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1.  Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation 
Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia.
doi:10.1038/jcbfm.2014.158
PMCID: PMC4269742  PMID: 25248834
cell death; cortex; dendritic spine; hippocampus; ischemia; OGD
2.  Insula–amygdala functional connectivity is correlated with habituation to repeated negative images 
Behavioral habituation during repeated exposure to aversive stimuli is an adaptive process. However, the way in which changes in self-reported emotional experience are related to the neural mechanisms supporting habituation remains unclear. We probed these mechanisms by repeatedly presenting negative images to healthy adult participants and recording behavioral and neural responses using functional magnetic resonance imaging. We were particularly interested in investigating patterns of activity in insula, given its significant role in affective integration, and in amygdala, given its association with appraisal of aversive stimuli and its frequent coactivation with insula. We found significant habituation behaviorally along with decreases in amygdala, occipital cortex and ventral prefrontal cortex (PFC) activity with repeated presentation, whereas bilateral posterior insula, dorsolateral PFC and precuneus showed increased activation. Posterior insula activation during image presentation was correlated with greater negative affect ratings for novel presentations of negative images. Further, repeated negative image presentation was associated with increased functional connectivity between left posterior insula and amygdala, and increasing insula–amygdala functional connectivity was correlated with increasing behavioral habituation. These results suggest that habituation is subserved in part by insula–amygdala connectivity and involves a change in the activity of bottom-up affective networks.
doi:10.1093/scan/nst160
PMCID: PMC4221205  PMID: 24170933
habituation; emotion; functional connectivity; insula; amygdala
3.  Development and validation of new glomerular filtration rate predicting models for Chinese patients with type 2 diabetes 
Background
Previous researches has depicted that the performance of the recommended glomerular filtration rate (GFR)-estimating equations in the type 2 diabetic population is inferior to that in the non-diabetic population. We attempted to develop new GFR-predicting models for use in Chinese patients with type 2 diabetes in this study.
Methods
We enrolled 519 type 2 diabetic patients including a development data-set (n = 276), an internal validation data-set (n = 138) and an external validation data-set (n = 105) to establish new GFR-predicting models. 99mTc-DTPA-GFR revised by the dual sample method was referred to as the gold GFR standard.
Results
Based on sex, age, serum creatinine and new predictor variables [body mass index (BMI), hemoglobinA1C, and urinary albumin creatinine ratio], eight new regression models and eight artificial neural network (ANN) models were developed. In the external validation group, only ANN3 was superior in both precision and accuracy over the original CKD-EPI equation (precision, 20.5 vs. 24.2 mL/min/1.73 m2, P < 0.001; 30 % accuracy, 88.6 vs. 80.6 %, P = 0.02).
Conclusions
ANN3 based on sex, age, serum creatinine and BMI is the optimal model for GFR estimation in Chinese patients with type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0674-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0674-y
PMCID: PMC4591744  PMID: 26412455
Glomerular filtration rate; Type 2 diabetes; Artificial neural network; Serum creatinine; Body mass index
4.  New Conclusions Regarding Comparison of Sevelamer and Calcium-Based Phosphate Binders in Coronary-Artery Calcification for Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2015;10(7):e0133938.
Background
Sevelamer hydrochloride is used widely, but its impact upon cardiovascular calcification, cardiovascular mortality, all-cause mortality and hospitalization is not known.
Outcomes
Primary outcome was cardiovascular calcification (coronary artery calcification scores (CACS) and aortic calcification scores (ACS)). Secondary outcomes were serum characteristics, hospitalization, cardiovascular mortality and all-cause mortality. Risk ratio (RR), mean differences and standard mean difference with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models.
Results
We identified 31 studies (on 23 randomized controlled trials with 4395 participants). An analysis pooling showed a significant decrease in serum levels of phosphate with calcium-based phosphate binders (CBPBs) by 0.17 mg/dL [mean difference (MD), 95% CI, 0.03, 0.31] than sevelamer. A significant difference in the change of CACS by –102.66 [MD: 95% CI, –159.51, –45.80] and ACS by –1008.73 [MD, 95% CI, –1664.75, –352.72] between sevelamer and CBPBs was observed. Prevalence of hypercalcemia (serum levels of calcium >10.2–10.5 mg/dL and >11.0 mg/dL) was significantly smaller for sevelamer (RR = 0.44, 95% CI, 0.33, 0.58; RR = 0.24, 95% CI, 0.14, 0.40). No significant difference was found in hospitalization, all-cause mortality or cardiovascular mortality.
