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1.  Ultrafast 3D spin-echo acquisition improves Gadolinium-enhanced MRI signal contrast enhancement 
Scientific Reports  2014;4:5061.
Long scan times of 3D volumetric MR acquisitions usually necessitate ultrafast in vivo gradient-echo acquisitions, which are intrinsically susceptible to magnetic field inhomogeneities. This is especially problematic for contrast-enhanced (CE)-MRI applications, where non-negligible T2* effect of contrast agent deteriorates the positive signal contrast and limits the available range of MR acquisition parameters and injection doses. To overcome these shortcomings without degrading temporal resolution, ultrafast spin-echo acquisitions were implemented. Specifically, a multiplicative acceleration factor from multiple spin echoes (×32) and compressed sensing (CS) sampling (×8) allowed highly-accelerated 3D Multiple-Modulation-Multiple-Echo (MMME) acquisition. At the same time, the CE-MRI of kidney with Gd-DOTA showed significantly improved signal enhancement for CS-MMME acquisitions (×7) over that of corresponding FLASH acquisitions (×2). Increased positive contrast enhancement and highly accelerated acquisition of extended volume with reduced RF irradiations will be beneficial for oncological and nephrological applications, in which the accurate in vivo 3D quantification of contrast agent concentration is necessary with high temporal resolution.
doi:10.1038/srep05061
PMCID: PMC4034007  PMID: 24863102
2.  Menin mediates epigenetic regulation via histone H3 lysine 9 methylation 
Cell Death & Disease  2013;4(4):e583-.
Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor that leads to multiple endocrine tumors upon loss of its function. Menin functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation. It also functions as a repressor. However, the molecular mechanism of how menin contributes to the opposite outcome in gene expression is largely unknown. Here, we investigated the role of menin in the epigenetic regulation of transcription mediated by histone covalent modification. We show that the global methylation level of histone H3 K9, as well as H3 K4, was decreased in Men1−/− MEF cells. Consistently, menin was able to interact with the suppressor of variegation 3–9 homolog family protein, SUV39H1, to mediate H3 K9 methylation. This interaction decreased when patient-derived MEN1 mutation was introduced into the SUV39H1-interaction domain. We show that menin mediated different chromatin changes depending on target genes. Chromatin immunoprecipitation studies showed that menin directly associated with the GBX2 promoter and menin-dependent recruitment of SUV39H1 was essential for chromatin remodeling and transcriptional regulation. These results provide a molecular basis of how menin functions as a transcriptional repressor and suggest that menin-dependent integration of H3 K9 methylation might play an important role in preventing tumors.
doi:10.1038/cddis.2013.98
PMCID: PMC3668625  PMID: 23579270
menin; tumor suppressor; histone methylation; SUV39H1
3.  Optimization of pulsed DEER measurements for Gd-based labels: choice of operational frequencies, pulse durations and positions, and temperature 
Applied magnetic resonance  2013;44(6):10.1007/s00723-012-0434-6.
In this work, the experimental conditions and parameters necessary to optimize the long-distance (≥ 60 Å) Double Electron-Electron Resonance (DEER) measurements of biomacromolecules labeled with Gd(III) tags are analyzed. The specific parameters discussed are the temperature, microwave band, the separation between the pumping and observation frequencies, pulse train repetition rate, pulse durations and pulse positioning in the electron paramagnetic resonance spectrum. It was found that: (i) in optimized DEER measurements, the observation pulses have to be applied at the maximum of the EPR spectrum; (ii) the optimal temperature range for Ka-band measurements is 14–17 K, while in W-band the optimal temperatures are between 6–9 K; (iii) W-band is preferable to Ka-band for DEER measurements. Recent achievements and the conditions necessary for short-distance measurements (<15 Å) are also briefly discussed.
doi:10.1007/s00723-012-0434-6
PMCID: PMC3654798  PMID: 23687407
Gd(III) spin labels; long distance pulsed DEER; Ka -and W-microwave bands
4.  Mapping shape quantitative trait loci using a radius-centroid-contour model 
Fu, G | Bo, W | Pang, X | Wang, Z | Chen, L | Song, Y | Zhang, Z | Li, J | Wu, R
Heredity  2013;110(6):511-519.
