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1.  MiR-125a-3p Regulates Glioma Apoptosis and Invasion by Regulating Nrg1 
PLoS ONE  2015;10(1):e0116759.
The current study was designed to examine the functional role and mechanism of miR-125a-3p in glioma development. Quantitative RT-PCR was used to evaluate miR-125a-3p expression in 60 glioma cases of different malignant grades. Then, the clinic pathologic significance of miR-125a-3p expression was determined in combination with the prognosis of the patients. In addition, the effects and mechanisms of miR-125a-3p on the proliferation, apoptosis and invasion of glioma cells were further investigated. The results showed that the expression of miR-125a-3p was decreased significantly in most malignant glioma samples relative to normal brain tissues and glioma tissues of low-malignant degree. Further kaplan-meier survival analysis showed that the lower expression of miR-125a-3p was associated with a poor prognosis of GBM patients. Functional analysis showed that the reintroduction of miR-125a-3p into glioblastoma cell lines induces markedly the apoptosis and suppresses the proliferation and migration of glioblastoma cells in vitro and in vivo. Luciferase assay and Western blot analysis revealed that Nrg1 is a direct target of miR-125a-3p. Furthermore, an increased expression of Nrg1 could reverse the effects of overexpression of miR-125a-3p on the proliferation, apoptosis and migration of glioblastoma cells. These findings suggest that miR-125a-3p performed an important role in glioma development mediated by directly regulating the expression of Nrg1. This study also provides a potential target for diagnosis and treatment of malignant glioma.
doi:10.1371/journal.pone.0116759
PMCID: PMC4283963  PMID: 25560389
2.  Baseline neutrophil-lymphocyte ratio (≥2.8) as a prognostic factor for patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation 
Background
The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response and may predict the clinical outcome in some cancers, such as head and neck cancer and gastric cancer. However, the value of this ratio is variable in different cancers. Studies of the relationship between NLR and both survival and response to chemoradiation have been limited with respect to locally advanced rectal cancer.
Methods and materials
From 2006 to 2011, 199 consecutive locally advanced rectal cancer patients who were treated with neoadjuvant chemoradiation in the Shanghai Cancer Center were enrolled and analysed retrospectively. Tumor response was evaluated by pathological findings. The baseline total white blood cell count (WBC) and the neutrophil, lymphocyte, platelet counts were recorded. The neutrophil-lymphocyte ratio (NLR) and the relationship with clinical outcomes such as overall survival (OS) and disease-free survival (DFS) was analyzed.
Results
With ROC analysis, the baseline NLR value was found to significantly predict prognosis in terms of OS well in locally advanced rectal cancer patients. A multivariate analysis identified that a cut-off value of NLR ≥ 2.8 could be used as an independent factor to indicate decreased OS (HR, 2.123; 95% CI, 1.140-3.954; P = 0.018). NLR ≥ 2.8 was also associated with worse DFS in univariate analysis (HR, 1.662; 95% CI, 1.037-2.664; P = 0.035), though it was not significant in the multivariate analysis (HR, 1.363; 95% CI, 0.840-2.214; P = 0.210). There was no observed significant correlation of mean value of NLR to the response to neoadjuvant chemoradiation. The mean NLR in the ypT0-2 N0 group was 2.68 ± 1.38, and it was 2.77 ± 1.38 in the ypT3-4/N+ group, with no statistical significance (P = 0.703). The mean NLR in the TRG 0–1 group was 2.68 ± 1.42, and it was 2.82 ± 1.33 in the TRG 2–3 group with no statistical significance (P = 0.873).
Conclusions
An elevated baseline NLR is a valuable and easily available prognostic factor for OS in addition to tumor response after neoadjuvant therapy. Baseline NLR could be a useful candidate factor for stratifying patients and making treatment decisions in locally advanced rectal cancer.
doi:10.1186/s13014-014-0295-2
PMCID: PMC4300208  PMID: 25518933
Rectal cancer; Neoadjuvant chemoradiation; Neutrophil-lymphocyte ratio
3.  Human Influenza A(H7N9) Virus Infection Associated with Poultry Farm, Northeastern China 
Emerging Infectious Diseases  2014;20(11):1902-1905.
We report on a case of human infection with influenza A(H7N9) virus in Jilin Province in northeastern China. This case was associated with a poultry farm rather than a live bird market, which may point to a new focus for public health surveillance and interventions in this evolving outbreak.
doi:10.3201/eid2011.140608
PMCID: PMC4214311  PMID: 25340624
H7N9; avian influenza; China; poultry farm; influenza; flu; avian flu; human; Suggested citation for this article: Fan M; Huang B; Wang A; Deng L; Wu D; Lu X; et al. Human influenza A(H7N9) virus infection associated with poultry farm; northeastern China. Emerg Infect Dis [Internet]. 2014 Nov [date cited]. http://dx.doi.org/10.3201/eid2011.140608
4.  Role of rostral ventrolateral medullary ERK/JNK/p38 MAPK signaling in the pressor effects of ethanol and its oxidative product acetaldehyde 
Alcoholism, clinical and experimental research  2013;37(11):10.1111/acer.12179.
