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1.  Nonplantigrade Foot Posture: A Constraint on Dinosaur Body Size 
PLoS ONE  2016;11(1):e0145716.
Dinosaurs had functionally digitigrade or sub-unguligrade foot postures. With their immediate ancestors, dinosaurs were the only terrestrial nonplantigrades during the Mesozoic. Extant terrestrial mammals have different optimal body sizes according to their foot posture (plantigrade, digitigrade, and unguligrade), yet the relationship of nonplantigrade foot posture with dinosaur body size has never been investigated, even though the body size of dinosaurs has been studied intensively. According to a large dataset presented in this study, the body sizes of all nonplantigrades (including nonvolant dinosaurs, nonvolant terrestrial birds, extant mammals, and extinct Nearctic mammals) are above 500 g, except for macroscelid mammals (i.e., elephant shrew), a few alvarezsauroid dinosaurs, and nondinosaur ornithodirans (i.e., the immediate ancestors of dinosaurs). When nonplantigrade tetrapods evolved from plantigrade ancestors, lineages with nonplantigrade foot posture exhibited a steady increase in body size following Cope’s rule. In contrast, contemporaneous plantigrade lineages exhibited no trend in body size evolution and were largely constrained to small body sizes. This evolutionary pattern of body size specific to foot posture occurred repeatedly during both the Mesozoic and the Cenozoic eras. Although disturbed by the end-Cretaceous extinction, species of mid to large body size have predominantly been nonplantigrade animals from the Jurassic until the present; conversely, species with small body size have been exclusively composed of plantigrades in the nonvolant terrestrial tetrapod fauna.
doi:10.1371/journal.pone.0145716
PMCID: PMC4720450  PMID: 26790003
2.  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant 
The Journal of Clinical Investigation  2013;123(11):4909-4917.
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
doi:10.1172/JCI69277
PMCID: PMC3809787  PMID: 24216480
3.  The stratum corneum comprises three layers with distinct metal-ion barrier properties 
Scientific Reports  2013;3:1731.
The stratum corneum (SC), the outermost barrier of mammalian bodies, consists of layers of cornified keratinocytes with intercellular spaces sealed with lipids. The insolubility of the SC has hampered in-depth analysis, and the SC has been considered a homogeneous barrier. Here, we applied time-of-flight secondary ion mass spectrometry to demonstrate that the SC consists of three layers with distinct properties. Arginine, a major component of filaggrin-derived natural moisturizing factors, was concentrated in the middle layer, suggesting that this layer functions in skin hydration. Topical application of metal ions revealed that the outer layer allowed their passive influx and efflux, while the middle and lower layers exhibited distinct barrier properties, depending on the metal tested. Notably, filaggrin deficiency abrogated the lower layer barrier, allowing specific metal ions to permeate viable layers. These findings elucidate the multi-layered barrier function of the SC and its defects in filaggrin-deficient atopic disease patients.
doi:10.1038/srep01731
PMCID: PMC3635058  PMID: 23615774
5.  Long-Term Culture of Astrocytes Attenuates the Readily Releasable Pool of Synaptic Vesicles 
PLoS ONE  2012;7(10):e48034.
The astrocyte is a major glial cell type of the brain, and plays key roles in the formation, maturation, stabilization and elimination of synapses. Thus, changes in astrocyte condition and age can influence information processing at synapses. However, whether and how aging astrocytes affect synaptic function and maturation have not yet been thoroughly investigated. Here, we show the effects of prolonged culture on the ability of astrocytes to induce synapse formation and to modify synaptic transmission, using cultured autaptic neurons. By 9 weeks in culture, astrocytes derived from the mouse cerebral cortex demonstrated increases in β-galactosidase activity and glial fibrillary acidic protein (GFAP) expression, both of which are characteristic of aging and glial activation in vitro. Autaptic hippocampal neurons plated on these aging astrocytes showed a smaller amount of evoked release of the excitatory neurotransmitter glutamate, and a lower frequency of miniature release of glutamate, both of which were attributable to a reduction in the pool of readily releasable synaptic vesicles. Other features of synaptogenesis and synaptic transmission were retained, for example the ability to induce structural synapses, the presynaptic release probability, the fraction of functional presynaptic nerve terminals, and the ability to recruit functional AMPA and NMDA glutamate receptors to synapses. Thus the presence of aging astrocytes affects the efficiency of synaptic transmission. Given that the pool of readily releasable vesicles is also small at immature synapses, our results are consistent with astrocytic aging leading to retarded synapse maturation.