As the consequence of complex interactions between different parts of an organ, shape can be used as a predictor of structural–functional relationships implicated in changing environments. Despite such importance, however, it is no surprise that little is known about the genetic detail involved in shape variation, because no approach is currently available for mapping quantitative trait loci (QTLs) that control shape. Here, we address this problem by developing a statistical model that integrates the principle of shape analysis into a mixture-model-based likelihood formulated for QTL mapping. One state-of-the-art approach for shape analysis is to identify and analyze the polar coordinates of anatomical landmarks on a shape measured in terms of radii from the centroid to the contour at regular intervals. A procrustes analysis is used to align shapes to filter out position, scale and rotation effects on shape variation. To the end, the accurate and quantitative representation of a shape is produced with aligned radius-centroid-contour (RCC) curves, that is, a function of radial angle at the centroid. The high dimensionality of the RCC data, crucial for a comprehensive description of the geometric feature of a shape, is reduced by principal component (PC) analysis, and the resulting PC axes are treated as phenotypic traits, allowing specific QTLs for global and local shape variability to be mapped, respectively. The usefulness and utilization of the new model for shape mapping in practice are validated by analyzing a mapping data collected from a natural population of poplar, Populus szechuanica var tibetica, and identifying several QTLs for leaf shape in this species. The model provides a powerful tool to compute which genes determine biological shape in plants, animals and humans.
doi:10.1038/hdy.2012.97
PMCID: PMC3656636  PMID: 23572125
genetic mapping; shape variation; QTL; poplar; statistical model
5.  Understanding the roadmaps to induced pluripotency 
Liu, K | Song, Y | Yu, H | Zhao, T
Cell Death & Disease  2014;5(5):e1232-.
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by ectopic expression of transcription factors Oct4, Sox2, Klf4 and cMyc. Recent advancements have shown that small-molecule compounds can induce pluripotency, indicating that cell fate can be regulated by direct manipulation of intrinsic cell signaling pathways, thereby innovating our current understanding of reprogramming. The fact that lineage specifiers can induce pluripotency suggests that the pluripotent state is a fine balance between competing differentiation forces. Dissection of pluripotent roadmaps indicates that reprogramming is a process of reverse development, involving a series of complicated and distinct reprogramming stages. Evidence from mouse iPSC transplantation studies demonstrated that some certain but not all cells derived from iPSCs are immunogenic. These studies provide new ways to minimize reprogramming-induced abnormalities and maximize reprogramming efficiency to facilitate clinical development and use of iPSCs.
doi:10.1038/cddis.2014.205
PMCID: PMC4047905  PMID: 24832604
induced pluripotent stem cells (iPSC); see-saw model; mesenchymal-to-epithelial transition (MET); epithelial-to-mesenchymal transition (EMT); small molecules; immunogenicity
6.  Comparative analysis of lifestyle factors, screening test use, and clinicopathologic features in association with survival among Asian Americans with colorectal cancer 
Yi, M | Xu, J | Liu, P | Chang, G J | Du, X L | Hu, C-y | Song, Y | He, J | Ren, Y | Wei, Y | Yang, J | Hunt, K K | Li, X
British Journal of Cancer  2013;108(7):1508-1514.
Background:
Colorectal cancer (CRC) diagnoses and disease-specific survival (DSS) vary between ethnic groups in the United States. However, few studies have assessed differences among Asian subgroups.
Methods:
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with invasive CRC between 1988 and 2008. Differences in clinicopathologic features, and DSS rates were compared among Asian subgroups. The California Health Interview Survey was used to examine risk factors and screening patterns for CRC.