Background
We tested the hypothesis that alterations of the phosphorylation/dephosphorylation profile of mitogen-activated protein kinases (MAPKs) in the rostral ventrolateral medulla (RVLM) underlies the pressor response elicited by ethanol microinjection into the RVLM of spontaneously hypertensive rats (SHRs). The studies were extended to determine if acetaldehyde (ACA), the primary oxidative product of ethanol, replicates the molecular effects of ethanol within the RVLM and the consequent pressor response.
Methods
Effects of ethanol or ACA on blood pressure (BP) were evaluated in the absence or presence of selective JNK (SP600125), ERK (PD98059), p38 (SB203580), or ser/thr phosphatases (okadaic acid, OKA) inhibitor.
Results
Intra-RVLM ethanol (10 µg/rat) or ACA (2 µg/rat) caused a similar ERK2-dependent pressor response because ethanol or ACA-evoked increases in BP and in RVLM p-ERK2 level were abolished after pharmacologic inhibition of ERK phosphorylation. SP600125 abrogated the pressor action of ethanol, but not ACA, thus implicating JNK in ethanol action on BP. Despite ethanol enhancement of p38 phosphorylation, pharmacological studies argued against a causal role for this kinase in ethanol-evoked pressor response. RVLM phosphatase catalytic activity was not influenced by ethanol or ACA. Interestingly, pharmacologic phosphatase inhibition (OKA), which increased RVLM p-ERK2 and BP, abrogated the pressor effect of subsequently administered ethanol or ACA.
Conclusions
Enhancement of RVLM ERK2 phosphorylation constitutes a major molecular mechanism for the pressor response elicited by intra-RVLM ethanol or its metabolite, ACA, in conscious SHRs. Further, RVLM kinases dephosphorylation does not contribute to intra-RVLM ethanol- or ACA-evoked pressor response.
doi:10.1111/acer.12179
PMCID: PMC3812351  PMID: 23905689
Ethanol; acetaldehyde; hypertension; mitogen activated protein kinases; spontaneously hypertensive rats
5.  CyclinB1/Cdk1 Coordinates Mitochondrial Respiration for Cell Cycle G2/M Progression 
Developmental cell  2014;29(2):217-232.
SUMMARY
A substantial amount of mitochondrial energy is required for cell cycle progression. However, the mechanisms coordinating the mitochondrial respiration with G2/M transition, a critical step in cell division, remains to be elucidated. Here we show that a fraction of cell cycle CyclinB1/Cdk1 proteins localizes into the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins including the complex I (CI) subunits in the respiratory chain. The CyclinB1/Cdk1-mediated CI subunit phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function. Mitochondria-targeted CyclinB1/Cdk1 increases mitochondrial respiration with enhanced oxygen consumption and ATP generation, which provides cells with efficient bioenergy for G2/M transition and shortens overall cycling time. Thus, CyclinB1/Cdk1-mediated phosphorylation of mitochondrial substrates allows cells to sense and respond to an increased energy demand for G2/M transition, and subsequently to up-regulate mitochondrial respiration for a successful cell cycle progression.
doi:10.1016/j.devcel.2014.03.012
PMCID: PMC4156313  PMID: 24746669
CyclinB1/Cdk1; Mitochondrial respiration; Phosphorylation; Cell cycle; G2/M-checkpoint
6.  Co-activation of ERK, NF-κB, and GADD45β in Response to Ionizing Radiation* 
The Journal of biological chemistry  2005;280(13):12593-12601.
NF-κB has been well documented to play a critical role in signaling cell stress reactions. The extracellular signal-regulated kinase (ERK) regulates cell proliferation and survival. GADD45β is a primary cell cycle element responsive to NF-κB activation in anti-apoptotic responses. The present study provides evidence demonstrating that NK-κB, ERK and GADD45β are co-activated by ionizing radiation (IR) in a pattern of mutually dependence to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single exposure of 5 Gy IR resulted in the activation of ERK but not p38 or JNK, along with an enhancement of the NF-κB transactivation and GADD45β expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF-κB. Transfection of dominant negative mutant IκB that blocks NF-κB nuclear translocation, inhibited ERK activity and GADD45β expression and increased cell radiosensitivity. Interaction of p65 and ERK was visualized in living MCF-7 cells by bimolecular fluorescence complementation analysis. Anti-sense inhibition of GADD45β strikingly blocked IR-induced NF-κB and ERK but not p38 and JNK. Overall, these results demonstrate a possibility that NF-κB, ERK, and GADD45β are able to coordinate in a loop-like signaling network to defend cells against the cytotoxicity induced by ionizing radiation.
doi:10.1074/jbc.M410982200
PMCID: PMC4130153  PMID: 15642734
7.  Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation 
PLoS ONE  2014;9(6):e99805.
