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1.  Health Professional Advice and Adult Action to Reduce Sodium Intake 
Excessive sodium intake is a key modifiable risk factor for hypertension and cardiovascular disease. Although 95% of U.S. adults exceed intake recommendations, knowledge is limited regarding whether doctor or health professional advice motivates patients to reduce intake. Our objectives were to describe the prevalence and determinants of taking action to reduce sodium, and to test whether receiving advice was associated with action.
Analyses, conducted in 2014, used data from the 2013 Behavioral Risk Factor Surveillance System, a state-based telephone survey representative of non-institutionalized adults. Respondents (n=173,778) from 26 states, the District of Columbia, and Puerto Rico used the new optional sodium module. We estimated prevalence ratios (PRs) based on average marginal predictions, accounting for the complex survey design.
Fifty-three percent of adults reported taking action to reduce sodium intake. Prevalence of action was highest among adults who received advice (83%), followed by adults taking antihypertensive medications, adults with diabetes, adults with kidney disease, or adults with a history of cardiovascular disease (range, 73%–75%), and lowest among adults aged 18–24 years (29%). Overall, 23% of adults reported receiving advice to reduce sodium intake. Receiving advice was associated with taking action (prevalence ratio=1.59; 95% CI=1.56, 1.61), independent of sociodemographic and health characteristics, although some disparities were observed across race/ethnicity and BMI categories.
Our results suggest that more than half of U.S. adults in 26 states and two territories are taking action to reduce sodium intake, and doctor or health professional advice is strongly associated with action.
PMCID: PMC5082829  PMID: 26163171
2.  Diet‐induced obese mice exhibit altered immune responses to acute lung injury induced by Escherichia coli  
Obesity (Silver Spring, Md.)  2016;24(10):2101-2110.
Obesity has been associated with impaired immunity and increased susceptibility to bacterial infection. It also exerts protective effects against mortality secondary to acute lung injury. The effects of obesity on immune responses to acute lung injury induced by Escherichia coli were investigated to determine if the above‐mentioned differences in its effects were related to infection severity.
Diet‐induced obesity (DIO) and lean control mice received intranasal instillations of 109 or 1010 CFUs of E. coli. The immune responses were examined at 0 h (uninfected), 24 h, and 96 h postinfection.
Following infection, the DIO mice exhibited higher leukocyte, interleukin (IL)−10, IL‐6, and tumor necrosis factor‐α levels and more severe lung injury than the lean mice. Following inoculation with 1010 CFUs of E. coli, the DIO mice exhibited higher mortality and more severe inflammation‐induced injury than the lean mice, but no differences in E. coli counts were noted between the two groups. However, inoculated with 109 CFUs of E. coli, the DIO mice exhibited smaller E. coli burdens at 24 h and 96 h after infection, as well as lower concentrations of IL‐10 and tumor necrosis factor‐α and less severe lung injury at 96 h after infection.
The results support the emerging view that obesity may be beneficial in the setting of milder infection but detrimental in the setting of more severe infection.
PMCID: PMC5095879  PMID: 27558300
3.  Nickel chloride (NiCl2) in hepatic toxicity: apoptosis, G2/M cell cycle arrest and inflammatory response 
Aging (Albany NY)  2016;8(11):3009-3027.
Up to now, the precise mechanism of Ni toxicology is still indistinct. Our aim was to test the apoptosis, cell cycle arrest and inflammatory response mechanism induced by NiCl2 in the liver of broiler chickens. NiCl2 significantly increased hepatic apoptosis. NiCl2 activated mitochondria-mediated apoptotic pathway by decreasing Bcl-2, Bcl-xL, Mcl-1, and increasing Bax, Bak, caspase-3, caspase-9 and PARP mRNA expression. In the Fas-mediated apoptotic pathway, mRNA expression levels of Fas, FasL, caspase-8 were increased. Also, NiCl2 induced ER stress apoptotic pathway by increasing GRP78 and GRP94 mRNA expressions. The ER stress was activated through PERK, IRE1 and ATF6 pathways, which were characterized by increasing eIF2α, ATF4, IRE1, XBP1 and ATF6 mRNA expressions. And, NiCl2 arrested G2/M phase cell cycle by increasing p53, p21 and decreasing cdc2, cyclin B mRNA expressions. Simultaneously, NiCl2 increased TNF-α, IL-1β, IL-6, IL-8 mRNA expressions through NF-κB activation. In conclusion, NiCl2 induces apoptosis through mitochondria, Fas and ER stress-mediated apoptotic pathways and causes cell cycle G2/M phase arrest via p53-dependent pathway and generates inflammatory response by activating NF-κB pathway.
