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1.  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.
PMCID: PMC3809787  PMID: 24216480
2.  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.
PMCID: PMC3635058  PMID: 23615774
4.  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.
PMCID: PMC3482238  PMID: 23110166
5.  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.
A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).
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.
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.
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.
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.
PMCID: PMC2727928  PMID: 18762586
6.  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.
PMCID: PMC2592648  PMID: 18829862
7.  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
8.  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
9.  Eyebrow Reconstruction Using a Composite Skin Graft from Sideburns 
Supplemental Digital Content is available in the text.
Wide resection of malignant skin tumors in the upper orbital region often results in soft-tissue defects involving the eyebrow. We used composite skin grafts from the area around the sideburns for 1-stage reconstruction of skin and eyebrow defects. The results were aesthetically satisfying because the hair and shape of these regions were similar to those of the original eyebrow, and donor-site closure was easy with inconspicuous scar. The survival of full-thickness skin graft area of composite grafts from sideburn facilitates revascularization of thicker hair follicles in the graft and allows safe, natural eyebrow reconstruction.
PMCID: PMC4323394
10.  Art Expertise Reduces Influence of Visual Salience on Fixation in Viewing Abstract-Paintings 
PLoS ONE  2015;10(2):e0117696.
When viewing a painting, artists perceive more information from the painting on the basis of their experience and knowledge than art novices do. This difference can be reflected in eye scan paths during viewing of paintings. Distributions of scan paths of artists are different from those of novices even when the paintings contain no figurative object (i.e. abstract paintings). There are two possible explanations for this difference of scan paths. One is that artists have high sensitivity to high-level features such as textures and composition of colors and therefore their fixations are more driven by such features compared with novices. The other is that fixations of artists are more attracted by salient features than those of novices and the fixations are driven by low-level features. To test these, we measured eye fixations of artists and novices during the free viewing of various abstract paintings and compared the distribution of their fixations for each painting with a topological attentional map that quantifies the conspicuity of low-level features in the painting (i.e. saliency map). We found that the fixation distribution of artists was more distinguishable from the saliency map than that of novices. This difference indicates that fixations of artists are less driven by low-level features than those of novices. Our result suggests that artists may extract visual information from paintings based on high-level features. This ability of artists may be associated with artists’ deep aesthetic appreciation of paintings.
PMCID: PMC4319974  PMID: 25658327
11.  Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1 
Nature genetics  2014;46(8):886-890.
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
PMCID: PMC4127632  PMID: 25038754
12.  Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults 
Journal of Virology  2014;88(15):8629-8639.
Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation.
IMPORTANCE Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong “legacy” impact.
PMCID: PMC4135944  PMID: 24850730
13.  A hierarchical Bayesian model to estimate the unobservable predation rate on sawfly cocoons by small mammals 
Ecology and Evolution  2015;5(3):733-742.
Predation by small mammals has been reported as an important mortality factor for the cocoons of sawfly species. However, it is difficult to provide an accurate estimate of newly spun cocoons and subsequent predation rates by small mammals for several reasons. First, all larvae do not spin cocoons at the same time. Second, cocoons are exposed to small mammal predation immediately after being spun. Third, the cocoons of the current generation are indistinguishable from those of the previous generation. We developed a hierarchical Bayesian model to estimate these values from annual one-time soil sampling datasets. To apply this model to an actual data set, field surveys were conducted in eight stands of larch plantations in central Hokkaido (Japan) from 2009 to 2012. Ten 0.04-m2 soil samples were annually collected from each site in mid-October. The abundance of unopened cocoons (I), cocoons emptied by small-mammal predation (M), and empty cocoons caused by something other than small-mammal predation (H) were determined. The abundance of newly spun cocoons, the predation rate by small mammals before and after cocoon sampling, and the annual rate of empty cocoons that remained were estimated. A posterior predictive check yielded Bayesian P-values of 0.54, 0.48, and 0.07 for I, M, and H, respectively. Estimated predation rates showed a significant positive correlation with the number of trap captures of small mammals. Estimates of the number of newly spun cocoons had a significant positive correlation with defoliation intensity. These results indicate that our model showed an acceptable fit, with reasonable estimates. Our model is expected to be widely applicable to all hymenopteran and lepidopteran insects that spin cocoons in soil.