Background
Vitamin D plays an important role in pulmonary resistance and immunity, and its deficiency has been linked to various respiratory infections. Little is known about the effect of vitamin D deficiency on host pulmonary defense to Aspergillus fumigatus (A. fumigatus).
Methods
Mice raised on vitamin D sufficient or deficient diets were infected intratracheally with A. fumigatus conidia. Mortality, fungal growth, weight loss and lung histology were monitored. Alveolar macrophages (AMs) were stimulated with A. fumigatus conidia in vitro. The kinetics of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (CXCL1, CCL3), and pattern recognition receptors (Toll-like receptor [TLR] 2, TLR 4 and dectin-1) expression in the lungs and AMs were measured.
Results
Upon A. fumigatus infection, vitamin D deficient mice showed higher mortality, greater fungal load, and more weight loss than its sufficient counterparts. Vitamin D deficient mice demonstrated aggravated and prolonged histological evidence of lung inflammation as well as enhanced BAL cell counts, dominated by neutrophils after A. fumigatus inoculation. Increased basal levels of pro-inflammatory cytokines in the lungs and AMs from naïve vitamin D deficient mice were observed. Upon A. fumigatus exposure, vitamin D deficiency led to enhanced and sustained expression of TNF-α, IL-1β, IL-6, CXCL1 and CCL3 both in vivo and in vitro. Up-regulation of TLR2, TLR4 and dectin-1was observed in the lungs and AMs from vitamin D deficient mice both at baseline and after A. fumigatus exposure.
Conclusions
Vitamin D deficiency causes defective pulmonary resistance to A. fumigatus in mice, possibly by the enhanced basal expression of pattern recognition receptors and pro-inflammatory cytokines, which induced excessive inflammatory response in response to A. fumigatus challenge.
doi:10.1371/journal.pone.0099805
PMCID: PMC4057384  PMID: 24926881
8.  Acute Aerobic Exercise Increases Cortical Activity during Working Memory: A Functional MRI Study in Female College Students 
PLoS ONE  2014;9(6):e99222.
There is increasing evidence that acute aerobic exercise is associated with improved cognitive function. However, neural correlates of its cognitive plasticity remain largely unknown. The present study examined the effect of a session of acute aerobic exercise on working memory task-evoked brain activity as well as task performance. A within-subjects design with a counterbalanced order was employed. Fifteen young female participants (M = 19.56, SD = 0.81) were scanned using functional magnetic resonance imaging while performing a working memory task, the N-back task, both following an acute exercise session with 20 minutes of moderate intensity and a control rest session. Although an acute session of exercise did not improve behavioral performance, we observed that it had a significant impact on brain activity during the 2-back condition of the N-back task. Specifically, acute exercise induced increased brain activation in the right middle prefrontal gyrus, the right lingual gyrus, and the left fusiform gyrus as well as deactivations in the anterior cingulate cortexes, the left inferior frontal gyrus, and the right paracentral lobule. Despite the lack of an effect on behavioral measures, significant changes after acute exercise with activation of the prefrontal and occipital cortexes and deactivation of the anterior cingulate cortexes and left frontal hemisphere reflect the improvement of executive control processes, indicating that acute exercise could benefit working memory at a macro-neural level. In addition to its effects on reversing recent obesity and disease trends, our results provide substantial evidence highlighting the importance of promoting physical activity across the lifespan to prevent or reverse cognitive and neural decline.
doi:10.1371/journal.pone.0099222
PMCID: PMC4050105  PMID: 24911975
9.  CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress 
Manganese superoxide dismutase (MnSOD), a major antioxidant enzyme within the mitochondria, is responsible for the detoxification of free radicals generated by cellular metabolism and environmental/therapeutic irradiation. Cell cycle-dependent kinase Cdk1, along with its regulatory partner CyclinB1, plays important roles in the regulation of cell cycle progression as well as in genotoxic stress response. Herein, we identified the presence of the minimal Cdk1 phosphorylation consensus sequence ([S/T]-P; Ser106) in human MnSOD, suggesting Cdk1 as a potential upstream kinase of MnSOD. A substantial amount of CyclinB1/Cdk1 was found to localize in the mitochondrion upon irradiation. The enhanced Cdk1/MnSOD interaction and MnSOD phosphorylation were detected in both the irradiated human cells and mouse tissues. We report that CyclinB1/Cdk1 can regulate MnSOD through reversible Ser106 phosphorylation, both in vivo and in vitro. The CyclinB1/Cdk1-mediated MnSOD Ser106 resulted in increased MnSOD activity and stability, along with improved mitochondrial function and cellular resistance to radiation-induced apoptosis. These results demonstrate a unique pro-survival mechanism by which cells enhance the survival via CyclinB1/Cdk1-mediated MnSOD activation under genotoxic stress conditions.