Conclusions
This meta-analysis suggests that sevelamer benefits dialysis patients in terms of CACS, ACS and hypercalcemia.
doi:10.1371/journal.pone.0133938
PMCID: PMC4521824  PMID: 26230677
5.  Nighttime Systolic Blood-Pressure Load Is Correlated with Target-Organ Damage Independent of Ambulatory Blood-Pressure Level in Patients with Non-Diabetic Chronic Kidney Disease 
PLoS ONE  2015;10(7):e0131546.
Background
The impacts of blood pressure (BP) load on target-organ damage in patients with chronic kidney disease (CKD) are largely unclear. We examined whether BP load is correlated with target-organ damage (TOD) in Chinese CKD patients independent of BP level.
Methods
We recruited 1219 CKD patients admitted to our hospital division in this cross-sectional study. The TOD were measured by estimated glomerular filtration rate (eGFR), proteinuria, left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) in this study. Univariate and multivariate linear analyses were used to evaluate the relationship between systolic blood pressure (SBP) load, diastolic blood pressure (DBP) load and these renal, cardiovascular parameters.
Results
In multivariable-adjusted models, BP load and ambulatory BP levels both independently correlated with LVMI, eGFR and proteinuria in all groups of CKD patients (p<0.05), 24-h SBP correlated with cIMT only in non-diabetic CKD patients without hypertension (p<0.05), while nighttime SBP load was associated with cIMT only in non-diabetic CKD patients (p<0.05). Furthermore, nighttime SBP load additionally increased coefficient of determination (R2) and correlated with LVMI, proteinuria in non-diabetic CKD patients without hypertension (R2 = 0.034, P<0.001 and R2 = 0.012, P = 0.006 respectively) and LVMI, cIMT, eGFR in non-diabetic CKD patients with hypertension (R2>0.008, P<0.05) in multivariable-adjusted model which already including the 24-h BP. BP load did not refine this correlation based on the 24-h BP level in diabetic CKD patients.
Conclusion
Night-time SBP load was correlated with TOD in patients with non-diabetic chronic kidney disease independent of BP level.
doi:10.1371/journal.pone.0131546
PMCID: PMC4506060  PMID: 26186336
6.  Simple Access to Elusive α-Boryl Carbanions and Their Alkylation: An Umpolung Construction for Organic Synthesis 
Journal of the American Chemical Society  2014;136(30):10581-10584.
The reaction of 1,1-bis(pinacolboronate) esters with alkyl halides can be effected by metal alkoxides and provides a strategy for the construction of organoboronate compounds. The reaction is found to occur by alkoxide-induced deborylation and generation of a boron-stabilized carbanion.
doi:10.1021/ja505455z
PMCID: PMC4353009  PMID: 25019925
7.  Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition 
Background
Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4 CRS, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4 CRS, and explore potential mechanisms.
Methods and Results
A cross-sectional study was conducted among patients with type 4 CRS (n=17) and controls (n=16). Compared with controls, patients with type 4 CRS showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague-Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4 CRS, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham-operated animals. Cardiac malondialdehyde, NADPH oxidase activity, fibroblast growth factor-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin II–induced NADPH oxidase–dependent oxidative stress, upregulation of fibroblast growth factor-2 and fibrosis biomarkers, and ERK1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor-2 and fibrosis biomarkers in angiotensin II–treated fibroblasts.