doi:10.1371/journal.pone.0048034
PMCID: PMC3482238  PMID: 23110166
6.  PCM1 is recruited to the centrosome by the cooperative action of DISC1 and BBS4 and is a candidate for psychiatric illness 
Archives of general psychiatry  2008;65(9):996-1006.
Context
A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).
Objectives
To show that pericentriolar material-1 protein (PCM1) forms a complex at the centrosome with Disrupted-In-Schizophrenia-1 (DISC1) and Bardet-Biedl syndrome-4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in a SZ population.
Design
Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and co-immunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNAi. PCM1 gene was examined by sequencing 39 exons and flanking splice sites.
Setting and Patients
Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22, and 219 Caucasian controls.
Main Outcome Measures
Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; variant discovery in PCM1 in SZ patients.
Results
PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4, and are exacerbated by the concomitant suppression of both. Furtheremore, a nonsense mutation that segregates with schizophrenia-spectrum psychosis is found in one family.
Conclusion
Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases including SZ.
doi:10.1001/archpsyc.65.9.996
PMCID: PMC2727928  PMID: 18762586
7.  Sentan: A Novel Specific Component of the Apical Structure of Vertebrate Motile Cilia 
Molecular Biology of the Cell  2008;19(12):5338-5346.
Human respiratory and oviductal cilia have specific apical structures characterized by a narrowed distal portion and a ciliary crown. These structures are conserved among vertebrates that have air respiration systems; however, the molecular components of these structures have not been defined, and their functions are unknown. To identify the molecular component(s) of the cilia apical structure, we screened EST libraries to identify gene(s) that are exclusively expressed in ciliated tissues, are transcriptionally up-regulated during in vitro ciliogenesis, and are not expressed in testis (because sperm flagella have no such apical structures). One of the identified gene products, named sentan, was localized to the distal tip region of motile cilia. Using anti-sentan polyclonal antibodies and electron microscopy, sentan was shown to localize exclusively to the bridging structure between the cell membrane and peripheral singlet microtubules, which specifically exists in the narrowed distal portion of cilia. Exogenously expressed sentan showed affinity for the membrane protrusions, and a protein–lipid binding assay revealed that sentan bound to phosphatidylserine. These findings suggest that sentan is the first molecular component of the ciliary tip to bridge the cell membrane and peripheral singlet microtubules, making the distal portion of the cilia narrow and stiff to allow for better airway clearance or ovum transport.
doi:10.1091/mbc.E08-07-0691
PMCID: PMC2592648  PMID: 18829862
8.  Centriolar Satellites 
The Journal of Cell Biology  1999;147(5):969-980.
We identified Xenopus pericentriolar material-1 (PCM-1), which had been reported to constitute pericentriolar material, cloned its cDNA, and generated a specific pAb against this molecule. Immunolabeling revealed that PCM-1 was not a pericentriolar material protein, but a specific component of centriolar satellites, morphologically characterized as electron-dense granules, ∼70–100 nm in diameter, scattered around centrosomes. Using a GFP fusion protein with PCM-1, we found that PCM-1–containing centriolar satellites moved along microtubules toward their minus ends, i.e., toward centrosomes, in live cells, as well as in vitro reconstituted asters. These findings defined centriolar satellites at the molecular level, and explained their pericentriolar localization. Next, to understand the relationship between centriolar satellites and centriolar replication, we examined the expression and subcellular localization of PCM-1 in ciliated epithelial cells during ciliogenesis. When ciliogenesis was induced in mouse nasal respiratory epithelial cells, PCM-1 immunofluorescence was markedly elevated at the apical cytoplasm. At the electron microscopic level, anti–PCM-1 pAb exclusively labeled fibrous granules, but not deuterosomes, both of which have been suggested to play central roles in centriolar replication in ciliogenesis. These findings suggested that centriolar satellites and fibrous granules are identical novel nonmembranous organelles containing PCM-1, which may play some important role(s) in centriolar replication.