doi:10.1093/jmcb/mjs062
PMCID: PMC3656610  PMID: 23243068
MnSOD; CyclinB1/Cdk1; radioadaptive response
10.  In Silico Insight into Potent of Anthocyanin Regulation of FKBP52 to Prevent Alzheimer's Disease 
Alzheimer's disease (AD) is caused by the hyperphosphorylation of Tau protein aggregation. FKBP52 (FK506 binding protein 52) has been found to inhibit Tau protein aggregation. This study found six different kinds of anthocyanins that have high binding potential. After analyzing the docking positions, hydrophobic interactions, and hydrogen bond interactions, several amino acids were identified that play important roles in protein and ligand interaction. The proteins' variation is described using eigenvectors and the distance between the amino acids during a molecular dynamics simulation (MD). This study investigates the three loops based around Glu85, Tyr113, and Lys121—all of which are important in inducing FKBP52 activation. By performing a molecular dynamic simulation process between unbound proteins and the protein complex with FK506, it was found that ligand targets that docked onto the FK1 domain will decrease the distance between Glu85/Tyr113 and Glu85/Lys121. The FKBP52 structure variation may induce FKBP52 activation and inhibit Tau protein aggregation. The results indicate that anthocyanins might change the conformation of FKBP52 during binding. In addition, the purple anthocyanins, such as cyanidin-3-glucoside and malvidin-3-glucoside, might be better than FK506 in regulating FKBP52 and treating Alzheimer's disease.
doi:10.1155/2014/450592
PMCID: PMC4036721  PMID: 24899909
11.  Performance of mass spectrometric identification of bacteria and yeasts routinely isolated in a clinical microbiology laboratory using MALDI-TOF MS 
Journal of Thoracic Disease  2014;6(5):524-533.
Background
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is an emerging technology newly applied to identifying bacterial and yeast strains. The aim of this study was to evaluate the clinical performance of the VITEK® MS system in the identification of bacteria and yeast strains routinely isolated from clinical samples.
Methods
We prospectively analyzed routine MALDI-TOF mass spectrometry identification in parallel with conventional phenotypic identification of bacteria and yeasts regardless of phylum or source of isolation. Discordant results were resolved with 16S rDNA or internal transcribed spacer (ITS) gene sequencing. Colonies (a single deposit on a MALDI disposable target without any prior extraction step) were analyzed using the VITEK® MS system. Peptide spectra acquired by the system were compared with the VITEK® MS IVD database Version 2.0, and the identification scores were recorded.
Results
Of the 1,181 isolates (1,061 bacterial isolates and 120 yeast isolates) analyzed, 99.5% were correctly identified by MALDI-TOF mass spectrometry; 95.7% identified to the species level, 3.6% identified to the genus level, and 0.3% identified within a range of species belonging to different genera. Conversely, 0.1% of isolates were misidentified and 0.4% were unidentified, partly because the species were not included in the database. Re-testing using a second deposit provided a successful identification for 0.5% of isolates unidentified with the first deposit. Our results show that the VITEK® MS system has exceptional performance in identifying bacteria and yeast by comparing acquired peptide spectra to those contained in its database.
Conclusions
MALDI-TOF mass spectrometry is a rapid, accurate, and relatively inexpensive method for bacterial and yeast identification. Our results demonstrate that the VITEK® MS system is a fast and reliable technique, and has the potential to replace conventional phenotypic identification for most bacterial and yeast strains routinely isolated in clinical microbiology laboratories.
doi:10.3978/j.issn.2072-1439.2014.02.17
PMCID: PMC4015010  PMID: 24822114
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS); VITEK-MS; bacteria; yeasts; identification
12.  Long-Term Effectiveness of Collaborative Depression Care in Older Primary Care Patients with and without PTSD Symptoms 
Objective
Depressed patients with comorbid posttraumatic stress disorder (PTSD) are more functionally impaired and may take longer to respond to depression treatment than patients without PTSD. This study examined the long-term effects of PTSD on depression severity, treatment response, and health care costs among older adults.