Results:
The study included 359 374 patients with 8.4% Asian. Patients in all Asian subgroups were younger (median: 68 years) at diagnosis than non-Hispanic white (NHW) patients (median: 72 years). Most Asian subgroups, except Hawaiians, had better DSS than NHW patients although Asian subgroups had more advanced disease than NHW. Indian/Pakistani patients had a higher 5-year DSS than other Asian subgroups. Obesity proportions were lower in Asian subgroups (<50.2%) than in NHW (59.8%). Vietnamese men and Korean women had the lowest proportions of CRC screening. Advance tumour stages were highly associated with worse DSS in each ethnicity group. High tumour grades were associated with worse DSS in NHW, Filipino, and Chinese. Older age at diagnosis was associated with worse DSS in most ethnicity groups except Hawaiian and Vietnamese.
Conclusion:
Disparities exist between Asians and NHW with CRC, and among various Asian subgroups. Differences in cancer clinicopathologic features, patients' behavioural habits, lifestyle, and screening patterns may explain some differences in CRC survival observed among ethnic groups.
doi:10.1038/bjc.2013.97
PMCID: PMC3629437  PMID: 23470470
Asian Americans; colorectal cancer; lifestyle factors; screening test; clinicopathologic; survival
7.  Large magnetoelectric coupling in Co4Nb2O9 
Scientific Reports  2014;4:3860.
Magnetoelectric materials which simultaneously exhibit electric polarization and magnetism have attracted more and more attention due to their novel physical properties and promising applications for next-generation devices. Exploring new materials with outstanding magnetoelectric performance, especially the manipulation of magnetization by electric field, is of great importance. Here, we demonstrate the cross-coupling between magnetic and electric orders in polycrystalline Co4Nb2O9, in which not only magnetic-field-induced electric polarization but also electric field control of magnetism is observed. These results reveal rich physical phenomenon and potential applications in this compound.
doi:10.1038/srep03860
PMCID: PMC3902385  PMID: 24463631
8.  Computationally Inexpensive Approach for Pitch Control of Offshore Wind Turbine on Barge Floating Platform 
The Scientific World Journal  2013;2013:357849.
Offshore floating wind turbine (OFWT) has gained increasing attention during the past decade because of the offshore high-quality wind power and complex load environment. The control system is a tradeoff between power tracking and fatigue load reduction in the above-rated wind speed area. In allusion to the external disturbances and uncertain system parameters of OFWT due to the proximity to load centers and strong wave coupling, this paper proposes a computationally inexpensive robust adaptive control approach with memory-based compensation for blade pitch control. The method is tested and compared with a baseline controller and a conventional individual blade pitch controller with the “NREL offshore 5 MW baseline wind turbine” being mounted on a barge platform run on FAST and Matlab/Simulink, operating in the above-rated condition. It is shown that the advanced control approach is not only robust to complex wind and wave disturbances but adaptive to varying and uncertain system parameters as well. The simulation results demonstrate that the proposed method performs better in reducing power fluctuations, fatigue loads and platform vibration as compared to the conventional individual blade pitch control.
doi:10.1155/2013/357849
PMCID: PMC3885285  PMID: 24453834
10.  Treatment results of post-operative radiotherapy in patients with salivary duct carcinoma of the major salivary glands 
The British Journal of Radiology  2012;85(1018):e947-e952.
Objective
Salivary duct carcinoma (SDC) is a rare malignancy of high-grade pathological type. We evaluated clinical outcomes and prognostic factors in 35 patients with SDC treated post-operatively with adjuvant radiation.
Methods
We retrospectively assessed overall survival, locoregional control and disease-free survival in 35 patients with SDC of the major salivary glands who underwent surgery and were subsequently treated with radiotherapy. The evaluated prognostic factors included gender, age, symptom duration, tumour site, tumour size, TNM classification, and the following pathological features: perineural invasion, lymphovascular invasion, extraparenchymal invasion and resection-margin status.
