca2+ activates PKC, which phosphorylates HuR and then promotes SIRT1 mRNA decay and subsequent neuronal death in NMDA model. Therefore, the study suggests that inhibition of Ca2+-PKC-HuR-SIRT1 pathway could be an effective strategy for preventing certain neurological diseases related to NMDA excitotoxicity.

PMID: 31945382 [PubMed - indexed for MEDLINE]

Preventing College Sexual Victimization by Reducing Hookups: a Randomized Controlled Trial of a Personalized Normative Feedback Intervention.

Recent Research Articles from UNTHSC - Sun, 02/16/2020 - 05:40
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Preventing College Sexual Victimization by Reducing Hookups: a Randomized Controlled Trial of a Personalized Normative Feedback Intervention.

Prev Sci. 2020 Feb 14;:

Authors: Testa M, Livingston JA, Wang W, Lewis MA

Abstract
Sexual activity, including hooking up, increases college women's vulnerability to sexual victimization. Reducing hookups may reduce rates of sexual victimization among this vulnerable population. Because college students overestimate how frequently their peers hook up, correcting their misperceptions may lead to more accurate perceived social norms, and consequently, less hookup behavior. The study was designed as a randomized controlled trial of the efficacy of a brief, computer-administered personalized normative feedback (PNF) intervention regarding hookups during the first semester of college. We tested an indirect effects model in which PNF was hypothesized to predict perceiving fewer peer hookups, which were expected to predict fewer actual hookups and consequently, less sexual victimization during the first semester of college. Entering first-year women (N = 760) were randomly assigned to receive web-delivered PNF or no information. At the end of the semester, perceived number of hookups of others, number of hookups during the semester, and sexual victimization experiences were assessed. Women who received the intervention perceived that their peers engaged in significantly fewer hookups than did control women. Consistent with the proposed indirect effects model, intervention had a significant indirect effect on the odds of first-semester victimization via lower perceived descriptive norms, which in turn predicted fewer hookups. The study provides proof of concept for the importance of hookups as a risk factor for sexual victimization and provides novel, preliminary support for intervention to change descriptive norms as a way of reducing hookups and consequently, sexual vulnerability.

PMID: 32060880 [PubMed - as supplied by publisher]

Time to referral to a nephrology clinic for pediatric hypertension.

Recent Research Articles from UNTHSC - Sun, 02/16/2020 - 05:40
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Time to referral to a nephrology clinic for pediatric hypertension.

Pediatr Nephrol. 2020 Feb 14;:

Authors: Hamby T, Pueringer MR, Noorani S, Khanna A, Barrow J, Razzouk R

Abstract
BACKGROUND: Rates of pediatric hypertension have increased, but adherence to the current diagnostic criteria for hypertension (HTN) in pediatrics is not well known. We investigated the timeline and predictors of time to referral for those referred to nephrology for elevated blood pressure (EBP).
METHODS: A retrospective study was conducted on patients, aged 3-18 years, referred to a nephrology clinic for EBP over a 3-year period. Patients were excluded if they were referred previously, were referred for other conditions, or did not have ≥ 1 prior visit with EBP. Analyses were performed to determine whether sex, age, ethnicity, socioeconomic status, and obesity predicted number of prior visits with EBP and time to referral.
RESULTS: There were 120 patients (64% male; 53% obese) included and 82 (68%) had ≥ 3 prior visits with EBP ≥ 95%. Medians were as follows: 15.08 years of age at referral; 5 visits with EBP and 3.45 years from first EBP ≥ 90%; 4 visits with EBP and 1.42 years from third EBP ≥ 95%. No variables significantly predicted number of prior visits with EBP or time to referral from the first EBP. Starting with the third EBP ≥ 95%, only obesity significantly predicted number of prior visits and time to referral: Obese patients had more visits (p = 0.01), and took longer to be referred (p = 0.03) than healthy patients.
CONCLUSION: Patients with EBP were generally not referred to nephrology promptly, which was especially true for obese patients. Further research is needed to identify interventions to improve time to referral for EBP.

PMID: 32060821 [PubMed - as supplied by publisher]

Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer.

Recent Research Articles from UNTHSC - Sat, 02/15/2020 - 05:15
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Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer.

Int J Mol Sci. 2020 Feb 11;21(4):

Authors: Sridharan S, Basu A

Abstract
The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.

PMID: 32054043 [PubMed - in process]

Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma.

Recent Research Articles from UNTHSC - Sat, 02/15/2020 - 05:15
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Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma.

Exp Eye Res. 2019 08;185:107703

Authors: Daniel S, Meyer KJ, Clark AF, Anderson MG, McDowell CM

Abstract
Glaucoma is a neurodegenerative disease with elevated intraocular pressure as one of the major risk factors. Glaucoma leads to irreversible loss of vision and its progression involves optic nerve head cupping, axonal degeneration, retinal ganglion cell (RGC) loss, and visual field defects. Despite its high global prevalence, glaucoma still remains a major neurodegenerative disease. Introduction of mouse models of experimental glaucoma has become integral to glaucoma research due to well-studied genetics as well as ease of manipulations. Many established inherent and inducible mouse models of glaucoma are used to study the molecular and physiological progression of the disease. One such model of spontaneous mutation is the nee model, which is caused by mutation of the Sh3pxd2b gene. In both humans and mice, mutations disrupting function of the SH3PXD2B adaptor protein cause a developmental syndrome including secondary congenital glaucoma. The purpose of this study was to characterize the early onset nee glaucoma phenotype on the C57BL/6J background and to evaluate the pattern of RGC loss and axonal degeneration in specific RGC subtypes. We found that the B6.Sh3pxd2bnee mutant animals exhibit glaucoma phenotypes of elevated intraocular pressure, RGC loss and axonal degeneration. Moreover, the non-image forming RGCs survived longer than the On-Off direction selective RGCs (DSGC), and the axonal death in these RGCs was independent of their respective RGC subtype. In conclusion, through this study we characterized an experimental model of early onset glaucoma on a C57BL/6J background exhibiting key glaucoma phenotypes. In addition, we describe that RGC death has subtype-specific sensitivities and follows a specific pattern of cell death under glaucomatous conditions.

PMID: 31211954 [PubMed - indexed for MEDLINE]

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