Methods
Patients were recruited from 18 primary care clinics in 5 states. A total of 1801 patients aged 60 years or older with major depression or dysthymia were randomized to IMPACT collaborative care or usual care. The study included 191 (10.6%) subjects who screened positive for PTSD. Depression severity, assessed by the Hopkins Depression Symptom Checklist, was used to estimate depression-free days (DFDs) over 24 months. Total health care costs included inpatient, outpatient, and pharmacy costs.
Results
Depressed patients with PTSD had higher depression severity than patients without PTSD symptoms at baseline. Over two years, intervention patients with PTSD symptoms had relatively the same benefits from collaborative care (99 more DFDs than usual care patients) as patients without PTSD (108 more DFDs than usual care) (p=0.85). Total health care costs did not differ significantly for depressed patients with and without PTSD symptoms.
Conclusion
Depressed older adults with PTSD symptoms were more depressed at baseline, but collaborative care (compared to usual care) produced similar improvements in depression severity in both groups. This reduction of depression symptoms was observed for up to 12 months after the intervention ended, suggesting that long-term improvements in depression are possible with collaborative care in patients with and without PTSD symptoms.
doi:10.1002/gps.2606
PMCID: PMC3998660  PMID: 21495079
Depression; PTSD; Primary Care; older adults
13.  Shadowless-illuminated variable-angle TIRF (siva-TIRF) microscopy for the observation of spatial-temporal dynamics in live cells 
Biomedical Optics Express  2014;5(5):1530-1540.
Total-internal-reflection fluorescence (TIRF) microscopy provides high optical-sectioning capability and a good signal-contrast ratio for structures near the surfaces of cells. In recent years, several improvements have been developed, such as variable-angle TIRF (VA-TIRF) and spinning TIRF (sp-TIRF), which permit quantitative image analysis and address non-uniform scattering fringes, respectively. Here, we present a dual-color DMD-based shadowless-illuminated variable-angle TIRF (siva-TIRF) system that provides a uniform illumination field. By adjusting the incidence angle of the illuminating laser on the back focal plane (BFP) of the objective, we can rapidly illuminate biological samples in layers of various thicknesses in TIRF or hollow-cone epi-fluorescence mode. Compared with other methods of accomplishing VA-TIRF/sp-TIRF illumination, our system is simple to build and cost-effective, and it provides optimal multi-plane dual-color images. By showing spatiotemporal correlated movement of clathrin-coated structures with microtubule filaments from various layers of live cells, we demonstrate that cortical microtubules are important spatial regulators of clathrin-coated structures. Moreover, our system can be used to prove superb axial information of three-dimensional movement of structures near the plasma membrane within live cells.
doi:10.1364/BOE.5.001530
PMCID: PMC4026904  PMID: 24877013
(180.0180) Microscopy; (110.0110) Imaging systems; (050.0050) Diffraction and gratings; (260.6970) Total internal reflection
14.  HER2-associated radiation resistance of breast cancer stem cells isolated from HER2-negative breast cancer cells 
Purpose
To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSCs); using radiation-resistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers.
Experimental Design
HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radiation resistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with 2-D DIGE and HPLC-MS/MS analysis and HER2-mediated signaling network was generated by MetaCore™ program.
Results
Compared to HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by matrigel invasion, tumor sphere formation and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells co-expressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC-MS/MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function and DNA repair. A specific feature of HER2-STAT3 network was identified.
Conclusion
This study provides the evidence that HER2-mediated pro-survival signaling network is responsible for the aggressive phenotype of breast cancer stem cells that could be targeted to control the therapy-resistant HER2−/low breast cancer.
doi:10.1158/1078-0432.CCR-12-1436
PMCID: PMC3593096  PMID: 23091114
15.  Activity Scheduling as a Core Component of Effective Care Management for Late-Life Depression 
Objective
Activity scheduling is an established component of evidenced-based treatment for late-life depression in primary care. We examined participant records from the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial to identify activity scheduling strategies used in the context of successful depression care management (CM), associations of activity scheduling with self-reported activity engagement, and depression outcomes.
Methods
Observational mixed methods analysis of 4,335 CM session notes from 597 participants in the intervention arm of the IMPACT trial. Grounded theory was used to identify seventeen distinct activity categories from CM notes. Logistic regression was used to evaluate associations between activity scheduling, activity engagement, and depression outcomes at 12 months. All relevant institutional review boards approved the research protocol.
Results
Seventeen distinct activity categories were generated. The majority of patients worked on at least one social and one solitary activity during their course of treatment. Common activity categories included physical activity (32%), medication management (22%), active-non-physical (19%) and passive (14%) activities. We found significant, positive associations between activity scheduling, self reported engagement in activities at 12 months, and depression outcomes at 12 months.
