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1.  Enhanced myeloid differentiation factor 88 promotes tumor metastasis via induction of epithelial–mesenchymal transition in human hepatocellular carcinoma 
Cell Death & Disease  2014;5(3):e1103-.
Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) after curative resection. Therefore, it is critical to understand the mechanisms underlying tumor metastasis in HCC. We have previously shown that elevated expression of myeloid differentiation factor 88 (MyD88) may promote tumor growth and metastasis in HCC. In this study, we reported that enhanced expression of MyD88 promoted epithelial–mesenchymal transition (EMT) properties and tumor-initiating capabilities in HCC cells. MyD88 was found to be able to interact with p85, a regulatory subunit of phosphoinositide 3-kinase (PI3-K), independent of TLR/IL-1R-mediated response and caused PI3-K/v-akt murine thymoma viral oncogene homolog (Akt) activation, which resulted in subsequent phosphorylation of glycogen synthase kinase-3β and stabilization of Snail, a critical EMT mediator. Consistently, we observed a significant correlation between MyD88 expression and p-Akt levels in a cohort of HCC patients, and found that the combination of these two parameters have better prognostic value for HCC patients. Taken together, these results suggest that elevated MyD88 may facilitate HCC metastasis by promoting EMT properties and tumor-initiating capabilities via PI3–K/Akt pathway.
PMCID: PMC3973199  PMID: 24603331
tumor metastasis; myeloid differentiation factor 88; epithelial–mesenchymal transition
2.  Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging 
Aging cell  2012;12(1):156-166.
While environmental stress likely plays a significant role in promoting aging, the relationship remains poorly understood. In order to characterize this interaction in a more comprehensive manner, we examined the stress response profiles for 46 long-lived yeast mutant strains across four different stress conditions (oxidative, ER, DNA damage, and thermal), grouping genes based on their associated stress response profiles. Unexpectedly, cells lacking the mitochondrial AAA protease gene AFG3 clustered strongly with long-lived strains lacking cytosolic ribosomal proteins of the large subunit. Similar to these ribosomal protein mutants, afg3Δ cells show reduced cytoplasmic mRNA translation, enhanced resistance to tunicamycin that is independent of the ER unfolded protein response, and Sir2-independent but Gcn4-dependent life span extension. These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging.
PMCID: PMC3687586  PMID: 23167605
aging; stress response; translation; mitochondria; ER stress; replicative lifespan; longevity; yeast; epistasis; phenotype mapping
3.  Predicting cooperative drug effects through the quantitative cellular profiling of response to individual drugs 
Quantitative prediction of cellular responses to drugs and drug combinations is a challenging and valuable topic in pharmaceutical research. In the past decade, microarray technology has become a routine tool for monitoring genome-wide expression changes and has been widely adopted for exploring drug response in the pharmaceutical field. However, how to predict the synergistic effect of drug combinations using microarray data is a challenging task. In this article, we report a simple prediction framework based on the genome-wide and quantitative profiling of cellular responses to individual drugs. By exploring the differential expression profiles, our correlation-based strategy can reveal the synergistic effects of drug combinations. The comparison with gold-standard experimental results demonstrates the strengths and weaknesses in relation to prediction based only on cellular response to individual drugs. Specifically, the prediction strategy may work for a drug combination whose individual drugs show related transcriptomic mechanisms but not for others.
PMCID: PMC3944117  PMID: 24573337
4.  Highly Stable Wideband Microwave Extraction by Synchronizing Widely Tunable Optoelectronic Oscillator with Optical Frequency Comb 
Scientific Reports  2013;3:3509.
Optical frequency combs (OFCs), based on mode-locked lasers (MLLs), have attracted considerable attention in many fields over recent years. Among the applications of OFCs, one of the most challenging works is the extraction of a highly stable microwave with low phase noise. Many synchronisation schemes have been exploited to synchronise an electronic oscillator with the pulse train from a MLL, helping to extract an ultra-stable microwave. Here, we demonstrate novel wideband microwave extraction from a stable OFC by synchronising a single widely tunable optoelectronic oscillator (OEO) with an OFC at different harmonic frequencies, using an optical phase detection technique. The tunable range of the proposed microwave extraction extends from 2 GHz to 4 GHz, and in a long-term synchronisation experiment over 12 hours, the proposed synchronisation scheme provided a rms timing drift of 18 fs and frequency instabilities at 1.2 × 10−15/1 s and 2.2 × 10−18/10000 s.
