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1.  Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials 
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n = 562; ceftriaxone, n = 554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P = 0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P = 0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at under registration no. NCT00621504 and NCT00509106.)
PMCID: PMC4335888  PMID: 25487791
2.  SIFT-Based Indoor Localization for Older Adults Using Wearable Camera 
This paper presents an image-based indoor localization system for tracking older individuals’ movement at home. In this system, images are acquired at a low frame rate by a miniature camera worn conveniently at the chest position. The correspondence between adjacent frames is first established by matching the SIFT (scale-invariant feature transform) based key points in a pair of images. The location changes of these points are then used to estimate the position of the wearer based on use of the pinhole camera model. A preliminary study conducted in an indoor environment indicates that the location of the wearer can be estimated with an adequate accuracy.
PMCID: PMC4502573  PMID: 26190909
3.  Assessing Physical Performance in Free-Living Older Adults with a Wearable Computer 
This study investigates the use of a chest-worn wearable computer, the eButton, to assess physical performance of older adults. The Short Physical Performance Battery (SPPB), a standard cliniucal test, is first conducted on older human subjects. Then, a triaxial accelerometer and a triaxial gyroscope within the eButton are utilized to record acceleration and angular velocity of body motion on the same subjects for one week. The sensor data corresponding to walking episodes are segmented and features in the time and frequency domains are extracted. Comparison between these features and the total SPPB scores shows that the sensor data acquired in free-living conditions can be used as indicators of the subjects physical performance.
PMCID: PMC4503234  PMID: 26190910
4.  Discovery of porcine maternal factors related to nuclear reprogramming and early embryo development by proteomic analysis 
Proteome Science  2015;13:18.
Differentiated cell nuclei can be reprogrammed to a pluripotent state in several ways, including incubation with oocyte extracts, transfer into enucleated oocytes, and induced pluripotent stem cell technology. Nuclear transfer-mediated reprogramming has been proven to be the most efficient method. Maternal factors stored in oocytes have critical roles on nuclear reprogramming and early embryo development, but remain elusive.
In this study, we showed most of porcine oocytes became nuclear matured at 33 h of IVM and the rate had no significant difference with oocytes at 42 h of IVM (p > 0.05). Moreover, the cleavage and blastocyst rates of SCNT and PA embryos derived from 42O were significantly higher than that of 33O (p < 0.05). But 33O could sustain IVF embryo development with higher cleavage and blastocyst rates comparing to 42O (p < 0.05). To clarify the development potential difference between 33O and 42O, 18 differentially expressed proteins were identified by proteomic analysis, and randomly selected proteins were confirmed by Western blot. Bioinformatic analysis of these proteins revealed that 33O highly synthesized proteins related to fertilization, and 42O was rich in nuclear reprogramming factors.
These results present a unique insight into maternal factors related to nuclear reprogramming and early embryo development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12953-015-0074-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4493956  PMID: 26155198
Proteomics; IVF; Nuclear transfer; Maternal factors
5.  The Study of Dynamic Characteristic of Acupoints Based on the Primary Dysmenorrhea Patients with the Tenderness Reflection on Diji (SP 8) 
In TCM theory, acupoint is not a fixed point but a portal with dynamic characteristics where the channel qi enters and flows out. The dynamic characteristics have been verified primarily by detecting the tenderness reaction on Diji (SP 8) in primary dysmenorrhea patients. In this study, finger pressing and algometer were applied in Diji (SP 8) area of participants in menstrual period and nonmenstrual period, respectively, to detect the tenderness occurrence rate, the VAS score of the tenderest point, the tenderness threshold of the tenderest point, and the location of the tenderest point. The result suggests that the acupoint may not be a fixed location but a point in a dynamic state within a certain range in time and space varying with different physiological and pathological status.
PMCID: PMC4487270  PMID: 26161116
6.  Structural Insights into 5' Flap DNA Unwinding and Incision by the Human FAN1 Dimer 
Nature communications  2014;5:5726.
Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5’ flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA, and unwind a 5’ flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure-informed mutations that disrupt protein dimerization, substrate orientation, or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1.
PMCID: PMC4268874  PMID: 25500724
7.  Measurement of Mass-Based Carbon Nanotube Penetration through Filtering Facepiece Respirator Filtering Media 
Annals of Occupational Hygiene  2014;58(5):646-656.