Conclusion
Older primary care patients in CM for depression worked on a wide range of activities. Consistent with depression theory that has placed emphasis on social activities, our data indicates a benefit for intentional social engagement versus passive social and solitary activities. Care Managers should encourage patients to balance instrumental activities (e.g. attending to medical problems) with social activities targeting direct interpersonal engagement.
doi:10.1002/gps.3784
PMCID: PMC3429703  PMID: 22367982
Care Management; Depression; Geriatric; Behavioral Activation
16.  Differential modulation by vascular nitric oxide synthases of the ethanol-evoked hypotension and autonomic dysfunction in female rats 
Alcohol (Fayetteville, N.Y.)  2012;46(8):727-735.
We recently reported that chronic exposure to ethanol lowers blood pressure (BP) via altering cardiac contractility and autonomic control in female rats. In this investigation we conducted pharmacological and molecular studies to elucidate the role of constitutive and inducible nitric oxide synthase (NOS) in these hemodynamic effects of ethanol. Changes caused by selective inhibition of eNOS [N5-(1-iminoethyl)-L-ornithine; L-NIO], nNOS (Nω-propyl-L-arginine; NPLA), or iNOS (1400W) in BP, heart rate (HR), myocardial contractility index (dP/dtmax), and power spectral indices of hemodynamic variability were evaluated in telemetered female rats receiving ethanol (5%, w/v) or control liquid diet for 8 weeks. Ethanol increased plasma nitrite/nitrate (NOx) and enhanced the phosphorylation of eNOS and nNOS, but not iNOS, in the tail artery. Ethanol also reduced BP, +dP/dtmax, low-frequency bands of interbeat intervals (IBILF, 0.25–0.75 Hz) and IBILF/HF ratio while high-frequency bands (IBIHF, 0.75–3 Hz) were increased, suggesting parasympathetic overactivity. L-NIO (20 mg/kg i.p.) caused greater increases in BP in control than in ethanol-fed rats but elicited similar reductions in IBILF/HF and +dP/dtmax both groups. NPLA (1 mg/kg i.p.) caused minimal effects in control rats but exacerbated the reductions in BP, +dP/dtmax, and IBILF/HF in ethanol-fed rats. No hemodynamic modifications were caused by 1400W (5 mg/kg i.p.) in either rat group. Together, these findings suggest that nNOS acts tonically to offset the detrimental cardiovascular actions of ethanol in female rats, and the enhanced vascular NO bioavailability may explain the blunted L-NIO evoked pressor response in ethanol-fed rats.
doi:10.1016/j.alcohol.2012.09.001
PMCID: PMC3496835  PMID: 23046587
Ethanol; blood pressure; cardiac autonomic control; nitric oxide synthases; female rats
17.  Bullying and School Safety 
The Journal of pediatrics  2007;152(1):10.1016/j.jpeds.2007.05.045.
Objective
To identify an association between involvement in bullying and problems in school.
Study design
This was a cross-sectional study of 5391 students in grades 7, 9, and 11 in an urban public school district. The main outcome measure was involvement in bullying. Secondary outcomes included attendance, grade point average, psychosocial distress, and perceived acceptability of carrying guns to school.
Results
Of the 5391 children surveyed, 26% were involved in bullying either as victim, bully, or both (bully-victim). All 3 groups were significantly more likely than bystanders to feel unsafe at school and sad most days. Victims and bully-victims were more likely to say they are “no good.” Victims were more likely to feel that they “do not belong” in their school. The odds of being a victim (vs a bystander) were 10% lower for every 1 point increase in grade point average. Bully-victims were more likely to say that it is “not wrong” to take a gun to school.
Conclusions
Associations between involvement in bullying and academic achievement, psychological distress, and the belief that it is not wrong to take a gun to school reinforce the notion that school environment is interrelated with mental health and school success.
doi:10.1016/j.jpeds.2007.05.045
PMCID: PMC3839286  PMID: 18154913
18.  Manganese superoxide dismutase interacts with a large scale of cellular and mitochondrial proteins in low dose radiation-induced adaptive radioprotection 
Free radical biology & medicine  2012;53(10):1838-1847.