Conclusions
Oxidative stress is a candidate mediator for type 4 CRS. Apocynin attenuated cardiac injury in type 4 CRS rats via inhibiting NADPH oxidase–dependent oxidative stress-activated ERK1/2 pathway and subsequent fibroblast growth factor-2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS.
doi:10.1161/JAHA.114.001598
PMCID: PMC4608061  PMID: 26109504
cardiac remodeling; cardiorenal syndrome; extracellular signal-regulated kinase 1/2; fibroblast growth factor; pharmacology
8.  Multi-Stage Tuberculosis Subunit Vaccine Candidate LT69 Provides High Protection against Mycobacterium tuberculosis Infection in Mice 
PLoS ONE  2015;10(6):e0130641.
Effective tuberculosis (TB) vaccine should target tubercle bacilli with various metabolic states and confer long-term protective immunity. In this study, we constructed a novel multi-stage TB subunit vaccine based on fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-HspX (LT69 for short) which combined early expressed antigens and latency-associated antigen. The fusion protein was mixed with an adjuvant being composed of N, N’-dimethyl-N, N’-dioctadecylammonium bromide (DDA) and polyriboinosinic polyribocytidylic acid (PolyI:C) to construct subunit vaccine, whose immunogenicity and protective ability were evaluated in C57BL/6 mice. The results showed that LT69 had strong immunogenicity and high protective effect against Mycobacterium tuberculosis (M. tuberculosis) H37Rv aerosol challenge. Low-dose (2 μg) of LT69 generated long-term immune memory responses and provided effective protection, which was even higher than traditional vaccine BCG did at 30 weeks post the last vaccination. In conclusion, multistage subunit vaccine LT69 showed high and long-term protection against M. tuberculosis infection in mice, whose effect could be enhanced by using a relative low dosage of antigen.
doi:10.1371/journal.pone.0130641
PMCID: PMC4476732  PMID: 26098302
9.  Differential signaling mechanism for HIV-1 Nef-mediated production of IL-6 and IL-8 in human astrocytes 
Scientific Reports  2015;5:9867.
Variety of HIV-1 viral proteins including HIV-1 Nef are known to activate astrocytes and microglia in the brain and cause the release of pro-inflammatory cytokines, which is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. IL-6 and IL-8 have been found in the CSF of patients with HIV-1 associated dementia (HAD), suggesting that they might play important roles in HIV-1 neuropathology. In the present study we examined the effects of HIV-1 Nef on IL-6 and IL-8 induction in astrocytes. The results demonstrate that both IL-6 and IL-8 are significantly induced in HIV-1 Nef-transfected SVGA astrocytes and HIV-1 Nef-treated primary fetal astrocytes. We also determined the molecular mechanisms responsible for the HIV-1 Nef-induced increased IL-6 and IL-8 by using chemical inhibitors and siRNAs against PI3K/Akt/PKC, p38 MAPK, NF-κB, CEBP and AP-1. Our results clearly demonstrate that the PI3K/PKC, p38 MAPK, NF-κB and AP-1 pathways are involved in HIV-1 Nef-induced IL-6 production in astrocytes, while PI3K/PKC and NF-κB pathways are involved in HIV-1 Nef-induced IL-8 production. These results offer new potential targets to develop therapeutic strategy for treatment of HIV-1 associated neurological disorders, prevalent in > 40% of individuals infected with HIV-1.
doi:10.1038/srep09867
PMCID: PMC4467202  PMID: 26075907
10.  Polysaccharide Hydrogel Combined with Mesenchymal Stem Cells Promotes the Healing of Corneal Alkali Burn in Rats 
PLoS ONE  2015;10(3):e0119725.
Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti-inflammatory cytokine (TGF-β), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-α), chemotaxis (MIP-1α and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder.
doi:10.1371/journal.pone.0119725
PMCID: PMC4366244  PMID: 25789487
11.  Long-Term Therapeutic Effects of Mesenchymal Stem Cells Compared to Dexamethasone on Recurrent Experimental Autoimmune Uveitis of Rats 
Purpose.
We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental autoimmune uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX).
Methods.
One or two courses of MSC treatments were applied to R16-specific T cell–induced rEAU rats before or after disease onsets. The DEX injections were given for 7 or 50 days continuously after disease onsets. Clinical appearances were observed until the 50th day after transfer. On the 10th day, T cells from control and MSC groups were analyzed by flow cytometry. Supernatants from the proliferation assay and aqueous humor were collected for cytokine detection. Functions of T cells and APCs in spleens also were studied by lymphocyte proliferation assays.