Recent studies suggest that a wide range of human health effects could result from exposure to carbon nanotubes (CNTs). A National Institute for Occupational Safety and Health survey of the carbonaceous nanomaterial industry found that 77% of the companies used respiratory protection, such as filtering facepiece respirators (FFRs). Despite CNT studies in some occupational settings being reported, the literature for mass-based penetration of CNTs through FFRs is lacking. The aim of this study was to conduct a quantitative study of single-walled CNT (SWCNT) and multiwalled CNT (MWCNT) penetration through FFRs. A CNT aerosol respirator testing system was used to generate charge-neutralized airborne SWCNTs and MWCNTs for this study. The size distribution was 20–10000nm, with 99% of the particles between 25 and 2840nm. Mass median diameters were 598 and 634nm with geometric standard deviations of 1.34 and 1.48 for SWCNTs and MWCNTs, respectively. Upstream and downstream CNTs were collected simultaneously using closed-face 3.7-cm-diameter filter cassettes. These samples were subsequently analyzed for organic carbon and elemental carbon (EC), with EC as a measure of mass-based CNTs. The mass-based penetration of SWCNTs and MWCNTs through six FFR models at constant flow rates of 30 l min−1 (LPM) was determined. Generally, the penetrations of SWCNTs and MWCNTs at 30 LPM had a similar trend and were highest for the N95 FFRs, followed by N99 and P100 FFRs. The mass-based penetration of MWCNTs through six FFR models at two constant flow rates of 30 and 85 LPM was also determined. The penetration of MWCNTs at 85 LPM was greater compared with the values of MWCNTs at 30 LPM.
PMCID: PMC4305111  PMID: 24802251
aerosol respirator testing system; elemental carbon; filtering facepiece respirators; mass-based penetration; multiwalled carbon nanotubes; single-walled carbon nanotubes
8.  Quality of life and its association with direct medical costs for COPD in urban China 
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Few studies have focused on the quality of life (QoL) associated medical costs for COPD in China.
A cross-sectional survey of 678 COPD patients was conducted in four major cities (Beijing, Shanghai, Guangzhou and Chengdu), China, in 2011. Data on socio-demographic information, health conditions and medical costs were collected through a face-to-face interview combined with medical record searching. The EuroQol (EQ-5D) health questionnaire was applied to assess the QoL of COPD patients.
Among 678 patients with COPD, nearly 40% had difficulties in mobility, usual activities and pain/discomfort, one third had various degrees of anxiety/depression, and one fifth had difficulties in self-care. The COPD patients had a median utility score of 0.768 and a median visual analog scale score of 70. The degree of difficulties in any dimensions significantly increased, and utility and health scores decreased with severity of the disease. Age, gender and disease severity were significantly associated with the quality of life after taking other covariates into consideration. Poorer QoL was a significant indicator of higher direct medical costs for COPD patients.
Impaired quality of life was significantly linked to increased medical costs for COPD patients and could be an important measure for policy- and decision-making in COPD care.
PMCID: PMC4429937  PMID: 25972271
Chronic obstructive pulmonary disease; Quality of life; A cross-sectional study; Medical cost
9.  Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers 
Cancer immunology research  2013;2(4):371-379.
Cancer-testis (CT) antigens are potential targets for cancer immunotherapy because of their restricted expression in immune-privileged germ cells and various malignancies. Current application of CT-based immunotherapy has been focused on CT expression-rich tumors such as melanoma and lung cancers. In this study, we surveyed CT expression using the Cancer Genome Atlas (TCGA) datasets for ten common cancer types. We show that, CT expression is specific and enriched within certain cancer molecular subtypes. For example, HORMAD1, CXorf61, ACTL8 and PRAME are highly enriched in the basal subtype of breast cancer; MAGE and CSAG are most frequently activated in the magnoid subtype of lung adenocarcinoma; and PRAME is highly upregulated in the ccB subtype of clear cell renal cell carcinoma. Analysis of CT gene expression and DNA methylation indicates that some CTs are regulated epigenetically while others are controlled primarily by tissue- and subtype-specific transcription factors. Our results suggest that although for some CTs expression is associated with patient outcome, not many are independent prognostic markers. Thus, CTs with shared expression pattern are heterogeneous molecules with distinct activation modes and functional properties in different cancers and cancer subtypes. These data suggest a cancer subtype-orientated application of CT antigen as biomarkers and immunotherapeutic targets.