Results
Of the 35 patients, 30 (85.7%) were male. Median age at initial diagnosis was 62 years (range 38–75 years). The parotid gland was the main site affected in 22 patients (62.9%). 18 patients (51.5%) had pathological T3/T4 tumours, and 26 (74.3%) showed pathological nodal involvement. Actuarial 5-year locoregional control, disease-free survival and overall survival rates were 63.3%, 47.4% and 55.1%, respectively. The cause-specific death rate was 31.4% (n=11). Pathological nodal involvement was correlated with distant metastasis (p=0.011). Lymphovascular invasion was significantly prognostic for distant metastasis-free survival (p=0.049), locoregional control (p=0.012) and overall survival (p=0.003) in a Cox proportional hazard model, whereas perineural invasion was only significantly prognostic for overall survival (p=0.005).
Conclusions
Surgery and post-operative radiotherapy were effective for locoregional control. Lymphovascular invasion and perineural invasion were significant prognostic factors in patients with SDC.
doi:10.1259/bjr/21574486
PMCID: PMC3474035  PMID: 22573301
11.  Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: expression of GRIA2 predicts better survival 
British Journal of Cancer  2012;107(1):91-99.
Background:
The purpose of this study was to identify genes that are differentially expressed in chemosensitive serous papillary ovarian carcinomas relative to those expressed in chemoresistant tumours.
Methods:
To identify novel candidate biomarkers, differences in gene expression were analysed in 26 stage IIIC/IV serous ovarian adenocarcinomas (12 chemosensitive tumours and 14 chemoresistant tumours). We subsequently investigated the immunohistochemical expression of GRIA2 in 48 independent sets of advanced ovarian serous carcinomas.
Results:
Microarray analysis revealed a total of 57 genes that were differentially expressed in chemoresistant and chemosensitive tumours. Of the 57 genes, 39 genes were upregulated and 18 genes were downregulated in chemosensitive tumours. Five differentially expressed genes (CD36, LIFR, CHL1, GRIA2, and FCGBP) were validated by quantitative real-time PCR. The expression of GRIA2 was validated at the protein level by immunohistochemistry, and patients with GRIA2 expression showed a longer progression-free and overall survival (P=0.051 and P=0.031 respectively).
Conclusions:
We found 57 differentially expressed genes to distinguish between chemosensitive and chemoresistant tumours. We also demonstrated that the expression of GRIA2 among the differentially expressed genes provides better prognosis of patients with advanced serous papillary ovarian adenocarcinoma.
doi:10.1038/bjc.2012.217
PMCID: PMC3389416  PMID: 22644307
gene expression profiling; microarray; ovarian serous adenocarcinoma; GRIA2; survival
12.  8-Chloro­methyl-5-(2,5-dioxooxolan-3-yl)-3,3a,4,5-tetra­hydro-1H-naphtho­[1,2-c]furan-1,3-dione 
The title compound, C17H13ClO6, is an asymmetric alicyclic dianhydride containing a chloro­methyl-substituted tetra­hydro­naphthalene moiety. The cyclo­hexene ring in the tetra­hydro­naphthalene moiety exhibits an envelope conformation with the tertiary C atom as the flap The dihedral angle between the two anhydride rings is 79.96 (6)°, while those between the benzene ring and the non-fused and fused anhydride rings are 71.03 (5) and 42.57 (7)°, respectively. In the crystal, mol­ecules are connected by weak C—H⋯O inter­actions, forming a three-dimensional supramolecular structure.
doi:10.1107/S1600536813014943
PMCID: PMC3772467  PMID: 24046610
13.  Dielectric Resonator for Ka-Band Pulsed EPR Measurements at Cryogenic Temperatures: Probehead Construction and Applications 
Applied magnetic resonance  2012;42(4):441-452.