PMCID: PMC5191883  PMID: 27824316
NiCl2; apoptosis; cell cycle G2/M phase arrest; inflammatory response; liver
4.  A novel method of C1–C2 transarticular screw insertion for symptomatic atlantoaxial instability using a customized guiding block 
Medicine  2016;95(43):e5100.
Atlantoaxial instability treated with the C1-2 transarticular screw fixation is biomechanically more stable; however, the technique demanding and the potential risk of neurovascular injury create difficulties for clinical usage, and there is still lack of clinical experience till now.
We reported an adult female patient with symptomatic atlantoaxial instability due to rheumatoid arthritis that was successfully treated with a bilateral C1–C2 transarticular screw fixation using a customized guiding block. We preoperatively determined the trajectories for bilateral C1–C2 transarticular screws on a 3-dimensional reconstruction model from the computed tomography (CT) and self-developed computer software, and designed a rapid prototyping customized guiding block in order to offer a guide for the entry point and insertion angle of the C1–C2 transarticular screws.
The clinical outcome was good, and the follow-up period was >3 years. The accuracy of the screws is good in comparison with preoperative and postoperative CT findings, and no neurovascular injury occurred.
The patient was accurately and successfully treated with a bilateral C1–C2 transarticular screw fixation using a customized guiding block.
PMCID: PMC5089091  PMID: 27787362
atlantoaxial instability; customized guiding block; transarticular screw
5.  Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia 
Oncology Letters  2016;12(5):4013-4020.
Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia.
PMCID: PMC5104228  PMID: 27895764
mitofusin-2; cancer; cachexia; muscle wasting
6.  A long non-coding RNA signature to improve prognosis prediction of gastric cancer 
Molecular Cancer  2016;15:60.
Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed at developing alncRNA signature to improve prognosis prediction of gastric cancer (GC).
Using a lncRNA-mining approach, we performed lncRNA expression profiling in large GC cohorts from Gene Expression Ominus (GEO), including GSE62254 data set (N = 300) and GSE15459 data set (N = 192). We established a set of 24-lncRNAs that were significantly associated with the disease free survival (DFS) in the test series.
Based on this 24-lncRNA signature, the test series patients could be classified into high-risk or low-risk subgroup with significantly different DFS (HR = 1.19, 95 % CI = 1.13–1.25, P < 0.0001). The prognostic value of this 24-lncRNA signature was confirmed in the internal validation series and another external validation series, respectively. Further analysis revealed that the prognostic value of this signature was independent of lymph node ratio (LNR) and postoperative chemotherapy. Gene set enrichment analysis (GSEA) indicated that high risk score group was associated with several cancer recurrence and metastasis associated pathways.
The identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GC biogenesis. Our results may provide an efficient classification tool for clinical prognosis evaluation of GC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-016-0544-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5029104  PMID: 27647437
Gastric cancer; LncRNAs; LNR; GSEA; Survival
7.  Reporting of Adherence to Healthy Lifestyle Behaviors among Hypertensive Adults in the 50 States and the District of Columbia, 2013 
Achieving and maintaining a healthy lifestyle is an important part of hypertension management. The purpose of this study was to assess US state-level prevalence of adherence to healthy lifestyle behaviors among those with self-reported hypertension. Using 2013 data from the Behavioral Risk Factor Surveillance System, a state-based telephone survey, we examined the adherence to 5 healthy lifestyle behaviors related to hypertension management: having a “normal” weight, not smoking, avoiding or limiting alcohol intake, consuming the recommended amount of fruits and vegetables, and engaging in the recommended amount of physical activity. We estimated age-standardized percentages of each healthy lifestyle behavior overall and by state, as well as prevalence of all 5 healthy lifestyle behaviors. Overall, the prevalence of healthy lifestyle behaviors varied widely among those with self-reported hypertension: 20.5% had a normal weight, 82.3% did not smoke, 94.1% reported no or limited alcohol intake, 14.1% consumed the recommended amounts of fruits or vegetables, and 46.6% engaged in the recommended amount of physical activity. Overall, only 1.7% of adults with self-reported hypertension reported all 5 healthy lifestyle behaviors, with significant variation by state. Age-standardized prevalence of individuals reporting all 5 healthy lifestyle behaviors ranged from 0.3% in Louisiana to 3.8% in the District of Columbia. In conclusion, adherence to healthy lifestyle behaviors varied among those with hypertension; fewer than 2% reported meeting current recommendations and standards when assessed collectively. Disparities were observed by demographic and descriptive characteristics, including geography.