Results.
One course of MSC therapy, administered after disease onset, led to a lasting therapeutic effect, with a decreased incidence, reduced mean clinical score, and reduced retinal impairment after 50 days of observation, while multiple courses of treatment did not improve the therapeutic benefit. Although DEX and MSCs equally reduced the severity of the first episode of rEAU, the effect of DEX was shorter lasting, and DEX therapy failed to control the disease even with long periods of treatment. The MSCs significantly decreased T helper 1 (Th1) and Th17 responses, suppressed the function of antigen-presenting cells, and upregulated T regulatory cells.
Conclusions.
These results suggested that MSCs might be new corticosteroid spring agents, while providing fewer side effects and longer lasting suppressive effects for recurrent uveitis.
In this paper, we report for the first time to our knowledge that one course of MSC therapy, administered after disease is established, can provide a better alternative than corticosteroid with fewer side effects and longer lasting suppressive effects for chronic and recurrent autoimmune uveitis.
doi:10.1167/iovs.14-14788
PMCID: PMC4580152  PMID: 25125599
mesenchymal stem cells; recurrent experimental autoimmune uveitis; dexamethasone; T cells; antigen-presenting cells
12.  Pyrosequencing Reveals Fungal Communities in the Rhizosphere of Xinjiang Jujube 
BioMed Research International  2015;2015:972481.
Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research.
doi:10.1155/2015/972481
PMCID: PMC4313056  PMID: 25685820
13.  The Neural Correlates of Anomalous Habituation to Negative Emotional Pictures in Borderline and Avoidant Personality Disorder Patients 
Objective
Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
Method
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Results
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Conclusions
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
doi:10.1176/appi.ajp.2013.13070852
PMCID: PMC3947284  PMID: 24275960
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
14.  A novel visual sputum suctioning system is useful for endotracheal suctioning in a dog model 
Objective: This study is to test the effectiveness of fiber-optic-guided endotracheal suction catheter (visual sputum suctioning system or VSSS) in dog models. Methods: Dog sputum models were established by administering dimethoate emulsifiable. Twenty-seven intubated dogs were equally randomized into three groups of conventional suctioning (CS) group, VSSS with no supplemental oxygen (VSSS) group and VSSS with 100% oxygen (VSSS/O2) group. The suctioning efficiency, vital signs and tracheal wall injury were assessed. Results: The VSSS/O2 (8.6 ± 0.7g) and VSSS groups (8.5 ± 0.9 g) collected significantly more sputum than the CS group (5.9 ± 0.8 g) (P < 0.05 for VSSS/O2 group versus CS group; P < 0.05 for VSSS group versus CS group). Immediately after suctioning, the arterial partial pressure of oxygen (PaO2) of VSSS/O2 group was significantly higher than that of the VSSS group or the CS group (both P < 0.05), and 5 min after suction the PaO2, the mean arterial pressure (MAP) and heart rate (HR) in all groups returned to the baseline (p = 0.54, P = 0.67, P = 0.11, respectively). Moreover, in the VSSS/O2 and VSSS groups all the three variables were higher than the CS group at 5 min after suctioning (P < 0.01, P = 0.03; P = 0.02, P < 0.01; P = 0.02, P = 0.01 respectively). Conclusions: Visual sputum suctioning system collected more sputum and caused less tracheal mucosa damage than conventional suctioning.