The construction and performance of a Ka-band pulsed electron paramagnetic resonance (EPR) cryogenic probehead that incorporates dielectric resonator (DR) is presented. We demonstrate that the use of DR allows one to optimize pulsed double electron–electron resonance (DEER) measurements utilizing large resonator bandwidth and large amplitude of the microwave field B1. In DEER measurements of Gd-based spin labels, use of this probe finally allows one to implement the potentials of Gd-based labels in distance measurements. Evidently, this DR is well suited to any applications requiring large B1-fields and resonator bandwidths, such as electron spin echo envelope modulation spectroscopy of nuclei having low magnetic moments and strong hyperfine interactions and double quantum coherence dipolar spectroscopy as was recently demonstrated in the application of a similar probe based on an loop-gap resonator and reported by Forrer et al. (J Magn Reson 190:280, 2008).
doi:10.1007/s00723-012-0313-1
PMCID: PMC3634706  PMID: 23626406
15.  Alcohol intake and renal cell cancer risk: a meta-analysis 
British Journal of Cancer  2012;106(11):1881-1890.
Background:
An inverse association between alcoholic beverage intake and risk of renal cell cancer has been suggested in recent studies.
Methods:
We examined the association between alcoholic beverages and renal cell cancer risk in a meta-analysis. We identified relevant studies by searching the database of PubMed, EMBASE, and MEDLINE published through August 2011. We combined the study-specific relative risks (RRs) using a random-effects model.
Results:
A total of 20 case–control studies, 3 cohort studies, and 1 pooled analysis of cohort studies were included in the meta-analysis. We observed that alcoholic beverage intake was associated with a lower risk of renal cell cancer in combined analysis of case–control and cohort studies; for total alcoholic beverage intake, combined RRs (95% confidence intervals) comparing top with bottom categories were 0.76 (0.68–0.85) in case–control studies, and 0.71 (0.63–0.78) in cohort studies (P for difference by study design=0.02). The inverse associations were observed for both men and women and for each specific type alcoholic beverage (beer, wine, and liquor). Also, we found that one drink per day of alcoholic beverage conferred the reduction in renal cell cancer risk, but further drinking above that level did not add benefit.
Conclusion:
The findings from our meta-analysis support the hypothesis that alcoholic beverage intake is inversely associated with a lower risk of renal cell cancer, with moderate consumption conferring the protection and higher consumption conferring no additional benefits.
doi:10.1038/bjc.2012.136
PMCID: PMC3364130  PMID: 22516951
alcohol; renal cell cancer; meta-analysis
16.  Transferability of Newly Developed Pear SSR Markers to Other Rosaceae Species 
A set of 120 simple sequence repeats (SSRs) was developed from the newly assembled pear sequence and evaluated for polymorphisms in seven genotypes of pear from different genetic backgrounds. Of these, 67 (55.8 %) primer pairs produced polymorphic amplifications. Together, the 67 SSRs detected 277 alleles with an average of 4.13 per locus. Sequencing of the amplification products from randomly picked loci NAUPy31a and NAUpy53a verified the presence of the SSR loci. When the 67 primer pairs were tested on 96 individual members of eight species in the Rosaceae family, 61.2 % (41/67) of the tested SSRs successfully amplified a PCR product in at least one of the Rosaceae genera. The transferability from pear to different species varied from 58.2 % (apple) to 11.9 % (cherry). The ratio of transferability also reflected the closer relationships within Maloideae over Prunoideae. Two pear SSR markers, NAUpy43c and NAUpy55k, could distinguish the 20 different apple genotypes thoroughly, and UPGMA cluster analysis grouped them into three groups at the similarity level of 0.56. The high level of polymorphism and good transferability of pear SSRs to Rosaceae species indicate their promise for application to future molecular screening, map construction, and comparative genomic studies among pears and other Rosaceae species.
Electronic supplementary material
The online version of this article (doi:10.1007/s11105-013-0586-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11105-013-0586-z
PMCID: PMC3881569  PMID: 24415844
Simple sequence repeat (SSR); Pear; Rosaceae; Transferability
17.  Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma 
Yu, X | Zhen, Y | Yang, H | Wang, H | Zhou, Y | Wang, E | Marincola, F M | Mai, C | Chen, Y | Wei, H | Song, Y | Lyu, X | Ye, Y | Cai, L | Wu, Q | Zhao, M | Hua, S | Fu, Q | Zhang, Y | Yao, K | Liu, Z | Li, X | Fang, W
Cell Death & Disease  2013;4(5):e634-.
Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.
doi:10.1038/cddis.2013.153
PMCID: PMC3674361  PMID: 23681229
CTGF; NPC; miR-18b; PI3K/AKT
18.  Complex Population Dynamics and the Coalescent Under Neutrality 
Genetics  2012;190(1):187-201.
Estimates of the coalescent effective population size Ne can be poorly correlated with the true population size. The relationship between Ne and the population size is sensitive to the way in which birth and death rates vary over time. The problem of inference is exacerbated when the mechanisms underlying population dynamics are complex and depend on many parameters. In instances where nonparametric estimators of Ne such as the skyline struggle to reproduce the correct demographic history, model-based estimators that can draw on prior information about population size and growth rates may be more efficient. A coalescent model is developed for a large class of populations such that the demographic history is described by a deterministic nonlinear dynamical system of arbitrary dimension. This class of demographic model differs from those typically used in population genetics. Birth and death rates are not fixed, and no assumptions are made regarding the fraction of the population sampled. Furthermore, the population may be structured in such a way that gene copies reproduce both within and across demes. For this large class of models, it is shown how to derive the rate of coalescence, as well as the likelihood of a gene genealogy with heterochronous sampling and labeled taxa, and how to simulate a coalescent tree conditional on a complex demographic history. This theoretical framework encapsulates many of the models used by ecologists and epidemiologists and should facilitate the integration of population genetics with the study of mathematical population dynamics.
doi:10.1534/genetics.111.134627
PMCID: PMC3249372  PMID: 22042576
19.  Pulsed Dipolar Spectroscopy Distance Measurements in Biomacromolecules Labeled with Gd(III) Markers 
doi:10.1016/j.jmr.2011.02.010
PMCID: PMC3081411  PMID: 21388847
Pulse Dipolar Spectroscopy (PDS); Gd(III) tags; oligonucleotides; DEER; distance measurements
20.  Nanoscale phase separation of antiferromagnetic order and superconductivity in K0.75Fe1.75Se2 
Scientific Reports  2012;2:221.
We report an in-plane optical spectroscopy study on the iron-selenide superconductor K0.75Fe1.75Se2. The measurement revealed the development of a sharp reflectance edge below Tc at frequency much smaller than the superconducting energy gap on a relatively incoherent electronic background, a phenomenon which was not seen in any other Fe-based superconductors so far investigated. Furthermore, the feature could be noticeably suppressed and shifted to lower frequency by a moderate magnetic field. Our analysis indicates that this edge structure arises from the development of a Josephson-coupling plasmon in the superconducting condensate. Together with the transmission electron microscopy analysis, our study yields compelling evidence for the presence of nanoscale phase separation between superconductivity and magnetism. The results also enable us to understand various seemingly controversial experimental data probed from different techniques.
doi:10.1038/srep00221
PMCID: PMC3256564  PMID: 22355735
21.  A General Mechanistic Model for Admixture Histories of Hybrid Populations 
Genetics  2011;189(4):1413-1426.
Admixed populations have been used for inferring migrations, detecting natural selection, and finding disease genes. These applications often use a simple statistical model of admixture rather than a modeling perspective that incorporates a more realistic history of the admixture process. Here, we develop a general model of admixture that mechanistically accounts for complex historical admixture processes. We consider two source populations contributing to the ancestry of a hybrid population, potentially with variable contributions across generations. For a random individual in the hybrid population at a given point in time, we study the fraction of genetic admixture originating from a specific one of the source populations by computing its moments as functions of time and of introgression parameters. We show that very different admixture processes can produce identical mean admixture proportions, but that such processes produce different values for the variance of the admixture proportion. When introgression parameters from each source population are constant over time, the long-term limit of the expectation of the admixture proportion depends only on the ratio of the introgression parameters. The variance of admixture decreases quickly over time after the source populations stop contributing to the hybrid population, but remains substantial when the contributions are ongoing. Our approach will facilitate the understanding of admixture mechanisms, illustrating how the moments of the distribution of admixture proportions can be informative about the historical admixture processes contributing to the genetic diversity of hybrid populations.
doi:10.1534/genetics.111.132787
PMCID: PMC3241432  PMID: 21968194
22.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2370-7
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
23.  Bayesian Population Genomic Inference of Crossing Over and Gene Conversion 
Genetics  2011;189(2):607-619.