Cellular adaptive response to certain low level genotoxic stresses including the exposure to low dose ionizing radiation (LDIR) shows promise as a tool to enhance radioprotection in normal cells but not in tumor cells. Manganese superoxide dismutase (MnSOD), a fundamental mitochondrial antioxidant in mammalian cells plays a key role in LDIR-induced adaptive response. In this study, we aim to elucidate the signaling network associated with the MnSOD-induced radiation protection. A MnSOD-interacting protein profile was established in LDIR-treated human skin cells. Human skin keratinocytes (HK18) were irradiated with a single dose LDIR (10 cGy x-ray) and the cell lysates were immunoprecipitated using α-MnSOD and applied to two different gel-based proteomics followed by mass spectrometry for protein identification. Analysis of the profiles of MnSOD interacting partners before and after LDIR detected different patterns of MnSOD protein-protein interactions in response to LDIR. Interestingly, many of the MnSOD interacting proteins are known to have functions related to mitochondrial regulations on cell metabolism, apoptosis and DNA repair. These results provide the evidence indicating that in addition to the enzymatic action detoxifying superoxide, the antioxidant MnSOD may function as a signaling regulator in stress induced adaptive protection through cell survival pathways.
doi:10.1016/j.freeradbiomed.2012.08.589
PMCID: PMC3494792  PMID: 23000060
MnSOD; protein interaction; low dose radiation; adaptive response; human keratinocytes
19.  Long-term Cost Effects of Collaborative Care for Late-life Depression 
Objective
To determine the long-term effects on total healthcare costs of the Improving Mood: Promoting Access to Collaborative Treatment (IMPACT) program for late-life depression compared with usual care.
Study Design
Randomized controlled trial with enrollment from July 1999 through August 2001. The IMPACT trial, conducted in primary care practices in 8 delivery organizations across the United States, enrolled 1801 depressed primary care patients 60 years or older. Data are from the 2 IMPACT sites for which 4-year cost data were available. Trial enrollment across these 2 health maintenance organizations was 551 patients.
Methods
Participants were randomly assigned to the IMPACT intervention (n = 279) or to usual primary care (n = 272). Intervention patients had access to a depression care manager who provided education, behavioral activation, support of antidepressant medication management prescribed by their regular primary care provider, and problem-solving treatment in primary care for up to 12 months. Care managers were supervised by a psychiatrist and a primary care provider. The main outcome measures were healthcare costs during 4 years.
Results
IMPACT participants had lower mean total healthcare costs ($29 422; 95% confidence interval, $26 479-$32 365) than usual care patients ($32 785; 95% confidence interval, $27 648-$37 921) during 4 years. Results of a bootstrap analysis suggested an 87% probability that the IMPACT program was associated with lower healthcare costs than usual care.
Conclusion
Compared with usual primary care, the IMPACT program is associated with a high probability of lower total healthcare costs during a 4-year period.
PMCID: PMC3810022  PMID: 18269305
20.  Age and Sex Trends in Long-term Opioid Use in Two Large American Health Systems Between 2000 and 2005 
Pain medicine (Malden, Mass.)  2009;11(2):248-256.
Objective
To estimate recent age- and sex-specific changes in long-term opioid prescription among patients with chronic pain in two large American Health Systems.
Design
Analysis of administrative pharmacy data to calculate changes in prevalence of long-term opioid prescription (90 days or more during a calendar year) from 2000 to 2005, within groups based on sex and age (18–44, 45–64, and 65 years and older). Separate analyses were conducted for patients with and without a diagnosis of a mood disorder or anxiety disorder. Changes in mean dose between 2000 and 2005 were estimated, as were changes in the rate of prescription for different opioid types (short-acting, long-acting, and non-Schedule 2).
Patients
Enrollees in HealthCore (N = 2,716,163 in 2000) and Arkansas Medicaid (N = 115,914 in 2000).
Results
Within each of the age and sex groups, less than 10% of patients with a chronic pain diagnosis in HealthCore, and less than 33% in Arkansas Medicaid, received long-term opioid prescriptions. All age, sex, and anxiety/depression groups showed similar and statistically significant increases in long-term opioid prescription between 2000 and 2005 (35–50% increase). Per-patient daily doses did not increase.
Conclusions
No one group showed especially large increases in long-term opioid prescriptions between 2000 and 2005. These results argue against a recent epidemic of opioid prescribing. These trends may result from increased attention to pain in clinical settings, policy or economic changes, or provider and patient openness to opioid therapy. The risks and benefits to patients of these changes are not yet established.
doi:10.1111/j.1526-4637.2009.00740.x
PMCID: PMC3773537  PMID: 20002323
Opioids; Prescriptions; Chronic Pain; Disparities—Gender; Aged; Mood; Anxiety
21.  Emergency Department Visits Among Recipients of Chronic Opioid Therapy 
Archives of internal medicine  2010;170(16):1425-1432.
Background
There has been an increase in over dose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear.
Methods
Data were obtained from administrative claim records from Arkansas Medicaid and HealthCore commercially insured enrollees, 18 years and older, who used prescription opioids for at least 90 continuous days within a 6-month period between 2000 and 2005 and had no cancer diagnoses. Regression analysis was used to examine risk factors for EDVs and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids.
Results
Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non–Schedule II opioids alone (relative risk range, 1.09–1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64–4.00).