PMCID: PMC4307425  PMID: 25663978
Suctioning; sputum; endotracheal tube; intubation; dogs
15.  An open science resource for establishing reliability and reproducibility in functional connectomics 
Zuo, Xi-Nian | Anderson, Jeffrey S | Bellec, Pierre | Birn, Rasmus M | Biswal, Bharat B | Blautzik, Janusch | Breitner, John C.S | Buckner, Randy L | Calhoun, Vince D | Castellanos, F. Xavier | Chen, Antao | Chen, Bing | Chen, Jiangtao | Chen, Xu | Colcombe, Stanley J | Courtney, William | Craddock, R Cameron | Di Martino, Adriana | Dong, Hao-Ming | Fu, Xiaolan | Gong, Qiyong | Gorgolewski, Krzysztof J | Han, Ying | He, Ye | He, Yong | Ho, Erica | Holmes, Avram | Hou, Xiao-Hui | Huckins, Jeremy | Jiang, Tianzi | Jiang, Yi | Kelley, William | Kelly, Clare | King, Margaret | LaConte, Stephen M | Lainhart, Janet E | Lei, Xu | Li, Hui-Jie | Li, Kaiming | Li, Kuncheng | Lin, Qixiang | Liu, Dongqiang | Liu, Jia | Liu, Xun | Liu, Yijun | Lu, Guangming | Lu, Jie | Luna, Beatriz | Luo, Jing | Lurie, Daniel | Mao, Ying | Margulies, Daniel S | Mayer, Andrew R | Meindl, Thomas | Meyerand, Mary E | Nan, Weizhi | Nielsen, Jared A | O’Connor, David | Paulsen, David | Prabhakaran, Vivek | Qi, Zhigang | Qiu, Jiang | Shao, Chunhong | Shehzad, Zarrar | Tang, Weijun | Villringer, Arno | Wang, Huiling | Wang, Kai | Wei, Dongtao | Wei, Gao-Xia | Weng, Xu-Chu | Wu, Xuehai | Xu, Ting | Yang, Ning | Yang, Zhi | Zang, Yu-Feng | Zhang, Lei | Zhang, Qinglin | Zhang, Zhe | Zhang, Zhiqiang | Zhao, Ke | Zhen, Zonglei | Zhou, Yuan | Zhu, Xing-Ting | Milham, Michael P
Scientific Data  2014;1:140049.
Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.
doi:10.1038/sdata.2014.49
PMCID: PMC4421932  PMID: 25977800
16.  Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic–ischemic pig model 
Autoregulation of cerebral perfusion is impaired in hypoxic–ischemic encephalopathy. We investigated whether cerebrovascular pressure reactivity (PRx), an element of cerebral autoregulation that is calculated as a moving correlation coefficient between averages of intracranial and mean arterial blood pressure (MABP) with values between −1 and +1, is impaired during and after a hypoxic–ischemic insult (HI) in newborn pigs. Associations between end-tidal CO2, seizures, neuropathology, and PRx were investigated. The effect of hypothermia (HT) and Xenon (Xe) on PRx was studied. Pigs were randomized to Sham, and after HI to normothermia (NT), HT, Xe or xenon hypothermia (XeHT). We defined PRx >0.2 as peak and negative PRx as preserved. Neuropathology scores after 72 hours of survival was grouped as ‘severe' or ‘mild.' Secondary PRx peak during recovery, predictive of severe neuropathology and associated with insult severity (P=0.05), was delayed in HT (11.5 hours) than in NT (6.5 hours) groups. Seizures were associated with impaired PRx in NT pigs (P=0.0002), but not in the HT/XeHT pigs. PRx was preserved during normocapnia and impaired during hypocapnia. Xenon abolished the secondary PRx peak, increased (mean (95% confidence interval (CI)) MABP (6.5 (3.8, 9.4) mm Hg) and cerebral perfusion pressure (5.9 (2.9, 8.9) mm Hg) and preserved the PRx (regression coefficient, −0.098 (95% CI (−0.18, −0.01)), independent of the insult severity.
doi:10.1038/jcbfm.2013.123
PMCID: PMC3824173  PMID: 23899927
cerebrovascular pressure reactivity; hypothermia; hypoxia–ischemia; newborn; pig; xenon
17.  A New Modified CKD-EPI Equation for Chinese Patients with Type 2 Diabetes 
PLoS ONE  2014;9(10):e109743.
Objective
To improve the performance of glomerular filtration rate (GFR) estimating equation in Chinese type 2 diabetic patients by modification of the CKD-EPI equation.