PMCID: PMC3863813  PMID: 24336459
5.  Targeting annexin A7 by a small molecule suppressed the activity of phosphatidylcholine-specific phospholipase C in vascular endothelial cells and inhibited atherosclerosis in apolipoprotein E−/− mice 
Li, H | Huang, S | Wang, S | Zhao, J | Su, L | Zhao, B | Zhang, Y | Zhang, S | Miao, J
Cell Death & Disease  2013;4(9):e806-.
Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key factor in apoptosis and autophagy of vascular endothelial cells (VECs), and involved in atherosclerosis in apolipoprotein E−/− (apoE−/−) mice. But the endogenous regulators of PC-PLC are not known. We recently found a small chemical molecule (6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine, ABO) that could inhibit oxidized low-density lipoprotein (oxLDL)-induced apoptosis and promote autophagy in VECs, and further identified ABO as an inhibitor of annexin A7 (ANXA7) GTPase. Based on these findings, we hypothesize that ANXA7 is an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO may inhibit atherosclerosis in apoE−/− mice. In this study, we tested our hypothesis. The results showed that ABO suppressed oxLDL-induced increase of PC-PLC level and activity and promoted the co-localization of ANXA7 and PC-PLC in VECs. The experiments of ANXA7 knockdown and overexpression demonstrated that the action of ABO was ANXA7-dependent in cultured VECs. To investigate the relation of ANXA7 with PC-PLC in atherosclerosis, apoE−/− mice fed with a western diet were treated with 50 or 100 mg/kg/day ABO. The results showed that ABO decreased PC-PLC levels in the mouse aortic endothelium and PC-PLC activity in serum, and enhanced the protein levels of ANXA7 in the mouse aortic endothelium. Furthermore, both dosages of ABO significantly enhanced autophagy and reduced apoptosis in the mouse aortic endothelium. As a result, ABO significantly reduced atherosclerotic plaque area and effectively preserved a stable plaques phenotype, including reduced lipid deposition and pro-inflammatory macrophages, increased anti-inflammatory macrophages, collagen content and smooth muscle cells, and less cell death in the plaques. In conclusion, ANXA7 was an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO inhibited atherosclerosis in apoE−/− mice.
PMCID: PMC3789175  PMID: 24052074
apoptosis; autophagy; PC-PLC; ANXA7; ABO; atherosclerosis
6.  pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast 
Cell Cycle  2012;11(16):3087-3096.
Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.
PMCID: PMC3442919  PMID: 22871733
chronological lifespan; longevity; replication stress; replicative lifespan; yeast
7.  Application of Micro-Computed Tomography with Iodine Staining to Cardiac Imaging, Segmentation and Computational Model Development 
Micro-computed tomography (micro-CT) has been widely used to generate high-resolution 3D tissue images from small animals non-destructively, especially for mineralized skeletal tissues. However, its application to the analysis of soft cardiovascular tissues has been limited by poor inter-tissue contrast. Recent ex vivo studies have shown that contrast between muscular and connective tissue in micro-CT images can be enhanced by staining with iodine. In the present study, we apply this novel technique for imaging of cardiovascular structures in canine hearts. We optimize the method to obtain high resolution X-ray micro-CT images of the canine atria and its distinctive regions - including the Bachmann’s bundle, atrioventricular node, pulmonary arteries and veins - with clear inter-tissue contrast. The imaging results are used to reconstruct and segment the detailed 3D geometry of the atria. Structure tensor analysis shows that the arrangement of atrial fibres can also be characterised using the enhanced micro-CT images, as iodine preferentially accumulates within the muscular fibres rather than in connective tissues. This novel technique can be particularly useful in non-destructive imaging of 3D cardiac architectures from large animals and humans, due to the combination of relatively high speed (~1 hour/scan of a large canine heart) and high voxel resolution (36 μm) provided. In summary, contrast micro-CT facilitates fast and non-destructive imaging and segmenting of detailed 3D cardiovascular geometries, as well as measuring fibre orientation, which are crucial in constructing biophysically detailed computational cardiac models.