PMCID: PMC2169353  PMID: 10579718
centriole; centriolar satellites; fibrous granule; pericentriolar material-1; ciliogenesis
9.  Indole and (E)-2-hexenal, phytochemical potentiators of polymyxins against Pseudomonas aeruginosa and Escherichia coli. 
Combinations of polymyxins and phytochemicals were tested for antimicrobial activity against two gram-negative bacteria. Various degrees of potentiation were found against Pseudomonas aeruginosa and Escherichia coli with (E)-2-hexenal and indole. Three-compound combinations were found to further increase the activity of polymyxin B sulfate and colistin methanesulfonate against both bacteria. Combinations with colistin against P. aeruginosa resulted in the highest degree of potentiation, with a 512-fold increase in colistin antimicrobial activity. These results indicate the potential efficacy of phytochemical combinations with antibiotics to enhance total biological activity.
PMCID: PMC163346  PMID: 8726016
10.  Residential Segregation and Diabetes Risk among Latinos 
Ethnicity & Disease  null;25(4):451-458.
Objective
To examine whether residence in ethnically segregated metropolitan areas is associated with increased diabetes risk for Latinos in the United States.
Methods
Population data from the 2005 Behavioral Risk Factor Surveillance System and the 2005 American Community Survey were used to determine whether higher levels of Latino-White segregation across metropolitan statistical areas (MSAs) in the United States is associated with increased diabetes risk among Latinos (n=7462).
Results
No significant relationship (P<.05) between levels of segregation and diabetes risk was observed.
Conclusion
The research literature examining the impact of residential segregation on health outcomes remains equivocal for Latinos.
doi:10.18865/ed.25.4.451
PMCID: PMC4671436  PMID: 26672728
Segregation; Diabetes; Latinos
11.  Genome-wide association study of leukotriene modifier response in asthma 
The Pharmacogenomics Journal  2015;16(2):151-157.
Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene–environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10−08); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10−07). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.
doi:10.1038/tpj.2015.34
PMCID: PMC4668236  PMID: 26031901
12.  Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes 
Annals of the Rheumatic Diseases  2015;75(4):652-659.
Objective
Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.
Methods
A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.
Results
Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion).
Conclusions
Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.
doi:10.1136/annrheumdis-2014-206191
PMCID: PMC4819613  PMID: 25646370
Gout; Arthritis; Gene Polymorphism
13.  Suppressing molecular vibrations in organic semiconductors by inducing strain 
Nature Communications  2016;7:11156.
Organic molecular semiconductors are solution processable, enabling the growth of large-area single-crystal semiconductors. Improving the performance of organic semiconductor devices by increasing the charge mobility is an ongoing quest, which calls for novel molecular and material design, and improved processing conditions. Here we show a method to increase the charge mobility in organic single-crystal field-effect transistors, by taking advantage of the inherent softness of organic semiconductors. We compress the crystal lattice uniaxially by bending the flexible devices, leading to an improved charge transport. The mobility increases from 9.7 to 16.5 cm2 V−1 s−1 by 70% under 3% strain. In-depth analysis indicates that compressing the crystal structure directly restricts the vibration of the molecules, thus suppresses dynamic disorder, a unique mechanism in organic semiconductors. Since strain can be easily induced during the fabrication process, we expect our method to be exploited to build high-performance organic devices.