Design and patients
A total of 1196 subjects were enrolled. Measured GFR was calibrated to the dual plasma sample 99mTc-DTPA-GFR. GFRs estimated by the re-expressed 4-variable MDRD equation, the CKD-EPI equation and the Asian modified CKD-EPI equation were compared in 351 diabetic/non-diabetic pairs. And a new modified CKD-EPI equation was reconstructed in a total of 589 type 2 diabetic patients.
Results
In terms of both precision and accuracy, GFR estimating equations all achieved better results in the non-diabetic cohort comparing with those in the type 2 diabetic cohort (30% accuracy, P≤0.01 for all comparisons). In the validation data set, the new modified equation showed less bias (median difference, 2.3 ml/min/1.73 m2 for the new modified equation vs. ranged from −3.8 to −7.9 ml/min/1.73 m2 for the other 3 equations [P<0.001 for all comparisons]), as was precision (IQR of the difference, 24.5 ml/min/1.73 m2 vs. ranged from 27.3 to 30.7 ml/min/1.73 m2), leading to a greater accuracy (30% accuracy, 71.4% vs. 55.2% for the re-expressed 4 variable MDRD equation and 61.0% for the Asian modified CKD-EPI equation [P = 0.001 and P = 0.02]).
Conclusion
A new modified CKD-EPI equation for type 2 diabetic patients was developed and validated. The new modified equation improves the performance of GFR estimation.
doi:10.1371/journal.pone.0109743
PMCID: PMC4196932  PMID: 25313918
18.  Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect? 
PLoS ONE  2014;9(10):e109845.
Background
Breathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.
Design/Methods
After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37°C, HT35°C, HT32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.
Results
Immediate HT32°C (p = 0.042), but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.
Conclusions
Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.
doi:10.1371/journal.pone.0109845
PMCID: PMC4186877  PMID: 25286345
19.  Methamphetamine toxicity and its implications during HIV-1 infection 
Journal of neurovirology  2011;17(5):401-415.
Over the past two decades methamphetamine (MA) abuse has seen a dramatic increase. The abuse of MA is particularly high in groups that are at higher risk for HIV-1 infection, especially men who have sex with men (MSM). This review is focused on MA toxicity in the CNS as well as in the periphery. In the CNS, MA toxicity is comprised of numerous effects, including, but not limited to, oxidative stress produced by dysregulation of the dopaminergic system, hyperthermia, apoptosis, and neuroinflammation. Multiple lines of evidence demonstrate that these effects exacerbate the neurodegenerative damage caused by CNS infection of HIV perhaps because both MA and HIV target the frontostriatal regions of the brain. MA has also been demonstrated to increase viral load in the CNS of SIV-infected macaques. Using transgenic animal models, as well as cultured cells, the HIV proteins Tat and gp120 have been demonstrated to have neurotoxic properties that are aggravated by MA. In addition, MA has been shown to exhibit detrimental effects on the blood–brain barrier (BBB) that have the potential to increase the probability of CNS infection by HIV. Although the effects of MA in the periphery have not been as extensively studied as have the effects on the CNS, recent reports demonstrate the potential effects of MA on HIV infection in the periphery including increased expression of HIV co-receptors and increased expression of inflammatory cytokines.
doi:10.1007/s13365-011-0043-4
PMCID: PMC4118146  PMID: 21786077
Methamphetamine toxicity; HIV-1 infection; MSM; CNS
20.  Effects of yoga training in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis 
Journal of Thoracic Disease  2014;6(6):795-802.
Introduction
Currently, several studies have assessed the effect of yoga training on the management of chronic obstructive pulmonary disease (COPD), but these studies involved a wide variation of sample and convey inconclusive results. Hence, the present study was performed a systematic review and meta-analysis to investigate the efficacy of yoga training in COPD patients.
Methods
PubMed, EMBASE, the Cochrane Library, Google Scholar, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcomes were forced expiratory volume in one second (FEV1), FEV1% predicted (% pred). Secondary outcomes included 6-min walking distance (6 MWD), arterial oxygen tension (PaO2), and arterial carbon dioxide tension (PaCO2). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed with the I2 test.