PMCID: PMC3493467  PMID: 22829390
8.  Bright betatron X-ray radiation from a laser-driven-clustering gas target 
Scientific Reports  2013;3:1912.
Hard X-ray sources from femtosecond (fs) laser-produced plasmas, including the betatron X-rays from laser wakefield-accelerated electrons, have compact sizes, fs pulse duration and fs pump-probe capability, making it promising for wide use in material and biological sciences. Currently the main problem with such betatron X-ray sources is the limited average flux even with ultra-intense laser pulses. Here, we report ultra-bright betatron X-rays can be generated using a clustering gas jet target irradiated with a small size laser, where a ten-fold enhancement of the X-ray yield is achieved compared to the results obtained using a gas target. We suggest the increased X-ray photon is due to the existence of clusters in the gas, which results in increased total electron charge trapped for acceleration and larger wiggling amplitudes during the acceleration. This observation opens a route to produce high betatron average flux using small but high repetition rate laser facilities for applications.
PMCID: PMC3665959  PMID: 23715033
9.  Sir2 deletion prevents lifespan extension in 32 long-lived mutants 
Aging cell  2011;10(6):1089-1091.
Activation of Sir2-orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe life span extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution.
PMCID: PMC3215821  PMID: 21902802
aging; replicative lifespan; longevity; yeast; epistasis
10.  Ghrelin Contributes to Derangements of Glucose Metabolism Induced by Rapamycin in Mice 
Xu, G | Wang, Z | Li, Y | Li, Z | Tang, H | Zhao, J | Xiang, X | Ding, L | Ma, L | Yuan, F | Fei, J | Wang, W | Wang, N | Guan, Y | Tang, C | Mulholland, M | Zhang, W
Diabetologia  2012;55(6):1813-1823.
Rapamycin impaired glucose tolerance and insulin sensitivity. Our previous study demonstrated that rapamycin significantly increases the expression of gastric ghrelin, which is critical in the regulation of glucose metabolism. Here, we investigated whether ghrelin contributes to derangements of glucose metabolism induced by rapamycin.
The effects of rapamycin on glucose metabolism were examined in mice receiving ghrelin receptor antagonist or with ghrelin receptor gene deletion. Changes in Glut4, JNK, and pS6 were investigated by immnuofluorescent staining or Western. Related hormones were detected by radioimmuno-assay kits.
Rapamycin impaired glucose metabolism and insulin sensitivity not only in normal C57BL/6J mice but also in both obese mice induced by high fat diet and db/db mice. This was accompanied by elevation of plasma acylated ghrelin. Rapamycin significantly increased the levels of plasma acylated ghrelin in normal C57BL/6J mice, high fat diet induced obese mice, and db/db mice. Elevation in plasma acylated ghrelin and derangements of glucose metabolism upon administration of rapamycin was significantly correlated. The deterioration in glucose homeostasis induced by rapamycin was blocked by D-Lys3-GHRP-6, a ghrelin receptor antagonist, or by deletion of ghrelin receptor gene. Ghrelin receptor antagonism and ghrelin receptor gene deletion blocked the up-regulation of JNK activity, and GLUT4 expression and translocation in the gastrocnemius muscle induced by rapamycin.
The current study demonstrates that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the expression and translocation of GLUT4 in muscles.
PMCID: PMC3496261  PMID: 22391948
Ghrelin; glucose metabolism; rapamycin
11.  Enhanced Osseointegration of Titanium Implant Through the Local Delivery of Transcription Factor SATB2 
Biomaterials  2011;32(33):8676-8683.