The mobility of organic semiconductors can be tuned by modifying their chemical composition or crystalline properties. Here, the authors show that bending organic single crystals increases their field effect transistor mobility due to restrained molecular vibrations and subsequently reduced dynamic disorder.
doi:10.1038/ncomms11156
PMCID: PMC4822010  PMID: 27040501
14.  The transfer of titanium dioxide nanoparticles from the host plant to butterfly larvae through a food chain 
Scientific Reports  2016;6:23819.
This study aimed to examine the transfer of nanoparticles within a terrestrial food chain. Oviposited eggs of the swallowtail butterfly (Atrophaneura alcinous) were hatched on the leaves of the host plant (Aristolochia debilis), and the root stock and root hairs were submerged in a suspension of 10 μg/ml titanium dioxide nanoparticles (TiO2-NPs) in a 100 ml bottle. The presence of TiO2-NPs in the veins of the leaves was confirmed by X-ray analytical microscopy (X-ray AM). The hatched 1st instar larvae fed on the leaves to moult into 2nd instar larvae. Small agglomerates of TiO2-NPs less than 150 nm in diameter were identified in the vascular tissue of the exposed plant, the midgut and the excreta of the larvae by transmission electron microscopy. The image of Ti elemental mapping by X-ray AM was analysed with the quantitative spatial information mapping (QSIM) technique. The results demonstrated that TiO2-NPs were transferred from the plant to the larvae and they were disseminated throughout the environment via larval excreta.
doi:10.1038/srep23819
PMCID: PMC4814876  PMID: 27030539
15.  A Case of Nonunion Avulsion Fracture of the Anterior Tibial Eminence 
Case Reports in Orthopedics  2016;2016:9648473.
Avulsion fracture of the anterior tibial eminence is an uncommon injury. If bone union does not occur, knee extension will be limited by impingement of the avulsed fragment and knee instability will be induced by dysfunction of the anterior cruciate ligament (ACL). This report describes a 55-year-old woman who experienced an avulsion fracture of the right anterior tibial eminence during recreational skiing. Sixteen months later, she presented at our hospital with limitation of right knee extension. Plain radiography showed nonunion of the avulsion fracture region, and arthroscopy showed that the avulsed fragment impinged the femoral intercondylar notch during knee extension. The anterior region of the bony fragment was debrided arthroscopically until the knee could be extended completely. There was no subsequent instability, and the patient was able to climb a mountain 6 months after surgery. These findings indicate that arthroscopic debridement of an avulsed fragment for nonunion of an avulsion fracture of the anterior tibial eminence is a minimally invasive and effective treatment for middle-aged and elderly patients with a low level of sports activity.
doi:10.1155/2016/9648473
PMCID: PMC4828548  PMID: 27119035
16.  Development of an HPLC Method with an ODS Column to Determine Low Levels of Aspartame Diastereomers in Aspartame 
PLoS ONE  2016;11(3):e0152174.
α-L-Aspartyl-D-phenylalanine methyl ester (L, D-APM) and α-D-aspartyl-L-phenylalanine methyl ester (D, L-APM) are diastereomers of aspartame (N-L-α-Aspartyl-L-phenylalanine-1-methyl ester, L, L-APM). The Joint FAO/WHO Expert Committee on Food Additives has set 0.04 wt% as the maximum permitted level of the sum of L, D-APM and D, L-APM in commercially available L, L-APM. In this study, we developed and validated a simple high-performance liquid chromatography (HPLC) method using an ODS column to determine L, D-APM and D, L-APM in L, L-APM. The limits of detection and quantification, respectively, of L, D-APM and D, L-APM were found to be 0.0012 wt% and 0.004 wt%. This method gave excellent accuracy, repeatability, and reproducibility in a recovery test performed on five different days. Moreover, the method was successfully applied to the determination of these diastereomers in commercial L, L-APM samples. Thus, the developed method is a simple, useful, and practical tool for determining L, D-APM and D, L-APM levels in L, L-APM.
doi:10.1371/journal.pone.0152174
PMCID: PMC4807810  PMID: 27015640
17.  Efficacy of multimodal treatment for leptomeningeal metastases in a lung cancer harboring an EGFR mutation 
OncoTargets and therapy  2016;9:1753-1758.
For lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the advent of EGFR tyrosine kinase inhibitors (TKIs) has prolonged survival rates. Even though disease sites have been well controlled by EGFR-TKIs, some patients develop carcinomatous meningitis, which reduces their quality of life drastically. Although multidisciplinary approaches have improved patient survival and quality of life, the outcomes are not yet satisfactory. We report the case of a 54-year-old Japanese woman diagnosed with leptomeningeal metastases (LM) from a lung adenocarcinoma harboring an EGFR exon 21 L858R point mutation. She was treated with gefitinib for 2 months, and symptoms of LM emerged during the treatment period. Although the treatment was switched to erlotinib, disturbance of consciousness worsened because of progressive hydrocephalus. Because all extracranial lesions remained responsive to treatment, and the exon 20 T790M point mutation was not detected in cerebrospinal fluid, we placed a ventriculoperitoneal shunt. The patient’s disturbed consciousness improved dramatically after the shunt was placed; however, the optic and auditory nerve impairments due to direct invasion of LM lesions into nerve canals persisted. Administration of bevacizumab subsequent to whole-brain radiotherapy reduced the cranial nerve impairment, and the patient survived for 10 months. In conclusion, a combination of erlotinib and ventriculoperitoneal shunt was effective for hydrocephalus, and the immediate administration of additional therapies, including bevacizumab and radiation therapy, was useful in a patient suffering from LM.
doi:10.2147/OTT.S95721
PMCID: PMC4809332  PMID: 27042125
bevacizumab; erlotinib; ventriculoperitoneal shunt; leptomeningeal metastases; lung cancer; EGFR
18.  Identification of Associations between Bacterioplankton and Photosynthetic Picoeukaryotes in Coastal Waters 
Photosynthetic picoeukaryotes are significant contributors to marine primary productivity. Associations between marine bacterioplankton and picoeukaryotes frequently occur and can have large biogeochemical impacts. We used flow cytometry to sort cells from seawater to identify non-eukaryotic phylotypes that are associated with photosynthetic picoeukaryotes. Samples were collected at the Santa Cruz wharf on Monterey Bay, CA, USA during summer and fall, 2014. The phylogeny of associated microbes was assessed through 16S rRNA gene amplicon clone and Illumina MiSeq libraries. The most frequently detected bacterioplankton phyla within the photosynthetic picoeukaryote sorts were Proteobacteria (Alphaproteobacteria and Gammaproteobacteria) and Bacteroidetes. Intriguingly, the presence of free-living bacterial genera in the photosynthetic picoeukaryote sorts could suggest that some of the photosynthetic picoeukaryotes were mixotrophs. However, the occurrence of bacterial sequences, which were not prevalent in the corresponding bulk seawater samples, indicates that there was also a selection for specific OTUs in association with photosynthetic picoeukaryotes suggesting specific functional associations. The results show that diverse bacterial phylotypes are found in association with photosynthetic picoeukaryotes. Taxonomic identification of these associations is a prerequisite for further characterizing and to elucidate their metabolic pathways and ecological functions.