PMCID: PMC4007352  PMID: 24764584
cancer-testis antigen; tumor subtype; immunotherapy; prognosis; biomarker
10.  Weight Gain in Pregnancy, Maternal Age and Gestational Age in Relation to Fetal Macrosomia 
Clinical Nutrition Research  2015;4(2):104-109.
To investigate the possible risk factors related to macrosomia. Pregnant women and their newborns (n = 1041) were recruited from a cohort study in Maternal and Child Care Center of Hefei from January 2011 to July 2012. Questionnaires were applied to collect the demographic data besides the medical records. Detailed health records of the entire pregnancy were obtained using retrospective study. Meanwhile the data of neonatal outcomes was prospectively tracked. Associations between exposure risk factors and macrosomia were analyzed using Pearson's chi squared test. Logistic regression models were used to assess the independent association between these potential predictors and macrosomia. The incidence of macrosomia of this cohort was 11.24% of which male: female = 2.55:1. Male incidence (8.07%) of macrosomia was higher than female (3.17%), p < 0.001. Body mass index (BMI) before pregnancy (pre-BMI), maternal height, parity were not independently associated with macrosomia; multiple logistic regression analysis indicated that macrosomia was mainly independently associated with weight gain in pregnancy (OR=1.14, 95% CI [1.10-1.19]), maternal age (OR = 1.09, 95% CI [1.03-1.15]) and gestational age (OR = 1.62, 95% CI [1.31-1.99]), respectively. Our findings indicate that weight gain in pregnancy, maternal age and gestational age should be considered as independent risk factors for macrosomia.
PMCID: PMC4418414  PMID: 25954731
Body mass index; Fetal macrosomia; Pregnancy; Risk factors
11.  Progress and Future Aspects in Genetics of Human Hypertension 
Current hypertension reports  2013;15(6):676-686.
Hypertension has become a major global health burden due to its high prevalence and associated increase in risk of cardiovascular disease and premature death. It is well established that hypertension is determined by both genetic and environmental factors and their complex interactions. Recent large-scale meta-analyses of genome-wide association studies (GWAS) have successfully identified a total of 38 loci which achieved genome-wide significance (P < 5×10−8) for their association with blood pressure (BP). Although the heritability of BP explained by these loci is very limited, GWAS meta-analyses have elicited renewed optimism in hypertension genomics research, highlighting novel pathways influencing BP and elucidating genetic mechanisms underlying BP regulation. This review summarizes evolving progress in the rapidly moving field of hypertension genetics and highlights several promising approaches for dissecting the remaining heritability of BP. It also discusses the future translation of genetic findings to hypertension treatment and prevention.
PMCID: PMC4368442  PMID: 24072558
Blood pressure; Genetic association studies; Genetic linkage; Genome-wide association study; Hypertension; Rare variants; Sequencing; Risk prediction
12.  Reproducibility of Blood Pressure Responses to Dietary Sodium and Potassium Interventions: The GenSalt Study 
Hypertension  2013;62(3):499-505.
Blood pressure responses to dietary sodium and potassium interventions vary among individuals. We studied the long-term reproducibility of blood pressure responses to dietary sodium and potassium intake. We repeated the dietary sodium and potassium interventions among 487 Chinese adults 4.5 years after the original dietary intervention. The identical dietary intervention protocol, which included a 7-day low-sodium feeding (51.3 mmol/day), a 7-day high-sodium feeding (307.8 mmol/day), and a 7-day high-sodium feeding with oral potassium supplementation (60.0 mmol/day), was applied in both the initial and repeated studies. Three blood pressure measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. The results from the 24-hour urinary excretion of sodium and potassium showed excellent compliance with the study diet. Blood pressure responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients (95% confidence interval) for systolic blood pressure levels were 0.77 (0.73, 0.80) at baseline, 0.79 (0.75, 0.82) during low-sodium, 0.80 (0.77, 0.83) during high-sodium, and 0.82 (0.79, 0.85) during high-sodium and potassium supplementation interventions (all P< 0.0001). The correlation coefficients for systolic blood pressure changes were 0.37 (0.29, 0.44) from baseline to low-sodium, 0.37 (0.29, 0.44) from low- to high-sodium, and 0.28 (0.20, 0.36) from high-sodium to high-sodium plus potassium supplementation (all P< 0.0001). These data indicate that blood pressure responses to dietary sodium and potassium interventions have long-term reproducibility and stable characteristics in the general population.