Results
Five randomized controlled trials (RCTs) involving 233 patients fulfilled the inclusion criteria. Yoga training significantly improved FEV1 (WMD: 123.57 mL, 95% CI: 4.12-243, P=0.04), FEV1% pred (WMD: 3.90%, 95% CI: 2.27-5.54, P<0.00001), and 6 MWD (WMD: 38.84 m, 95% CI: 15.52-62.16, P=0.001). However, yoga training had no significant effects on PaO2 (WMD: 1.29 mmHg, 95% CI: –1.21-3.78, P=0.31) and PaCO2 (WMD: –0.76 mmHg, 95% CI: –2.06-0.53, P=0.25).
Conclusions
The current limited evidence suggested that yoga training has a positive effect on improving lung function and exercise capacity and could be used as an adjunct pulmonary rehabilitation program in COPD patients. However, further studies are needed to substantiate our preliminary findings and to investigate the long-term effects of yoga training.
doi:10.3978/j.issn.2072-1439.2014.06.05
PMCID: PMC4073384  PMID: 24977005
Chronic obstructive pulmonary disease (COPD); yoga; pulmonary function; meta-analysis
21.  Coevolution of Axon Guidance Molecule Slit and Its Receptor Robo 
PLoS ONE  2014;9(5):e94970.
Coevolution is important for the maintenance of the interaction between a ligand and its receptor during evolution. The interaction between axon guidance molecule Slit and its receptor Robo is critical for the axon repulsion in neural tissues, which is evolutionarily conserved from planarians to humans. However, the mechanism of coevolution between Slit and Robo remains unclear. In this study, we found that coordinated amino acid changes took place at interacting sites of Slit and Robo by comparing the amino acids at these sites among different organisms. In addition, the high level correlation between evolutionary rate of Slit and Robo was identified in vertebrates. Furthermore, the sites under positive selection of slit and robo were detected in the same lineage such as mosquito and teleost. Overall, our results provide evidence for the coevolution between Slit and Robo.
doi:10.1371/journal.pone.0094970
PMCID: PMC4011710  PMID: 24801615
22.  Epoxyeicosatrienoic Acids Attenuating Hypotonic-Induced Apoptosis of IMCD Cells via γ-ENaC Inhibition 
PLoS ONE  2014;9(4):e94400.
Inner medulla collecting duct (IMCD) cells are the key part for urinary concentration. Hypotonic stress may trigger apoptosis of IMCD cells and induce renal injury. Epoxyeicosatrienoic acids (EETs) play an important role in anti-apoptosis, but their roles in hypotonic-induced apoptosis of IMCD cells are still unclear. Here we found increasing exogenous 11, 12-EET or endogenous EETs with Ad-CMV-CYP2C23-EGFP transfection decreased apoptosis of IMCD cells induced by hypotonic stress. Moreover, up-regulation of γ-ENaC induced by hypotonic stress was abolished by elevation of exogenous or endogenous EETs. Collectively, this study illustrated that EETs attenuated hypotonic-induced apoptosis of IMCD cells, and that regulation of γ-ENAC may be a possible mechanism contributing to the anti-apoptotic effect of EETs in response to hypotonic stress.
doi:10.1371/journal.pone.0094400
PMCID: PMC3979856  PMID: 24713619
23.  α-Melanocyte-Stimulating Hormone Protects Retinal Vascular Endothelial Cells from Oxidative Stress and Apoptosis in a Rat Model of Diabetes 
PLoS ONE  2014;9(4):e93433.
Aims
Oxidative stress and apoptosis are among the earliest lesions of diabetic retinopathy. This study sought to examine the anti-oxidative and anti-apoptotic effects of α-melanocyte-stimulating hormone (α-MSH) in early diabetic retinas and to explore the underlying mechanisms in retinal vascular endothelial cells.