Conclusions
Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. It may be possible to increase the safety of chronic opioid therapy by minimizing the prescription of Schedule II opioids in these higher-risk recipients.
doi:10.1001/archinternmed.2010.273
PMCID: PMC3715046  PMID: 20837827
22.  Adaptive Modulation of Adult Brain Gray and White Matter to High Altitude: Structural MRI Studies 
PLoS ONE  2013;8(7):e68621.
The aim of this study was to investigate brain structural alterations in adult immigrants who adapted to high altitude (HA). Voxel-based morphometry analysis of gray matter (GM) volumes, surface-based analysis of cortical thickness, and Tract-Based Spatial Statistics analysis of white matter fractional anisotropy (FA) based on MRI images were conducted on 16 adults (20–22 years) who immigrated to the Qinghai-Tibet Plateau (2300–4400 m) for 2 years. They had no chronic mountain sickness. Control group consisted of 16 matched sea level subjects. A battery of neuropsychological tests was also conducted. HA immigrants showed significantly decreased GM volumes in the right postcentral gyrus and right superior frontal gyrus, and increased GM volumes in the right middle frontal gyrus, right parahippocampal gyrus, right inferior and middle temporal gyri, bilateral inferior ventral pons, and right cerebellum crus1. While there was some divergence in the left hemisphere, surface-based patterns of GM changes in the right hemisphere resembled those seen for VBM analysis. FA changes were observed in multiple WM tracts. HA immigrants showed significant impairment in pulmonary function, increase in reaction time, and deficit in mental rotation. Parahippocampal and middle frontal GM volumes correlated with vital capacity. Superior frontal GM volume correlated with mental rotation and postcentral GM correlated with reaction time. Paracentral lobule and frontal FA correlated with mental rotation reaction time. There might be structural modifications occurred in the adult immigrants during adaptation to HA. The changes in GM may be related to impaired respiratory function and psychological deficits.
doi:10.1371/journal.pone.0068621
PMCID: PMC3712920  PMID: 23874692
23.  Structural Modulation of Brain Development by Oxygen: Evidence on Adolescents Migrating from High Altitude to Sea Level Environment 
PLoS ONE  2013;8(7):e67803.
The present study aimed to investigate structural modulation of brain by high level of oxygen during its peak period of development. Voxel-based morphometry analysis of gray matter (GM) and white matter (WM) volumes and Tract-Based Spatial Statistics analysis of WM fractional anisotropy (FA) and mean diffusion (MD) based on MRI images were carried out on 21 Tibetan adolencents (15–18 years), who were born and raised in Qinghai-Tibetan Plateau (2900–4700 m) and have lived at sea level (SL) in the last 4 years. The control group consisted of matched Tibetan adolescents born and raised at high altitude all the time. SL immigrants had increased GM volume in the left insula, left inferior parietal gyrus, and right superior parietal gyrus and decreased GM in the left precentral cortex and multiple sites in cerebellar cortex (left lobule 8, bilateral lobule 6 and crus 1/2). Decreased WM volume was found in the right superior frontal gyrus in SL immigrants. SL immigrants had higher FA and lower MD at multiple sites of WM tracts. Moreover, we detected changes in ventilation and circulation. GM volume in cerebellum lobule 8 positively correlated with diastolic pressure, while GM volume in insula positively correlated vital capacity and hypoxic ventilatory response. Our finding indicate that the structural modulations of GM by high level of oxygen during its peak period of development are related to respiratory and circulatory regulations, while the modulation in WM mainly exhibits an enhancement in myelin maturation.
doi:10.1371/journal.pone.0067803
PMCID: PMC3706444  PMID: 23874449
24.  Malignant meningioma of the cerebellopontine angle in a 2-year-old girl: a case report and literature review 
Chinese Journal of Cancer  2013;32(7):415-417.
Meningioma is a common intracranial tumor in adults. Pediatric cases account for approximately 1.5% of all intracranial meningiomas, and very few cases show malignant histological features. Primary pediatric malignant meningioma in the cerebellopontine angle is extremely uncommon. Herein, we report a 2-year-old girl with malignant meningioma in the cerebellopontine angle. The clinical features, diagnosis, and treatment protocol are discussed.
doi:10.5732/cjc.012.10211
PMCID: PMC3845606  PMID: 23470145
Malignant meningioma; the cerebellopontine angle; pediatric; craniotomy
25.  A framework for scalable parameter estimation of gene circuit models using structural information 
Bioinformatics  2013;29(13):i98-i107.
Motivation: Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation.
Results: Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems.
Availability: http://sfb.kaust.edu.sa/Pages/Software.aspx
Contact: xin.gao@kaust.edu.sa
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt232
PMCID: PMC3694671  PMID: 23813015

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