PMCID: PMC4364515  PMID: 23897070
blood pressure; potassium; dietary; reproducibility of results; sodium; dietary
13.  Screening and identification of the differential proteins in kidney with complete unilateral ureteral obstruction 
Obstructive nephropathy is a major cause of renal failure, particularly in infants and children, and indications for therapeutic intervention remain highly controversial. There is a great need for the development of new methods to monitor patients, and the biomarker research field is a promising approach for this purpose to be used as prognostic tools for early disease detection and the choice of the optimal treatment and monitoring. Here, we presented our comparative proteomics study of rat kidney with complete unilateral ureteral obstruction (CUUO). Proteins from the groups of CUUO and corresponding sham rat kidney tissues were subjected to 2-D gel electrophoresis, and then protein identification by mass spectrometry. We identified 39 proteins with differential expression between kidney tissues from sham operated group and those with CUUO. These identified proteins were reported to be involved in cell apoptosis, energy metabolism and injuries of mitochondrion and oxidative stress, and so on. We confirmed 3 identified proteins by immunoblot analysis and immunofluorescence staining and assessed their mRNA levels in renal tissues. Our results demonstrate protein alterations that reflect the pathological situation of the obstructed kidneys, which may help understand the relationship between oxidative stress and obstructive nephropathy.
PMCID: PMC4440076  PMID: 26045767
Obstructive nephropathy; proteome; oxidative stress; renal tissue
14.  Estrogen receptor α mediates the effects of notoginsenoside R1 on endotoxin-induced inflammatory and apoptotic responses in H9c2 cardiomyocytes 
Molecular Medicine Reports  2015;12(1):119-126.
Estrogen receptors (ERs) are important for preventing endotoxin-induced myocardial dysfunction. Therefore, plant-derived phytoestrogens, which target ERs may also affect endotoxin-induced toxicity in cardiomyocytes. Our previous study revealed that notoginsenoside-R1 (NG-R1), a predominant phytoestrogen from Panax notoginseng, protects against cardiac dysfunction. However, the effects of NG-R1 on cardiomyocytes and the precise cellular/molecular mechanisms underlying its action remain to be elucidated. In the present study, pretreatment with NG-R1 suppressed the lipopolysaccharide (LPS)-induced degradation of inhibitor of nuclear factor-κB (NF-κB) α, the activation of NF-κB and caspase-3, and the subsequent myocardial inflammatory and apoptotic responses in H9c2 cardiomyocytes. An increase in the mRNA and protein expression of ERα was also observed in the NG-R1-treated cardiomyocytes. However, the expression pattern of ERβ remained unaltered. Furthermore, the cardioprotective properties of NG-R1 against LPS-induced apoptosis and the inflammatory response in cardiomyocytes were attenuated by ICI 182780, a non-selective ERα antagonist, and methyl-piperidino-pyrazole, a selective ERα antagonist. These findings suggested that NG-R1 reduced endotoxin-induced cardiomyocyte apoptosis and the inflammatory response via the activation of ERα. Therefore, NG-R1 exerted direct anti-inflammatory and anti-apoptotic effects on the cardiomyocytes, representing a potent agent for the treatment of myocardial inflammation during septic shock.
PMCID: PMC4438911  PMID: 25738436
notoginsenoside R1; estrogen receptor; endotoxin; cardiomyocyte
15.  Modeling Spatial Heterogeneity with Excess Zeroes from School Absenteeism dSata 
PMCID: PMC4370936
School absenteeism; spatial heterogeneity; Random effects zero-inflated Poisson model; occurrence; intensity
18.  Association between cytokine gene polymorphisms and tuberculosis in a Chinese population in Shanghai: a case–control study 
BMC Immunology  2015;16:8.