Titanium implants are widely used in dentistry and orthopaedic surgery. Nevertheless, bone regeneration around the implant is a relatively slow process, after placement. This study assessed whether SATB2 can enhance osseointegration of a titanium implant. To determine the effect of SATB2 in implant integration, two different viruses encoding SATB2 (PBABE-Satb2 virus or RCAS-Satb2 virus) were locally administered to the bone defect prior to titanium implant placement in our established transgenic TVA mice. Seven and 21 days post implantation, the femurs were isolated for quantitative real-time RT-PCR, H&E staining, immunohistochemical (IHC) staining, and microcomputed tomography (microCT) analysis. Quantitative real-time RT-PCR results demonstrated that the in vivo overexpression of SATB2 enhanced expression levels of potent osteogenic transcription factors and bone matrix proteins. We also found that 21 days after implantation, there were no significant differences in the expression levels of SATB2, Osx, Runx2, COLI, OC, and BSP between the RCAS-Satb2 group and the RCAS group. Histological analysis showed that SATB2 overexpression significantly enhanced new bone formation and bone-to-implant contact after implantation. IHC staining analysis revealed that forced expression of SATB2 increased the number of BSP-positive cells surrounding the implant. MicroCT analysis demonstrated that in vivo overexpression of SATB2 significantly increased the density of the newly formed bone surrounding the implant. These results conclude that in vivo overexpression of SATB2 significantly accelerates osseointegration of titanium implants and SATB2 can serve as a potent molecule in promoting tissue regeneration.
PMCID: PMC3218567  PMID: 21862122
implant; SATB2; osseointegration; TVA mice
13.  Cross-bridge Kinetics in Myofibrils Containing Familial Hypertrophic Cardiomyopathy R58Q Mutation in the Regulatory Light Chain of Myosin 
Journal of theoretical biology  2011;284(1):71-81.
Familial hypertrophic cardiomyopathy (FHC) is a heritable form of cardiac hypertrophy caused by single-point mutations in genes encoding sarcomeric proteins including ventricular myosin regulatory light chain (RLC). FHC often leads to malignant outcomes and sudden cardiac death. The FHC mutations are believed to alter the kinetics of the interaction between actin and myosin resulting in inefficient energy utilization and compromised function of the heart. We studied the effect of the FHC-linked R58Q-RLC mutation on the kinetics of transgenic (Tg)-R58Q cardiac myofibrils. Kinetics was determined from the rate of change of orientation of actin monomers during muscle contraction. Actin monomers change orientation because myosin cross-bridges deliver to it periodic force impulses. An individual impulse (but not time average of impulses) carries the information about the kinetics of actomyosin interaction. To observe individual impulses it was necessary to scale down the experiments to the level of a few molecules. A small population (~4 molecules) was selected by using (deliberately) inefficient fluorescence labeling and observing fluorescent molecules by a confocal microscope. We show that the kinetic rates are significantly smaller in the contracting cardiac myofibrils from Tg-R58Q mice then in control Tg-wild type (WT). We also demonstrate a lower force per cross-section of muscle fiber in Tg-R58Q versus Tg-WT mice. We conclude that the R58Q mutation-induced decrease in cross-bridge kinetics underlines the mechanism by which Tg-R58Q fibers develop low force and thus compromise the ability of the mutated heart to efficiently pump blood.
PMCID: PMC3152379  PMID: 21723297
14.  The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress 
Cell Death & Disease  2012;3(8):e376-.
Falcarindiol (FAD) is a natural polyyne with various beneficial biological activities. We show here that FAD preferentially kills colon cancer cells but not normal colon epithelial cells. Furthermore, FAD inhibits tumor growth in a xenograft tumor model and exhibits strong synergistic killing of cancer cells with 5-fluorouracil, an approved cancer chemotherapeutic drug. We demonstrate that FAD-induced cell death is mediated by induction of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Decreasing the level of ER stress, either by overexpressing the ER chaperone protein glucose-regulated protein 78 (GRP78) or by knockout of components of the UPR pathway, reduces FAD-induced apoptosis. In contrast, increasing the level of ER stress by knocking down GRP78 potentiates FAD-induced apoptosis. Finally, FAD-induced ER stress and apoptosis is correlated with the accumulation of ubiquitinated proteins, suggesting that FAD functions at least in part by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of ER stress. Consistent with this, inhibition of protein synthesis by cycloheximide significantly decreases the accumulation of ubiquitinated proteins and blocks FAD-induced ER stress and cell death. Taken together, our study shows that FAD is a potential new anticancer agent that exerts its activity through inducing ER stress and apoptosis.