PMCID: PMC4992982  PMID: 26851000
Hypertension; states; healthy lifestyle; lifestyle intervention; surveillance
8.  Direct current stimulation over the human sensorimotor cortex modulates the brain’s hemodynamic response to tactile stimulation 
The European journal of neuroscience  2015;42(3):1933-1940.
Tactile stimuli produce afferent signals that activate specific regions of the cerebral cortex. Noninvasive transcranial direct current stimulation (tDCS) effectively modulates cortical excitability. We therefore hypothesized that a single session of tDCS targeting the sensory cortices would alter the cortical response to tactile stimuli. This hypothesis was tested with a block-design fMRI protocol designed to quantify the BOLD response to controlled sinusoidal pressure stimulation applied to the right foot sole, as compared to rest, in 16 healthy young adults. Following sham tDCS, right foot sole stimulation was associated with activation bilaterally within the precentral cortex, postcentral cortex, middle and superior frontal gyri, temporal lobe (sub-gyral) and cingulate gyrus. Activation was also observed in the left insula, middle temporal lobe, superior parietal lobule, supramarginal gyrus and thalamus, as well as the right inferior parietal lobule and claustrum (FDR corrected, p < 0.05). To explore the regional effects of tDCS, brain regions related to somatosensory processing, and cortical areas underneath each tDCS electrode, were chosen as regions-of-interest (ROIs). Real tDCS, as compared to sham tDCS, increased the percent signal change associated with foot stimulation relative to rest in the left posterior paracentral lobule. These results indicate that tDCS acutely modulates the cortical responsiveness to controlled foot pressure stimuli in healthy adults. Further study is warranted, in both healthy individuals and patients with sensory impairments, to link tDCS-induced modulation of the cortical response to tactile stimuli with changes in somatosensory perception.
PMCID: PMC4523467  PMID: 25989209
9.  Bactericidal Effects against S. aureus and Physicochemical Properties of Plasma Activated Water stored at different temperatures 
Scientific Reports  2016;6:28505.
Water activated by non-thermal plasma creates an acidified solution containing reactive oxygen and nitrogen species, known as plasma-activated water (PAW). The objective of this study was to investigate the effects of different storage temperatures (25 °C, 4 °C, −20 °C, −80 °C) on bactericidal activities against S. aureus and physicochemical properties of PAW up to 30 days. Interestingly, PAW stored at −80 °C yielded the best antibacterial activity against Staphylococcus aureus, 3~4 log reduction over a 30-day period after PAW generation; meanwhile, PAW stored at 25 °C, 4 °C, and −20 °C, respectively, yielded 0.2~2 log decrease in cell viability after the same exposure and storage time. These results were verified by scanning electron microscope (SEM). The physicochemical properties of PAW stored at different temperatures were evaluated, including pH, oxidation reduction potential (ORP), and hydrogen peroxide, nitrate, nitrite anion and NO radical levels. These findings suggested that bacterial activity of PAW stored at 25 °C, 4 °C, −20 °C decreased over time, and depended on three germicidal factors, specifically ORP, H2O2, and NO3−. Moreover, PAW stored at −80 °C retained bactericidal activity, with NO2− contributing to bactericidal ability in association with H2O2. Our findings provide a basis for PAW storage and practical applications in disinfection and food preservation.
PMCID: PMC4921907  PMID: 27346695
10.  Factors affecting occurrence of gastric varioliform lesions: A case-control study 
World Journal of Gastroenterology  2016;22(22):5228-5236.
AIM: To investigate the factors influencing the occurrence of gastric varioliform lesions (GVLs) and their possible link with gastric cancer.
METHODS: A 1:1 matched case-control study was performed to retrospectively analyze data from 1638 chronic gastritis patients who had undergone gastroscopy at one of two Chinese hospitals between 2009 and 2014. Patients with GVLs (cases) were compared to those without such lesions (controls). Endoscopic and pathological findings were recorded, along with interview information on Helicobacter pylori (H. pylori) infection, medical, drug and family histories, lifestyle and eating habits. The association between each factor and the occurrence of GVLs was estimated, and then multivariate conditional logistic regression was used to evaluate the independent factors.