Polymorphisms in cytokine genes are known to influence cytokine levels, which may influence susceptibility to tuberculosis (TB) infection and disease. Differences in cytokine expression probably determine whether TB progresses, resolves, or becomes latent. In particular, the balance between the Th1 and Th2 cytokine responses influences the expression of disease in individuals with pulmonary TB (PTB). We performed a case–control study of 120 patients diagnosed with PTB, 240 with latent TB infection (LTBI), and 480 healthy controls (HC), to explore the association between polymorphisms in cytokine genes and a predisposition to Mycobacterium tuberculosis infection and TB disease.
A single-gene analysis showed a dominant association between the AA genotype or A allele at nucleotide −874 of the interferon γ (IFN-γ) gene and LTBI. The A allele at nucleotide −1082 of the interleukin 10 (IL-10) gene was significantly more common in PTB patients than in LTBI subjects. Moreover, the polymorphisms at IFN-γ −874 and IL10 − 1082 were associated with protein levels of IFN-γ and IL-10, respectively, in the PTB group. The genotype frequencies of other polymorphisms did not differ between the PTB patients, LTBI and HC subjects. Furthermore, combinations of polymorphisms with IFN-γ −874 were associated with LTBI, whereas combinations with IL10 − 1082 were more likely associated with PTB.
There are positive associations between the IFN-γ −874 polymorphism and TB and between the IL10 − 1082 polymorphism and LTBI. Our data provide genetic evidence of the multiple disease hypothesis that many cytokine genes are involved in TB susceptibility.
PMCID: PMC4357147  PMID: 25887222
Tuberculosis; Latent tuberculosis infection; Cytokine; Polymorphism; Association
19.  Influence of bone morphogenetic protein type IA receptor conditional knockout in lens on expression of bone morphogenetic protein 4 in lens 
To investigate the influence of bone morphogenetic protein type IA receptor [BMPR-IA (ALK3)] conditional knockout in lens on expression of bone morphogenetic protein 4 (BMP4) in lens during the development of the vertebrate eye.
Cre-positive mice were mated with Cre-negative mice to generate 50% Cre-positive (conditional knockout, CKO) 4 embryos, 8 eyes and 50% Cre-negative offspring (wild type, WT) 4 embryos, 8 eyes. The embryos were fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned to a thickness of 4 µm. Removal of paraffin wax and dehydrating for sections, and then the procedure of in situ hybridization was processed, BMP4 MK1784-m (BOSTER) was used, and observed the expression of BMP4 in the lens in experimental group and control group. We selected SPSS11.0 software for statistical analysis, P<0.05 showed that the difference was statistically significant.
Four embryos of each genotype were examined, totally we had 8 embryos, 16 eyes. We got the uniform outcomes in all the embryos. We found ALK3 was required during lens growing, but was not essential for the formation of lens. We observed that the expression of Bmp4 in the lens was significantly reduced in all 8 ALK3 CKO lens, BMP4 expression was normal in all the 8 WT lens, P<0.01. This phenomenon became increasingly visible in accordance with embryo development. The most apparent alteration was present at stage E15.5.
ALK3 is essential for lens growth. The influence of ALK3 on the expression of BMP4 is present during the development of mice lens.
PMCID: PMC4325242  PMID: 25709908
bone morphogenetic protein type IA receptor; bone morphogenetic protein 4; lens
20.  Autism spectrum disorder, but not amygdala lesions, impairs social attention in visual search 
Neuropsychologia  2014;63:259-274.
People with autism spectrum disorders (ASD) have pervasive impairments in social interactions, a diagnostic component that may have its roots in atypical social motivation and attention. One of the brain structures implicated in the social abnormalities seen in ASD is the amygdala. To further characterize the impairment of people with ASD in social attention, and to explore the possible role of the amygdala, we employed a series of visual search tasks with both social (faces and people with different postures, emotions, ages, and genders) and non-social stimuli (e.g., electronics, food, and utensils). We first conducted trial-wise analyses of fixation properties and elucidated visual search mechanisms. We found that an attentional mechanism of initial orientation could explain the detection advantage of non-social targets. We then zoomed into fixation-wise analyses. We defined target-relevant effects as the difference in the percentage of fixations that fell on target-congruent vs. target-incongruent items in the array. In Experiment 1, we tested 8 high-functioning adults with ASD, 3 adults with focal bilateral amygdala lesions, and 19 controls. Controls rapidly oriented to target-congruent items and showed a strong and sustained preference for fixating them. Strikingly, people with ASD oriented significantly less and more slowly to target-congruent items, an attentional deficit especially with social targets. By contrast, patients with amygdala lesions performed indistinguishably from controls. In Experiment 2, we recruited a different sample of 13 people with ASD and 8 healthy controls, and tested them on the same search arrays but with all array items equalized for low-level saliency. The results replicated those of Experiment 1. In Experiment 3, we recruited 13 people with ASD, 8 healthy controls, 3 amygdala lesion patients and another group of 11 controls and tested them on a simpler array. Here our group effect for ASD strongly diminished and all four subject groups showed similar target-relevant effects. These findings argue for an attentional deficit in ASD that is disproportionate for social stimuli, cannot be explained by low-level visual properties of the stimuli, and is more severe with high-load top-down task demands. Furthermore, this deficit appears to be independent of the amygdala, and not evident from general social bias independent of the target-directed search.