PMCID: PMC3434669  PMID: 22914324
ER stress; falcarindiol; apoptosis; unfolded protein response; proteasome
15.  High-energy-resolution X-ray monochromator calibration using the detailed-balance principle 
Journal of Synchrotron Radiation  2012;19(Pt 4):602-608.
A sample-independent method is presented to calibrate an X-ray energy scale of a high-energy-resolution monochromator with sub-meV relative accuracy by using the detailed-balance principle.
A new method is presented to calibrate an X-ray energy scale with sub-meV relative accuracy by using the detailed-balance principle of the phonon creation and annihilation. This method is conveniently used to define or verify the energy scale of high-energy-resolution monochromators that are used in inelastic X-ray scattering and nuclear resonant inelastic X-ray scattering instruments at synchrotron radiation facilities. This method does not rely on sample properties and its precision only depends on the statistical data quality. Well calibrated instruments are essential for reliable comparison of data sets obtained at different synchrotron radiation beamlines, of data with theoretical predictions, and of data from other techniques such as neutron or light scattering. The principle of the detailed-balance method is described in this paper and demonstrated experimentally.
PMCID: PMC3579592  PMID: 22713897
X-ray; monochromator; energy calibration; nuclear resonant scattering
16.  Low agreement between T-SPOT®.TB assay and tuberculin skin test among college students in China 
T-SPOT®.TB and tuberculosis skin test (TST) were used to screen latent tuberculosis infection (LTBI) among 899 Chinese college students. The positive rates of T-SPOT®.TB and TST were 13.0% (95% confidence interval [CI], [10.4 – 15.9%]) and 24.9% (95% CI, [21.5 – 28.6%]) respectively among students with a BCG scar (agreement of both tests, 72.3%; 95% CI, [68.6 – 75.8%]; kappa = 0.118), and 17.3% (95% CI, [11.7 – 24.2%]) and 23.7% (95% CI, [17.3 – 31.2%]) respectively among students without a BCG scar (agreement, 73.1%; 95% CI (65.4 – 79.9%); kappa = 0.179). These results demonstrate low agreement between TST and T-SPOT®.TB in the studied Chinese population.
PMCID: PMC3118013  PMID: 21276310
latent tuberculosis infection; IFN-γ release assay; T-SPOT®.TB; Tuberculin skin test
17.  Heritability of flow-mediated dilation: a twin study 
Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker for early atherosclerotic vascular disease and future cardiovascular events.
To estimate the heritability of brachial artery FMD using a twin design.
We estimated the heritability of FMD using 94 middle-aged male twin pairs. FMD was measured by ultrasound, and traditional coronary heart disease risk factors were measured. Genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in FMD.
The mean age of the twin participants was 54.9 ± 2.8 years. The mean FMD was 0.047 ± 0.030. The intraclass correlation coefficient was higher in MZ twins [0.38, 95% confidence interval (CI) 0.32–0.43] than in DZ twins (0.19, 95% CI 0.11–0.26), suggesting a role of genetic influence in FMD variation. Structural equation modeling showed that both genetic and unique environmental factors contributed significantly to the variation in FMD. The crude FMD heritability was 0.37 (95% CI 0.15–0.54). After adjustment for traditional cardiovascular risk factors, including age, total cholesterol, blood pressure, and body mass index, the heritability of FMD was 39% (95% CI 0.18–0.56). The remaining variation in FMD could be explained by individual-specific environment.
This is the first study using twins to estimate the relative contributions of genetics and environment to the variation in FMD in a US population. Our results demonstrate a moderate genetic effect on brachial artery FMD, independent of traditional coronary risk factors. Our data also highlight the importance of unique environment on the variability in FMD.