RESULTS: The frequency and severity of glandular atrophy, intestinal metaplasia (IM) and low-grade intraepithelial neoplasia were significantly increased in the GVL group (P < 0.01). Overall analysis showed that H. pylori infection [3.051 (2.157, 4.317), P <0.001], allergic respiratory diseases [3.636 (2.183, 6.055), P < 0.001], work-related stress [2.019 (1.568, 2.600), P < 0.001], irregular meals [2.300 (1.462, 3.619), P < 0.001], high intake of spicy food [1.754 (1.227, 2.507), P = 0.002] and high intake of fresh fruit [0.231 (0.101, 0.529), P = 0.001] were significantly correlated with the occurrence of GVLs (positively, except for the latter). Stratified analyses indicated that pickled food consumption in patients over 50 years old [7.224 (2.360, 22.115), P = 0.001] and excessive smoking in men [2.013 (1.282, 3.163), P = 0.002] were also positively correlated, and that, for antral GVLs, vegetable consumption [0.491 (0.311, 0.776), P = 0.002] was negatively correlated.
CONCLUSION: Seven risk factors and two protective factors are determined for GVLs, which were found to be associated with premalignant abnormalities.
PMCID: PMC4893469  PMID: 27298565
Gastric cancer; Gastric varioliform lesions; Precancerous lesion; Risk factor; Varioliform gastritis
11.  The molecular mechanism of G2/M cell cycle arrest induced by AFB1 in the jejunum 
Oncotarget  2016;7(24):35592-35606.
Aflatoxin B1 (AFB1) has potent hepatotoxic, carcinogenic, genotoxic, immunotoxic and other adverse effects in human and animals. The aim of this study was to investigate the molecular mechanism of G2/M cell cycle arrest induced by AFB1 in the jejunum of broilers. Broilers, as experimental animals, were fed 0.6 mg/kg AFB1 diet for 3 weeks. Our results showed that AFB1 reduced the jejunal villus height, villus height/crypt ratio and caused G2/M cell cycle arrest. The G2/M cell cycle was accompanied by the increase of ataxia telangiectasia mutated (ATM), p53, Chk2, p21 protein and mRNA expression, and the decrease of Mdm2, cdc25C, cdc2, cyclin B and proliferating cell nuclear antigen protein and mRNA expression. In conclusion, AFB1 blocked G2/M cell cycle by ATM pathway in the jejunum of broilers.
PMCID: PMC5094947  PMID: 27232757
AFB1; G2/M phase; cell cycle arrest; mechanism; jejunum; Pathology Section
12.  Advanced assessment of the physicochemical characteristics of Remicade® and Inflectra® by sensitive LC/MS techniques 
mAbs  2016;8(6):1021-1034.
In this study, we demonstrate the utility of ultra-performance liquid chromatography coupled to mass spectrometry (MS) and ion-mobility spectrometry (IMS) to characterize and compare reference and biosimilar monoclonal antibodies (mAbs) at an advanced level. Specifically, we focus on infliximab and compared the glycan profiles, higher order structures, and their host cell proteins (HCPs) of the reference and biosimilar products, which have the brand names Remicade® and Inflectra®, respectively. Overall, the biosimilar attributes mirrored those of the reference product to a very high degree. The glycan profiling analysis demonstrated a high degree of similarity, especially among the higher abundance glycans. Some differences were observed for the lower abundance glycans. Glycans terminated with N-glycolylneuraminic acid were generally observed to be at higher normalized abundance levels on the biosimilar mAb, while those possessing α-linked galactose pairs were more often expressed at higher levels on the reference molecule. Hydrogen deuterium exchange (HDX) analyses further confirmed the higher-order similarity of the 2 molecules. These results demonstrated only very slight differences between the 2 products, which, interestingly, seemed to be in the area where the N-linked glycans reside. The HCP analysis by a 2D-UPLC IMS-MS approach revealed that the same 2 HCPs were present in both mAb samples. Our ability to perform these types of analyses and acquire insightful data for biosimilarity assessment is based upon our highly sensitive UPLC MS and IMS methods.