PMCID: PMC4317264  PMID: 25218953
Visual search; Autism; Amygdala; Saliency; Social
21.  Blood Pressure Responses to Dietary Sodium and Potassium Interventions and the Cold Pressor Test: The GenSalt Replication Study in Rural North China 
In the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, we observed that blood pressure (BP) responses to dietary sodium and potassium interventions and the cold pressor test (CPT) varied greatly among individuals. We conducted a replication study to confirm our previous findings among 695 study participants.
The dietary intervention included a 7-day low sodium (51.3 mmol/day), a 7-day high sodium (307.8 mmol/day), and a 7-day high sodium with potassium supplementation (307.8 mmol sodium and 60 mmol potassium/day). BP measurements were obtained during the baseline and each intervention phase. During the CPT, BP was measured before and at 0, 1, 2, and 4 minutes after the participants immersed their right hand in ice water for 1 minute.
Systolic and diastolic BP responses (mean ± SD (range), mm Hg) were 8.1±8.4 (−39.1 to 18.2) and −3.5±5.1 (−25.1 to 11.1) to low sodium, 9.1±8.4 (−13.3 to 33.1) and 4.0±5.4 (−16.0 to 20.7) to high sodium, and −4.6±5.8 (−31.8 to 11.6) and −1.9±4.3 (−16.9 to 14.2) to potassium supplementation, respectively (all P < 0.0001 for comparison with each former phase). The mean maximum systolic and diastolic BP responses to the CPT were 16.5±10.5 (−15.3 to 63.3) and 7.6±6.1 (−8.7 to 39.3), respectively (all P < 0.0001).
Our study indicates that there are large variations in BP responses to dietary sodium and potassium interventions and to the CPT among individuals.
PMCID: PMC3848630  PMID: 24004934
blood pressure; cold pressor test; dietary potassium; hypertension; salt sensitivity; sodium.
22.  A systematic simulation of the effect of salicylic acid on sphingolipid metabolism 
The phytohormone salicylic acid (SA) affects plant development and defense responses. Recent studies revealed that SA also participates in the regulation of sphingolipid metabolism, but the details of this regulation remain to beexplored. Here, we use in silico Flux Balance Analysis (FBA) with published microarray data to construct a whole-cell simulation model, including 23 pathways, 259 reactions, and 172 metabolites, to predict the alterations in flux of major sphingolipid species after treatment with exogenous SA. This model predicts significant changes in fluxes of certain sphingolipid species after SA treatment, changes that likely trigger downstream physiological and phenotypic effects. To validate the simulation, we used 15N-labeled metabolic turnover analysis to measure sphingolipid contents and turnover rate in Arabidopsis thaliana seedlings treated with SA or the SA analog benzothiadiazole (BTH). The results show that both SA and BTH affect sphingolipid metabolism, altering the concentrations of certain species and also changing the optimal flux distribution and turnover rate of sphingolipids. Our strategy allows us to estimate sphingolipid fluxes on a short time scale and gives us a systemic view of the effect of SA on sphingolipid homeostasis.