PMCID: PMC4328775
Apodemus argenteus; Apodemus speciosus; cocoon dynamic models; Myodes rufocanus bedfordiae; predation rate estimation
15.  Porous coordination polymers with ubiquitous and biocompatible metals and a neutral bridging ligand 
Nature Communications  2015;6:5851.
The design of inexpensive and less toxic porous coordination polymers (PCPs) that show selective adsorption or high adsorption capacity is a critical issue in research on applicable porous materials. Although use of Group II magnesium(II) and calcium(II) ions as building blocks could provide cheaper materials and lead to enhanced biocompatibility, examples of magnesium(II) and calcium(II) PCPs are extremely limited compared with commonly used transition metal ones, because neutral bridging ligands have not been available for magnesium(II) and calcium(II) ions. Here we report a rationally designed neutral and charge-polarized bridging ligand as a new partner for magnesium(II) and calcium(II) ions. The three-dimensional magnesium(II) and calcium(II) PCPs synthesized using such a neutral ligand are stable and show selective adsorption and separation of carbon dioxide over methane at ambient temperature. This synthetic approach allows the structural diversification of Group II magnesium(II) and calcium(II) PCPs.
Inexpensive porous materials synthesized from Group II metals may be useful for industrial applications. Here, the authors demonstrate that neutral bridging ligands can be used for the synthesis of magnesium(II) and calcium(II) porous coordination polymers.
PMCID: PMC4309420  PMID: 25592677
16.  Laparoscopy-assisted Total Gastrectomy: A Simplified Approach 
International Surgery  2014;99(1):79-85.
Laparoscopy-assisted total gastrectomy (LATG), esophagojejunostomy is an effective but difficult procedure to perform. We describe a simple modification that substantially facilitates insertion of the anvil into the esophagus and avoids oral injuries and complications. After mobilization of the stomach and esophagus, a semicircumferential esophagotomy is made at the anterior esophageal wall. An OrVil anvil (Orvil, Covidien, Norwalk, CT, USA) is delivered laparoscopically and secured with a POLYSORB (Covidien) suture to the esophagus. The suture is advanced anteriorly so that the center rod penetrates the esophageal wall. The esophagus is transected with the stapler at this point. A circular-stapled esophagojejunostomy is then performed using the hemidouble stapling technique. Laparoscopy-assisted total gastrectomies were performed for 40 patients with gastric cancers (T1N0M0). All procedures were completed laparoscopically without any complications. The time required to place the anvil averaged 5 min compared with 9 min reported by others. There were no major complications or mortality in this series. The major advantage of this technique is that circular stapling is much easier than linear stapling, allowing surgeons without advanced surgical skills in LATG to perform the procedure effectively and safely.
PMCID: PMC3897347  PMID: 24444275
Anvil; Esophagojejunostomy; Gastrectomy; Gastric cancer; Laparoscopy
17.  Gastric Metastasis From Renal Cell Carcinoma With Gastrointestinal Bleeding: A Case Report and Review of the Literature 
International Surgery  2014;99(1):86-90.
A 61-year-old man presented to our hospital with hypercalcemia and elevated C reactive protein (CRP). Evaluation revealed renal cell carcinoma (RCC) with metastasis to lung, bone, and brain. He underwent partial resection of the right kidney and a left nephrectomy. Histopathologic findings of resected tumors were consistent with clear cell RCC. Whole-brain irradiation was performed for management of brain metastasis. Postoperatively, he was treated with molecularly targeted therapy using a mammalian target of rapamycin inhibitor. Approximately 14 months later, he suffered an episode of upper gastrointestinal bleeding with secondary anemia and melena. Upper gastrointestinal endoscopy revealed a distinctly protruding lesion in the gastric body. Biopsy of the gastric lesion showed metastatic clear cell RCC. He underwent partial gastrectomy. His postoperative course was uneventful. However, 4 months after surgery, he died from brain metastasis. Metastatic RCC to the stomach, although rare, should be suspected in any patient with a history of RCC who presents with gastrointestinal symptoms.