PMCID: PMC4968138  PMID: 27260215
Host cell proteins; higher order structure; hydrogen deuterium exchange; HDMSE; ion mobility spectrometry; N-linked glycans; QTof; RapiFluor-MS; UPLC; 2D-LC
13.  Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy 
Nature Communications  2016;7:11432.
Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.
Identifying pathways that cause pathological cardiac hypertrophy holds great therapeutic potential. Here the authors discover one such pathway and show that SIKE, an inhibitor of interferon signalling, prevents pathological but not physiological cardiac hypertrophy by interacting with TBK1 and modulating the TBK1/AKT signalling in rodents and monkeys.
PMCID: PMC4895691  PMID: 27249321
14.  Raising the avermectins production in Streptomyces avermitilis by utilizing nanosecond pulsed electric fields (nsPEFs) 
Scientific Reports  2016;6:25949.
Avermectins, a group of anthelmintic and insecticidal agents produced from Streptomyces avermitilis, are widely used in agricultural, veterinary, and medical fields. This study presents the first report on the potential of using nanosecond pulsed electric fields (nsPEFs) to improve avermectin production in S. avermitilis. The results of colony forming units showed that 20 pulses of nsPEFs at 10 kV/cm and 20 kV/cm had a significant effect on proliferation, while 100 pulses of nsPEFs at 30 kV/cm exhibited an obvious effect on inhibition of agents. Ultraviolet spectrophotometry assay revealed that 20 pulses of nsPEFs at 15 kV/cm increased avermectin production by 42% and reduced the time for reaching a plateau in fermentation process from 7 days to 5 days. In addition, the decreased oxidation reduction potential (ORP) and increased temperature of nsPEFs-treated liquid were evidenced to be closely associated with the improved cell growth and fermentation efficiency of avermectins in S. avermitilis. More importantly, the real-time RT-PCR analysis showed that nsPEFs could remarkably enhance the expression of aveR and malE in S. avermitilis during fermentation, which are positive regulator for avermectin biosynthesis. Therefore, the nsPEFs technology presents an alternative strategy to be developed to increase avermectin output in fermentation industry.
PMCID: PMC4867605  PMID: 27181521
15.  HMGB1 exacerbates bronchiolitis obliterans syndrome via RAGE/NF-κB/HPSE signaling to enhance latent TGF-β release from ECM 
Bronchiolitis obliterans syndrome (BOS), characterized by progressive airflow obstruction, is the main barrier to long-term graft survival after lung transplantation. Despite extensive studies, the mechanisms underlying BOS remain poorly understood, and targeted interventions have not yet been fully developed. In the present study, we employed a mouse model of tracheal transplantation and demonstrated that blockade of HMGB1 alone or combined with heparanase (HPSE) attenuates the development of BOS. It was noted that HMGB1 was first passively released from necrotic/damaged cells as a result of early unavoidable allograft injuries, leading to macrophage infiltration along with HMGB1 active secretion. Mechanistic studies revealed that extracellular HMGB1 acted through its receptor, RAGE, to activate NF-κB, which then bound to the HPSE promoter to transcribe its expression. The enhanced HPSE next released HS-bonded latent TGF-β from myofibroblast ECM by cleaving HS chains to promote the initiation and progression of BOS. Together, our data suggest that HMGB1 and HPSE could be viable targets for prevention and intervention of fibrotic diseases such BOS after lung transplantation.
PMCID: PMC4891412  PMID: 27347307
Lung transplantation; BOS; HMGB1; RAGE/NF-κB pathway; HPSE; TGF-β
16.  Implication of microRNAs in the Pathogenesis of MDS 
Current pharmaceutical design  2012;18(22):3170-3179.
MicroRNAs (miRNAs) are significant regulators of human hematopoietic stem cells (HSC), and their deregulation contributes to hematological malignancies. Myelodysplastic syndromes (MDS) represent a spectrum of hematological disorders characterized by dysfunctional HSC, ineffective blood cell production, progressive marrow failure, and an increased risk of developing acute myeloid leukemia (AML). Although miRNAs have been primarily studied in AML, only recently have similar studies been performed on MDS. In this review, we describe the normal function and expression of miRNAs in human HSC, and describe mounting evidence that deregulation of miRNAs contributes to the pathogenesis of MDS.