PMCID: PMC4373270  PMID: 25859253
ceramides; salicylic acid; sphingolipid
23.  Cytological and proteomic analyses of horsetail (Equisetum arvense L.) spore germination 
Spermatophyte pollen tubes and root hairs have been used as single-cell-type model systems to understand the molecular processes underlying polar growth of plant cells. Horsetail (Equisetum arvense L.) is a perennial herb species in Equisetopsida, which creates separately growing spring and summer stems in its life cycle. The mature chlorophyllous spores produced from spring stems can germinate without dormancy. Here we report the cellular features and protein expression patterns in five stages of horsetail spore germination (mature spores, rehydrated spores, double-celled spores, germinated spores, and spores with protonemal cells). Using 2-DE combined with mass spectrometry, 80 proteins were found to be abundance changed upon spore germination. Among them, proteins involved in photosynthesis, protein turnover, and energy supply were over-represented. Thirteen proteins appeared as proteoforms on the gels, indicating the potential importance of post-translational modification. In addition, the dynamic changes of ascorbate peroxidase, peroxiredoxin, and dehydroascorbate reductase implied that reactive oxygen species homeostasis is critical in regulating cell division and tip-growth. The time course of germination and diverse expression patterns of proteins in photosynthesis, energy supply, lipid and amino acid metabolism indicated that heterotrophic and autotrophic metabolism were necessary in light-dependent germination of the spores. Twenty-six proteins were involved in protein synthesis, folding, and degradation, indicating that protein turnover is vital to spore germination and rhizoid tip-growth. Furthermore, the altered abundance of 14-3-3 protein, small G protein Ran, actin, and caffeoyl-CoA O-methyltransferase revealed that signaling transduction, vesicle trafficking, cytoskeleton dynamics, and cell wall modulation were critical to cell division and polar growth. These findings lay a foundation toward understanding the molecular mechanisms underlying fern spore asymmetric division and rhizoid polar growth.
PMCID: PMC4469821  PMID: 26136760
spore germination; Equisetum arvense L.; fern; proteomics; single cell; polar growth
24.  Genome-Wide Association Study Identifies Eight Novel Loci Associated with Blood Pressure Responses to Interventions in Han Chinese 
Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test (CPT) vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals’ BP responses to dietary intervention and CPT.
Methods and Results
We conducted a genome-wide association study of BP responses in 1,881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/day), a 7-day high-sodium (307.8 mmol/day), and a 7-day high-sodium plus potassium-supplementation (60 mmol/day). Nine BP measurements were obtained during baseline observation and each intervention period. The meta-analyses identified eight novel loci for BP phenotypes, which physically mapped in or near PRMT6 (P=7.29×10−9), CDCA7 (P=3.57×10−8), PIBF1 (P=1.78×10−9), ARL4C (P=1.86×10−8), IRAK1BP1 (P=1.44×10−10), SALL1 (P=7.01×10−13), TRPM8 (P=2.68×10−8), and FBXL13 (P=3.74×10−9). There was a strong dose-response relationship between the number of risk alleles of these independent SNPs and the risk of developing hypertension over 7.5-year follow-up in the study participants. Compared to those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively (P=0.0003 for trend).
Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and CPT. The effect size of these novel loci on BP phenotypes are much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline.
PMCID: PMC3952335  PMID: 24165912
blood pressure; genomics; sodium; potassium
25.  Systematic Characterization of Cell Cycle Phase-dependent Protein Dynamics and Pathway Activities by High-content Microscopy-assisted Cell Cycle Phenotyping 
Cell cycle progression is coordinated with metabolism, signaling and other complex cellular functions. The investigation of cellular processes in a cell cycle stage-dependent manner is often the subject of modern molecular and cell biological research. Cell cycle synchronization and immunostaining of cell cycle markers facilitate such analysis, but are limited in use due to unphysiological experimental stress, cell type dependence and often low flexibility. Here, we describe high-content microscopy-assisted cell cycle phenotyping (hiMAC), which integrates high-resolution cell cycle profiling of asynchronous cell populations with immunofluorescence microscopy. hiMAC is compatible with cell types from any species and allows for statistically powerful, unbiased, simultaneous analysis of protein interactions, modifications and subcellular localization at all cell cycle stages within a single sample. For illustration, we provide a hiMAC analysis pipeline tailored to study DNA damage response and genomic instability using a 3–4-day protocol, which can be adjusted to any other cell cycle stage-dependent analysis.
PMCID: PMC4411490  PMID: 25458086
hiMAC; Non-invasive cell cycle assay; Cell cycle profiling; DNA damage markers; Imaging

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