doi:10.3389/fmicb.2016.00339
PMCID: PMC4834442  PMID: 27148165
microbial associations; bacterivory; flow cytometry; photosynthetic picoeukaryotes; symbiosis
19.  Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci 
He, Meian | Xu, Min | Zhang, Ben | Liang, Jun | Chen, Peng | Lee, Jong-Young | Johnson, Todd A. | Li, Huaixing | Yang, Xiaobo | Dai, Juncheng | Liang, Liming | Gui, Lixuan | Qi, Qibin | Huang, Jinyan | Li, Yanping | Adair, Linda S. | Aung, Tin | Cai, Qiuyin | Cheng, Ching-Yu | Cho, Myeong-Chan | Cho, Yoon Shin | Chu, Minjie | Cui, Bin | Gao, Yu-Tang | Go, Min Jin | Gu, Dongfeng | Gu, Weiqiong | Guo, Huan | Hao, Yongchen | Hong, Jie | Hu, Zhibin | Hu, Yanling | Huang, Jianfeng | Hwang, Joo-Yeon | Ikram, Mohammad Kamran | Jin, Guangfu | Kang, Dae-Hee | Khor, Chiea Chuen | Kim, Bong-Jo | Kim, Hung Tae | Kubo, Michiaki | Lee, Jeannette | Lee, Juyoung | Lee, Nanette R. | Li, Ruoying | Li, Jun | Liu, JianJun | Longe, Jirong | Lu, Wei | Lu, Xiangfeng | Miao, Xiaoping | Okada, Yukinori | Ong, Rick Twee-Hee | Qiu, Gaokun | Seielstad, Mark | Sim, Xueling | Song, Huaidong | Takeuchi, Fumihiko | Tanaka, Toshihiro | Taylor, Phil R. | Wang, Laiyuan | Wang, Weiqing | Wang, Yiqin | Wu, Chen | Wu, Ying | Xiang, Yong-Bing | Yamamoto, Ken | Yang, Handong | Liao, Ming | Yokota, Mitsuhiro | Young, Terri | Zhang, Xiaomin | Kato, Norihiro | Wang, Qing K. | Zheng, Wei | Hu, Frank B. | Lin, Dongxin | Shen, Hongbing | Teo, Yik Ying | Mo, Zengnan | Wong, Tien Yin | Lin, Xu | Mohlke, Karen L. | Ning, Guang | Tsunoda, Tatsuhiko | Han, Bok-Ghee | Shu, Xiao-Ou | Tai, E. Shyong | Wu, Tangchun | Qi, Lu
Human Molecular Genetics  2014;24(6):1791-1800.
Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10−8, together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.
doi:10.1093/hmg/ddu583
PMCID: PMC4351379  PMID: 25429064
20.  The design and implementation of the immune epitope database and analysis resource 
Immunogenetics  2005;57(5):326-336.
Epitopes are defined as parts of antigens interacting with receptors of the immune system. Knowledge about their intrinsic structure and how they affect the immune response is required to continue development of techniques that detect, monitor, and fight diseases. Their scientific importance is reflected in the vast amount of epitope-related information gathered, ranging from interactions between epitopes and major histocompatibility complex molecules determined by X-ray crystallography to clinical studies analyzing correlates of protection for epitope based vaccines. Our goal is to provide a central resource capable of capturing this information, allowing users to access and connect realms of knowledge that are currently separated and difficult to access. Here, we portray a new initiative, “The Immune Epitope Database and Analysis Resource.” We describe how we plan to capture, structure, and store this information, what query interfaces we will make available to the public, and what additional predictive and analytical tools we will provide.
doi:10.1007/s00251-005-0803-5
PMCID: PMC4780685  PMID: 15895191
Epitope; Antibody; MHC; Database
21.  A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese 
Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A>G, P=2.60 × 10−9, odds ratio (OR)=0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A>C, P=3.84 × 10−9, OR=0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A>G: P=1.14 × 10−14, OR=1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci.
doi:10.1038/ejhg.2014.110
PMCID: PMC4326706  PMID: 24916648
22.  The Role of Smoking Status on the Progression-Free Survival of Non-Small Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First-Line EGFR Tyrosine Kinase Inhibitor Versus Platinum Doublet Chemotherapy: A Meta-Analysis of Prospective Randomized Trials 
The Oncologist  2015;20(3):307-315.
This meta-analysis was carried out to ascertain the role of smoking status in influencing progression-free survival (PFS) outcomes in patients with the two common activating epidermal growth factor receptor mutations (EGFRm) who received first-line EGFR tyrosine kinase inhibitors (TKIs) in comparison with platinum-doublet chemotherapy. EGFRm non-small-cell lung cancer patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy regardless of smoking status; however, PFS benefit is significantly better in never smokers by metaregression analysis.