PMCID: PMC4863958  PMID: 22571695
microRNA; Myelodysplastic syndrome; microarray
17.  An Evidence-Based Review of Related Metabolites and Metabolic Network Research on Cerebral Ischemia 
In recent years, metabolomics analyses have been widely applied to cerebral ischemia research. This paper introduces the latest proceedings of metabolomics research on cerebral ischemia. The main techniques, models, animals, and biomarkers of cerebral ischemia will be discussed. With analysis help from the MBRole website and the KEGG database, the altered metabolites in rat cerebral ischemia were used for metabolic pathway enrichment analyses. Our results identify the main metabolic pathways that are related to cerebral ischemia and further construct a metabolic network. These results will provide useful information for elucidating the pathogenesis of cerebral ischemia, as well as the discovery of cerebral ischemia biomarkers.
PMCID: PMC4871976  PMID: 27274780
18.  Nitrogen Stimulates the Growth of Subsurface Basalt-associated Microorganisms at the Western Flank of the Mid-Atlantic Ridge 
Oceanic crust constitutes the largest aquifer system on Earth, and microbial activity in this environment has been inferred from various geochemical analyses. However, empirical documentation of microbial activity from subsurface basalts is still lacking, particularly in the cool (<25°C) regions of the crust, where are assumed to harbor active iron-oxidizing microbial communities. To test this hypothesis, we report the enrichment and isolation of crust-associated microorganisms from North Pond, a site of relatively young and cold basaltic basement on the western flank of the Mid-Atlantic Ridge that was sampled during Expedition 336 of the Integrated Ocean Drilling Program. Enrichment experiments with different carbon (bicarbonate, acetate, methane) and nitrogen (nitrate and ammonium) sources revealed significant cell growth (one magnitude higher cell abundance), higher intracellular DNA content, and increased Fe3+/ΣFe ratios only when nitrogen substrates were added. Furthermore, a Marinobacter strain with neutrophilic iron-oxidizing capabilities was isolated from the basalt. This work reveals that basalt-associated microorganisms at North Pond had the potential for activity and that microbial growth could be stimulated by in vitro nitrogen addition. Furthermore, iron oxidation is supported as an important process for microbial communities in subsurface basalts from young and cool ridge flank basement.
PMCID: PMC4853389  PMID: 27199959
deep biosphere; geomicrobiology; iron oxidation; nitrogen stimulation; oceanic crust
19.  Emerging Roles of Hydrogen Sulfide in Inflammatory and Neoplastic Colonic Diseases 
Hydrogen sulfide (H2S) is a toxic gas that has been recognized as an important mediator of many physiological processes, such as neurodegeneration, regulation of inflammation, blood pressure, and metabolism. In the human colon, H2S is produced by both endogenous enzymes and sulfate-reducing bacteria (SRB). H2S is involved in the physiological and pathophysiological conditions of the colon, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), which makes the pharmacological modulation of H2S production and metabolism a potential chemical target for the treatment of colonic diseases. However, the exact mechanisms and pathways by which H2S-mediates normal physiological function and disease in the colon are not fully understood. Besides, the production and release of H2S are modulated by both endogenous and exogenous factors. This review will discuss the production and storage of H2S, its biological roles and the emerging importance in physiology and pathology of IBD and CRC.
PMCID: PMC4853395  PMID: 27199771
hydrogen sulfide; sulfate-reducing bacteria; pathophysiological roles; colonic diseases; chemical target
20.  Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor–TRAF6 signaling 
The Journal of Experimental Medicine  2015;212(11):1967-1985.
Varney et al. report that that deletion of the TRAF-interacting protein TIFAB contributes to an MDS-like phenotype in mice by up-regulating TRAF6 and contributing to hematopoietic dysfunction.
TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.
PMCID: PMC4612089  PMID: 26458771
21.  Nickel chloride (NiCl2) induces endoplasmic reticulum (ER) stress by activating UPR pathways in the kidney of broiler chickens 
Oncotarget  2016;7(14):17508-17519.
It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days. We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94. Concurrently, all the three UPR pathways were activated by dietary NiCl2. Firstly, the PERK pathway was activated by increasing eIF2a and ATF4 mRNA expression. Secondly, the IRE1 pathway was activated duo to increase in IRE1 and XBP1 mRNA expression. And thirdly, the increase of ATF6 mRNA expression suggested that ATF6 pathway was activated. The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound-induced nephrotoxicity.
PMCID: PMC4951229  PMID: 26956054
NiCl2; ER stress; UPR; PERK; IRE1; Immunology and Microbiology Section; Immune response; Immunity
22.  OncoBinder facilitates interpretation of proteomic interaction data by capturing coactivation pairs in cancer 
Oncotarget  2016;7(14):17608-17615.