PMCID: PMC3113515  PMID: 17848176
atherosclerosis; brachial artery flow-mediated dilation; heritability; twin study
18.  Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice 
Nutrition & Diabetes  2011;1(5):e7-.
Background: Maternal obesity is linked with offspring obesity and type 2 diabetes. Skeletal muscle (SM) insulin resistance is central to the development of diabetes. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited in SM of fetuses born to obese mothers.
Objective: The aim of this study was to evaluate the effect of maternal metformin administration on AMPK activity and reversion of adverse changes in offspring SM of obese mice.
Design: Female weanling C57BL/6J mice received either control diet (CON, 6 mice) or high-fat diet (HFD; OB, 12 mice) for 8 weeks before mating. After mating, mice continued receiving their respective CON or OB diets. In addition, 6 of those 12 mice fed with fat diet also received metformin administration (2 mg per ml in drinking water) throughout gestation and lactation (MET). After weaning at postnatal 21 days, offspring were fed a HFD to mimic a postnatal obesogenic environment until necropsy.
Results: Mothers receiving the fat diet developed obesity. OB offspring showed higher adiposity than CON and MET offspring. AMPK phosphorylation was lower in SM of OB offspring. β-Catenin and myogenic regulatory factors, MyoD and myogenin, were downregulated in OB muscle, whereas the adipogenic marker, peroxisome proliferator-activated receptor-γ, was upregulated compared with CON muscle. Metformin administration prevented these changes in OB offspring SM. OB but not MET offspring demonstrated glucose intolerance. Mitochondrial content decreased, and activities of citrate synthase and β-hydroxyacyl-CoA dehydrogenase also decreased in OB offspring SM, whereas they were recovered in MET offspring SM.
Conclusion: Maternal metformin administration improves SM development in OB offspring.
PMCID: PMC3302133  PMID: 23449382
developmental programming; maternal obesity; Amp-activated protein kinase; metformin; skeletal muscle
19.  Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin’s B-cell lymphomas 
B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell–cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3′UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.
PMCID: PMC3083119  PMID: 20966935
lymphoma; BCL-6; PRDM-1; miRNA; cell adhesion
20.  Genetic predisposition to obesity leads to increased risk of type 2 diabetes 
Diabetologia  2011;54(4):776-782.
Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort.
We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39–79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models.
Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005–1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967–1.039; p = 0.89).
The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2044-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3052481  PMID: 21267540
Genetic predisposition; Genome-wide association studies; Obesity; Type 2 diabetes
21.  The tale of the three sisters 
Netherlands Heart Journal  2010;18(11):552-554.
In this article we present the myocardial deformation imaging (MDI) studies of three daughters of a man with hypertrophic cardiomyopathy (HCM) who died suddenly. The daughters had been referred for genetic counselling several months earlier. We demonstrate that, despite the absence of conventional two-dimensional echo characteristics of HCM, MDI accurately and easily demonstrated the presence of the disease in the two daughters with the genetic disorder. (Neth Heart J 2010;18:552–4.)
PMCID: PMC2989450  PMID: 21113380
Hypertrophic Cardiomyopathy; Myocardial Deformation Imaging; Genetic Disorder
22.  Cornell University Life Sciences Core Laboratories Center 
The Cornell University Life Sciences Core Laboratories Center (CLC) provides an array of genomics, proteomics, imaging and informatics shared research resources and services to the university community and to outside investigators. The CLC includes fee-for-service research, technology testing and development, and educational components. The Center has nine core facilities, including DNA sequencing and genotyping, microarrays, epigenomics, proteomics and mass spectrometry, high throughput screening, microscopy and imaging, mouse transgenics, bioinformatics, and bio-IT. The CLC is part of a New York State designated Center for Advanced Technology in Life Science Enterprise. The mission of the CLC is to promote research in the life sciences with advanced technologies in a shared resource environment. Use of the CLC resources and services is steadily increasing due to the growth in the number and types of cores in the center, to the expansion of exiting services and the implementation of new core technologies, and to the coordinated integration and synergy of services between the CLC cores. Multidisciplinary support for multi-functional instrument platforms is implemented by coordinated operations of the CLC core facilities. CLC core users are offered coordinated project consultations with the directors and staff of all relevant cores during the design, data production and analysis phases of their projects. The CLC is also involved in establishing and supporting multidisciplinary research projects that involve both intercampus initiatives and multi-institutional collaborations. With a concentration of advanced instrumentation and expertise in their applications, the CLC is a key resource for life sciences basic research and medical research for investigators at Cornell University and at other academic institutions and commercial enterprises.