Background.
Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS).
Methods.
A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis.
Results.
Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE), 83.7% were Asians, and 30.0% were ever-smokers. An equal percentage of ever-smokers received doublet chemotherapy (30.2%) or EGFR TKI (30.0%). The pooled HR for PFS was 0.29 (95% confidence interval [CI]: 0.21–0.39) for never-smokers and 0.54 (95% CI: 0.38–0.76) for ever-smokers (p < .007 by metaregression). The pooled PFS HR for exon 19 deletion was 0.25 (95% CI: 0.19–0.31) and 0.44 for exon 21 substitution (95% CI: 0.34–0.57) (p < .001 by metaregression analysis). The pooled PFS HR was 0.33 (95% CI: 0.24–0.46) for Asians and 0.48 for non-Asians (95% CI: 0.28–0.84) (p = .261 by metaregression analysis).
Conclusion.
EGFRm NSCLC patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy as first-line treatment regardless of smoking status; however, PFS benefit is significantly better in never-smokers by metaregression analysis.
doi:10.1634/theoncologist.2014-0285
PMCID: PMC4350797  PMID: 25657199
Meta-analysis; EGFR TKIs; Smoking status; EGFR mutant non-small cell lung cancer; Gefitinib; Erlotinib; Afatinib
23.  Effect of refractive error on visual evoked potentials with pattern stimulation in dogs 
The purpose of this study was to investigate the effects of refractive error on canine visual evoked potentials with pattern stimulation (P-VEP). Six normal beagle dogs were used. The refractive power of the recorded eyes was measured by skiascopy. The refractive power was corrected to −4 diopters (D) to +2 D using contact lens. P-VEP was recorded at each refractive power. The stimulus pattern size and distance were 50.3 arc-min and 50 cm. The P100 appeared at almost 100 msec at −2 D (at which the stimulus monitor was in focus). There was significant prolongation of the P100 implicit time at −4, −3, 0 and +1 D compared with −2 D, respectively. We concluded that the refractive power of the eye affected the P100 implicit time in canine P-VEP recording.
doi:10.1292/jvms.15-0227
PMCID: PMC4829526  PMID: 26655769
canine; P100 implicit time; pattern stimulated visual evoked potential; refractive power
24.  A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site 
Scientific Reports  2016;6:22409.
The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells.
doi:10.1038/srep22409
PMCID: PMC4772627  PMID: 26926165
25.  Current status in remnant gastric cancer after distal gastrectomy 
World Journal of Gastroenterology  2016;22(8):2424-2433.
Remnant gastric cancer (RGC) and gastric stump cancer after distal gastrectomy (DG) are recognized as the same clinical entity. In this review, the current knowledges as well as the non-settled issues of RGC are presented. Duodenogastric reflux and denervation of the gastric mucosa are considered as the two main factors responsible for the development of RGC after benign disease. On the other hand, some precancerous circumstances which already have existed at the time of initial surgery, such as atrophic gastritis and intestinal metaplasia, are the main factors associated with RGC after gastric cancer. Although eradication of Helicobacter pylori (H. pylori) in remnant stomach is promising, it is still uncertain whether it can reduce the risk of carcinogenesis. Periodic endoscopic surveillance after DG was reported useful in detecting RGC at an early stage, which offers a chance to undergo minimally invasive endoscopic treatment or laparoscopic surgery and leads to an improved prognosis in RGC patients. Future challenges may be expected to elucidate the benefit of eradication of H. pylori in the remnant stomach if it could reduce the risk for RGC, to build an optimal endoscopic surveillance strategy after DG by stratifying the risk for development of RGC, and to develop a specific staging system for RGC for the standardization of the treatment by prospecting the prognosis.
doi:10.3748/wjg.v22.i8.2424
PMCID: PMC4768189  PMID: 26937131
Remnant gastric cancer; Helicobacter pylori; Endoscopic treatment; Surveillance; Laparoscopic surgery

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