High-throughput methods such as co-immunoprecipitationmass spectrometry (coIP-MS) and yeast 2 hybridization (Y2H) have suggested a broad range of unannotated protein-protein interactions (PPIs), and interpretation of these PPIs remains a challenging task. The advancements in cancer genomic researches allow for the inference of “coactivation pairs” in cancer, which may facilitate the identification of PPIs involved in cancer. Here we present OncoBinder as a tool for the assessment of proteomic interaction data based on the functional synergy of oncoproteins in cancer. This decision tree-based method combines gene mutation, copy number and mRNA expression information to infer the functional status of protein-coding genes. We applied OncoBinder to evaluate the potential binders of EGFR and ERK2 proteins based on the gastric cancer dataset of The Cancer Genome Atlas (TCGA). As a result, OncoBinder identified high confidence interactions (annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG) or validated by low-throughput assays) more efficiently than co-expression based method. Taken together, our results suggest that evaluation of gene functional synergy in cancer may facilitate the interpretation of proteomic interaction data. The OncoBinder toolbox for Matlab is freely accessible online.
PMCID: PMC4951236  PMID: 26872056
Chromosome Section; protein-protein interaction; cancer genome; copy number alteration; gene mutation
23.  The mitochondrial and death receptor pathways involved in the thymocytes apoptosis induced by aflatoxin B1 
Oncotarget  2016;7(11):12222-12234.
Aflatoxin B1 (AFB1) is a potent immunosuppressive agent in endotherms, which can be related to the up-regulated apoptosis of immune organs. In this study, we investigated the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in Aflatoxin B1 induced thymocytes apoptosis. Chickens were fed an aflatoxin B1 containing diet (0.6 mg/kg AFB1) for 3 weeks. Our results showed that (1) AFB1 diet induced the decrease of T-cell subsets, morphological changes, and excessive apoptosis of thymus. (2) The excessive apoptosis involved the mitochondrial pathway (up-regulation of Bax, Bak, cytC and down-regulation of Bcl-2 and Bcl-xL) and death receptor pathway (up-regulation of FasL, Fas and FADD). (3) Oxidative stress, an apoptosis inducer, was confirmed in the thymus. In conclusion, this is the first study to demonstrate that mitochondrial and death receptor pathways involved in AFB1 induced thymocytes apoptosis in broilers.
PMCID: PMC4914280  PMID: 26933817
aflatoxin B1; thymocytes; apoptosis; signaling pathways; broilers; Immunology and Microbiology Section; Immune response; Immunity
24.  Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome 
Oncotarget  2016;7(10):11056-11066.
Missense mutation of p53 not only impairs its tumor suppression function, but also causes oncogenic gain of function (GOF). The molecular underpinning of mutant p53 (mutp53) GOF is not fully understood, especially for the potential roles of non-coding genes. Here we identify the microRNA expression profile (microRNAome) of mutp53 on Arg282 by controlled microarray experiments, and clarify the prognostic significance of mutp53-regulated miRNAs in cancers. A predominant repression effect on miRNA expression was found for mutant p53, with 183 significantly downregulated and only 12 upregulated miRNAs. Mutp53 and wild-type (wtp53) commonly upregulate let-7i, and other two miRNAs were upregulated by wtp53 but repressed by mutp53 (miR-610 and miR-3065–3p). Based the mutp53-regulated miRNA signature, a non-negative matrix factorization (NMF) model classified gastric cancer (GC) cases into subgroups with significantly different Disease-free survival (Kaplan-Meier test, P = 0.013). In contrast, the NMF model based on all miRNAs did not associate with cancer outcome. The mutp53 miRNA signature associated with the outcomes of breast cancer (P = 0.024) and hepatocellular cancer (P = 0.012). The miRPath analysis revealed that mutp53-suppressed miRNAs associate with Hippo, TGF-β and stem cell signaling pathways. Taken together, our results highlight a miRNA-mediated GOF mechanism of mutant p53 on Arg282, and suggest the prognostic potential of mutp53-associated miRNA signature.
PMCID: PMC4905457  PMID: 26840456
cancer prognosis; miRNA; mutation; non-negative matrix factorization; p53
25.  Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes 
Diabetes  2014;64(3):1025-1034.
Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.
PMCID: PMC4338591  PMID: 25249577

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