Meiotic recombination is a fundamental cellular mechanism in sexually reproducing organisms and its different forms, crossing over and gene conversion both play an important role in shaping genetic variation in populations. Here, we describe a coalescent-based full-likelihood Markov chain Monte Carlo (MCMC) method for jointly estimating the crossing-over, gene-conversion, and mean tract length parameters from population genomic data under a Bayesian framework. Although computationally more expensive than methods that use approximate likelihoods, the relative efficiency of our method is expected to be optimal in theory. Furthermore, it is also possible to obtain a posterior sample of genealogies for the data using this method. We first check the performance of the new method on simulated data and verify its correctness. We also extend the method for inference under models with variable gene-conversion and crossing-over rates and demonstrate its ability to identify recombination hotspots. Then, we apply the method to two empirical data sets that were sequenced in the telomeric regions of the X chromosome of Drosophila melanogaster. Our results indicate that gene conversion occurs more frequently than crossing over in the su-w and su-s gene sequences while the local rates of crossing over as inferred by our program are not low. The mean tract lengths for gene-conversion events are estimated to be ∼70 bp and 430 bp, respectively, for these data sets. Finally, we discuss ideas and optimizations for reducing the execution time of our algorithm.
doi:10.1534/genetics.111.130195
PMCID: PMC3189816  PMID: 21840857
24.  Distance measurements in model Bis-Gd(III) complexes with flexible “bridge”. Emulation of biological molecules having flexible structure with Gd(III) labels attached 
In this work, we continue to explore Gd(III) as a possible spin label for high field Double Electron Electron Resonance (DEER) based distance measurements in biological molecules with flexible geometry. For this purpose, a bis-Gd(III) complex with a flexible “bridge” was used as a model. The distances in the model were expected to be distributed in the range of 5-26 Å, allowing us to probe the shortest limits of accessible distances which were found to be as small as 13 Å. The upper distance limit for these labels was also evaluated and was found to be about 60 Å. Various pulse duration setups can result in apparent differences in the distribution function derived from DEER kinetics due to short distance limit variations. The advantages, such as the ability to perform measurements at cryogenic temperatures and high repetition rates simultaneously, the use of very short pumping and observation pulses without mutual interference, the lack of orientational selectivity, as well as the shortcomings, such as the limited mw operational frequency range and intrinsically smaller amplitude of oscillation related to dipolar interaction as compared with nitroxide spin labels are discussed. Most probably the use of nitroxide and Gd based labels for distance measurements will be complementary depending on the particulars of the problem and the availability of instrumentation.
doi:10.1016/j.jmr.2010.03.019
PMCID: PMC2885582  PMID: 20418132
Gd(III) spin labels; high-field DEER; Ka and W-bands
25.  Quantitative Detection of Enterotoxigenic Bacteroides fragilis Subtypes Isolated from Children with and without Diarrhea▿  
Journal of Clinical Microbiology  2010;49(1):416-418.
A rapid real-time PCR (RT-PCR) approach was developed to detect the bft gene subtypes in Bacteroides fragilis isolated from fecal samples. DNA obtained from diarrhea (110) and nondiarrhea (150) samples was evaluated. Subtype 1 was observed in 9 (8.2%) diarrhea and 7 (4.7%) nondiarrhea samples. Subtype 2 was not detected in any DNA samples, and subtype 3 was observed in only 1 diarrhea sample. The presence of the bft-1 gene did not show any statistically significant differences between the groups of children. This technique could be used to evaluate a possible correlation between disease and the presence of B. fragilis enterotoxin.
doi:10.1128/JCM.01556-10
PMCID: PMC3020434  PMID: 20980581

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