Methods
Sprague-Dawley rats were injected intravenously with streptozocin to induce diabetes. The diabetic rats were injected intravitreally with α-MSH or saline. At week 5 after diabetes, the retinas were analyzed for reactive oxygen species (ROS) and gene expression. One week later, the retinas were processed for terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and transmission electron microscopy. Retinal vascular endothelial cells were stimulated by high glucose (HG) with or without α-MSH. The expression of Forkhead box O genes (Foxos) was examined through real-time PCR. The Foxo4 gene was overexpressed in endothelial cells by transient transfection prior to α-MSH or HG treatment, and oxidative stress and apoptosis were analyzed through CM-H2DCFDA and annexin-V assays, respectively.
Results
In diabetic retinas, the levels of H2O2 and ROS and the total anti-oxidant capacity were normalized, the apoptotic cell number was reduced, and the ultrastructural injuries were ameliorated by α-MSH. Treatment with α-MSH also corrected the aberrant changes in eNOS, iNOS, ICAM-1, and TNF-α expression levels in diabetic retinas. Furthermore, α-MSH inhibited Foxo4 up-regulation in diabetic retinas and in endothelial cells exposed to HG, whereas Foxo4 overexpression abrogated the anti-oxidative and anti-apoptotic effects of α-MSH in HG-stimulated retinal vascular endothelial cells.
Conclusions
α-MSH normalized oxidative stress, reduced apoptosis and ultrastructural injuries, and corrected gene expression levels in early diabetic retinas. The protective effects of α-MSH in retinal vascular endothelial cells may be mediated through the inhibition of Foxo4 up-regulation induced by HG. This study suggests an α-MSH-mediated potential intervention approach to early diabetic retinopathy and a novel regulatory mechanism involving Foxo4.
doi:10.1371/journal.pone.0093433
PMCID: PMC3973693  PMID: 24695675
24.  HIV-1 Nef Induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors 
Scientific Reports  2014;4:4450.
The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients infected with HIV-1. The production of pro-inflammatory cytokines by astrocytes/microglia exposed to viral proteins is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. In the present study we examined the effects of Nef on CCL5 induction in astrocytes. The results demonstrate that CCL5 is significantly induced in Nef-transfected SVGA astrocytes. To determine the mechanisms responsible for the increased CCL5 caused by Nef, we employed siRNA and chemical antagonists. Antagonists of NF-κB, PI3K, and p38 significantly reduced the expression levels of CCL5 induced by Nef transfection. Furthermore, specific siRNAs demonstrated that the Akt, p38MAPK, NF-κB, CEBP, and AP-1 pathways play a role in Nef-mediated CCL5 expression. The results demonstrated that the PI3K/Akt and p38 MAPK pathways, along with the transcription factors NF-κB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes.
doi:10.1038/srep04450
PMCID: PMC3963078  PMID: 24658403
25.  Modified Glomerular Filtration Rate-Estimating Equations Developed in Asiatic Population for Chinese Patients with Type 2 Diabetes 
Objectives. To evaluate eight modified equations developed in Asiatic populations in type 2 diabetic patients in China. Methods. A total of 209 Chinese patients with type 2 diabetes were recruited. Using the technetium—99m diethylenetriaminepentaacetic acid—glomerular filtration rate (GFR) to act as the reference, comparisons of their efficiency to estimate GFR in the subjects were made between various equations. Results. Median of difference of the Chinese equation 1 was the lowest (median of difference, 0.51 mL/min/1.73 m2). Median percent of absolute difference of the Chinese equation 2 was less than those of the other equations (26.97 versus ranged from 32.54 to 37.61 mL/min/1.73 m2, [P < 0.001 for all]). Precision of the simplified reexpressed MDRD equation was the best (92.9 mL/min/1.73 m2). Accuracies of the Chinese equation 2 were greater (P < 0.05 for all). There was also an improvement in chronic kidney disease (CKD) stage misclassification of the Chinese equation 2 (55.0 versus ranged from 61.2 to 64.6%, [P < 0.001 for all]). However, the 30% accuracies of all the equations were less than 70%. Conclusions. Our study highlighted a limitation in the use of the above equations in the majority of Chinese diabetic subjects. A better equation is needed in order to give an accurate estimation of GFR in type 2 diabetic patients in China.
doi:10.1155/2014/521071
PMCID: PMC3966408  PMID: 24734043

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