PMCID: PMC3897349  PMID: 24444276
Gastric metastasis; Renal cell carcinoma; Metastatic tumor
18.  Portal Vein Stenting to Treat Portal Vein Stenosis in a Patient With Malignant Tumor and Gastrointestinal Bleeding 
International Surgery  2014;99(1):91-95.
This report describes the successful use of portal venous stent placement for a patient with recurrent melena secondary to jejunal varices that developed after subtotal stomach preserved pancreatoduodenectomy (SSPPD). A 67-year-old man was admitted to our hospital with tarry stool and severe anemia at 2 years after SSPPD for carcinoma of the head of the pancreas. Abdominal computed tomography examination showed severe stenosis of the extrahepatic portal vein caused by local recurrence and showed an intensely enhanced jejunal wall at the choledochojejunostomy. Gastrointestinal bleeding scintigraphy also revealed active bleeding near the choledochojejunostomy. Based on these findings, jejunal varices resulting from portal vein stenosis were suspected as the cause of the melena. Portal vein stenting and balloon dilation was performed via the ileocecal vein after laparotomy. Coiling of the jejunal varices and sclerotherapy of the dilate postgastric vein with 5% ethanolamine oleate with iopamidol was performed. After portal stent placement, the patient was able to lead a normal life without gastrointestinal hemorrhage. However, he died 7 months later due to liver metastasis.
PMCID: PMC3897350  PMID: 24444277
Portal vein stenosis; Portal vein stent; Pancreatoduodenectomy
19.  Generation of Functional Insulin-Producing Cells From Mouse Embryonic Stem Cells Through 804G Cell-Derived Extracellular Matrix and Protein Transduction of Transcription Factors 
This study tried to establish an effective method of generating pancreatic β cells. Transduction of three transcription factors (Pdx1, NeuroD, and MafA) important to pancreatic β-cell development induced the differentiation of mouse embryonic stem and mouse induced pluripotent stem cells into insulin-producing cells. Results suggest the direct delivery of recombinant proteins and treatment with laminin-5-rich extracellular matrix to be useful for the generation of insulin-producing cells.
Embryonic stem (ES) and induced pluripotent stem (iPS) cells have potential applications to regenerative medicine for diabetes; however, a useful and safe way to generate pancreatic β cells has not been developed. In this study, we tried to establish an effective method of differentiation through the protein transduction of three transcription factors (Pdx1, NeuroD, and MafA) important to pancreatic β cell development. The method poses no risk of unexpected genetic modifications in target cells. Transduction of the three proteins induced the differentiation of mouse ES and mouse iPS cells into insulin-producing cells. Furthermore, a laminin-5-rich extracellular matrix efficiently induced differentiation under feeder-free conditions. Cell differentiation was confirmed with the expression of the insulin 1 gene in addition to marker genes in pancreatic β cells, the differentiated cells secreted glucose-responsive C-peptide, and their transplantation restored normoglycemia in diabetic mice. Moreover, Pdx1 protein transduction had facilitative effects on differentiation into pancreatic endocrine progenitors from human iPS cells. These results suggest the direct delivery of recombinant proteins and treatment with laminin-5-rich extracellular matrix to be useful for the generation of insulin-producing cells.
PMCID: PMC3902286  PMID: 24292793
Diabetes; Embryonic stem cells; Pancreatic differentiation; Transcription factors; Induced pluripotent stem cells
20.  Hydrostatic Pressure Influences HIF-2 Alpha Expression in Chondrocytes 
Hypoxia-inducible factor (HIF)-2α is considered to play a major role in the progression of osteoarthritis. Recently, it was reported that pressure amplitude influences HIF-2α expression in murine endothelial cells. We examined whether hydrostatic pressure is involved in expression of HIF-2α in articular chondrocytes. Chondrocytes were cultured and stimulated by inflammation or hydrostatic pressure of 0, 5, 10, or 50 MPa. After stimulation, heat shock protein (HSP) 70, HIF-2α, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-13, MMP-3, and vascular endothelial growth factor (VEGF) gene expression were evaluated. The levels of all gene expression were increased by inflammatory stress. When chondrocytes were exposed to a hydrostatic pressure of 5 MPa, HIF-2α, MMP-13, and MMP-3 gene expression increased significantly although those of HSP70 and NF-κB were not significantly different from the control group. In contrast, HIF-2α gene expression did not increase under a hydrostatic pressure of 50 MPa although HSP70 and NF-κB expression increased significantly compared to control. We considered that hydrostatic pressure of 5 MPa could regulate HIF-2α independent of NF-κB, because the level of HIF-2α gene expression increased significantly without upregulation of NF-κB expression at 5 MPa. Hydrostatic pressure may influence cartilage degeneration, inducing MMP-13 and MMP-3 expression through HIF-2α.