PMCID: PMC2918124
23.  Microarray Core Facility of Cornell University 
The Microarray Facility of the Cornell University Life Sciences Core Laboratories Center (CLC) offers a broad range of microarray services and shared research resources to the university research community and to outside investigators. The goal of the facility is to provide life science investigators with services that use advanced microarray instrumentation and extensive expertise in microarray based applications. The facility helps researchers with all aspects of microarray experiments, including project design, sample processing, and data analysis. Services include support for gene expression, microRNA, SNP genotyping and epigenomics projects using microarrays, including the Affymetrix, Illumina, NimbleGen, and Agilent microarray platforms, and support for RNA-Seq profiling projects (digital gene expression and microRNA) and protein-nucleic acid association studies (ChIP-Seq) using the Roche 454 GS FLX and the Illumina Genome Analyzer IIx sequencing insturments.
PMCID: PMC2918216
24.  Association analyses of vitamin D-binding protein gene with compression strength index variation in Caucasian nuclear families 
This study was conducted to test whether there exists an association between vitamin D-binding protein (DBP) gene and compression strength index (CSI) phenotype. Candidate gene association analyses were conducted in total sample, male subgroup, and female subgroup, respectively. Two single-nucleotide polymorphisms (SNPs) with significant association results were found in males, suggesting the importance of DBP gene polymorphisms on the variation in CSI especially in Caucasian males.
CSI of the femoral neck (FN) is a newly developed phenotype integrating information about bone size, body size, and bone mineral density. It is considered to have the potential to improve the performance of risk assessment for hip fractures because it is based on a combination of phenotypic traits influencing hip fractures rather than a single trait. CSI is under moderate genetic determination (with a heritability of ~44% found in this study), but the relevant genetic study is still rather scarce.
Based on the known physiological role of DBP in bone biology and the relatively high heritability of CSI, we tested 12 SNPs of the DBP gene for association with CSI variation in 405 Caucasian nuclear families comprising 1,873 subjects from the Midwestern US. Association analyses were performed in the total sample, male and female subgroups, respectively.
Significant associations with CSI were found with two SNPs (rs222029, P=0.0019; rs222020, P=0.0042) for the male subgroup. Haplotype-based association tests corroborated the single-SNP results.
Our findings suggest that the DBP gene might be one of the genetic factors influencing CSI phenotype in Caucasians, especially in males.
PMCID: PMC2914268  PMID: 19543766
Association; Compression strength index; DBP; Haplotype; SNP
25.  Tumor-targeted delivery of biologically active TRAIL protein 
Cancer Gene Therapy  2010;17(5):334-343.
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent inducer of tumor cell apoptosis, but concerns of considerable liver toxicity limit its uses in human cancer therapy. Here, we show that i.v. injected Escherichia coli DH5α (E. coli DH5α) specifically replicates in solid tumors and metastases in live animals. E. coli DH5α does not enter tumor cells and suits for being the vector for soluble TRAIL (sTRAIL), which induces apoptosis by activating cell-surface death receptors. With the high ‘tumor-targeting' nature, we demonstrate that intratumoral (i.t.) and intravenous injection of sTRAIL-expressing E. coli DH5α results in the tumor-targeted release of biologically active molecules, which leads to a dramatic reduction in the tumor growth rate and the prolonged survival of tumor-bearing mice. TRAIL delivery by E. coli DH5α did not cause any detectable toxicity to any organs, suggesting that E. coli DH5α-delivered sTRAIL protein therapy may provide a feasible and effective form of treatment for solid tumors.
PMCID: PMC2859322  PMID: 20075981
TRAIL; tumor targeting; Escherichia coli; apoptosis

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