PMCID: PMC4307289  PMID: 25569085
hypoxia inducible factor (HIF)-2α; hydrostatic pressure; chondrocytes; hypertrophic differentiation; osteoarthritis; cartilage degeneration; inflammation
21.  Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers 
The Journal of Experimental Medicine  2014;211(7):1297-1305.
S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.
Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. We report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared with T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.
PMCID: PMC4076581  PMID: 24913235
22.  Integrated Analysis of Whole Genome and Transcriptome Sequencing Reveals Diverse Transcriptomic Aberrations Driven by Somatic Genomic Changes in Liver Cancers 
PLoS ONE  2014;9(12):e114263.
Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.
PMCID: PMC4272259  PMID: 25526364
23.  Synthesis of C11-Desmethoxy Soraphen A1α: A natural product analog that inhibits acetyl-CoA carboxylase 
ACS medicinal chemistry letters  2013;4(12):1244-1248.
A synthesis of C11-desmethoxy soraphen A1α is described that proceeds in just 14 steps from readily available starting materials. This natural product analog was identified as a target of interest in a program aimed at identifying novel natural product-inspired inhibitors of acetyl-CoA carboxylase (ACC) as potential anticancer therapeutics. While describing the most efficient synthesis of a soraphen A1α analog (total syntheses of the natural product have been reported that proceed in 25 to ≥40 linear steps), we also present data supporting the conclusion that C11-heteroatom functionality is a beneficial but unnecessary structural characteristic of soraphen A1α analogs for inhibiting ACC.
PMCID: PMC3951358  PMID: 24639892
Soraphen A; function-oriented synthesis; acetyl-CoA carboxylase (ACC); polyketide synthesis
24.  Synthesis of C11-Desmethoxy Soraphen A1α: A Natural Product Analogue That Inhibits Acetyl-CoA Carboxylase 
ACS Medicinal Chemistry Letters  2013;4(12):1244-1248.
A synthesis of C11-desmethoxy soraphen A1α is described that proceeds in just 14 steps from readily available starting materials. This natural product analogue was identified as a target of interest in a program aimed at identifying novel natural product-inspired inhibitors of acetyl-CoA carboxylase (ACC) as potential anticancer therapeutics. While describing the most efficient synthesis of a soraphen A1α analogue (total syntheses of the natural product have been reported that proceed in 25 to ≥40 linear steps), we also present data supporting the conclusion that C11-heteroatom functionality is a beneficial but unnecessary structural characteristic of soraphen A1α analogues for inhibiting ACC.
PMCID: PMC3951358  PMID: 24639892
Soraphen A; function-oriented synthesis; acetyl-CoA carboxylase (ACC); polyketide synthesis
25.  Plant Omics Data Center: An Integrated Web Repository for Interspecies Gene Expression Networks with NLP-Based Curation 
Plant and Cell Physiology  2014;56(1):e9.
Comprehensive integration of large-scale omics resources such as genomes, transcriptomes and metabolomes will provide deeper insights into broader aspects of molecular biology. For better understanding of plant biology, we aim to construct a next-generation sequencing (NGS)-derived gene expression network (GEN) repository for a broad range of plant species. So far we have incorporated information about 745 high-quality mRNA sequencing (mRNA-Seq) samples from eight plant species (Arabidopsis thaliana, Oryza sativa, Solanum lycopersicum, Sorghum bicolor, Vitis vinifera, Solanum tuberosum, Medicago truncatula and Glycine max) from the public short read archive, digitally profiled the entire set of gene expression profiles, and drawn GENs by using correspondence analysis (CA) to take advantage of gene expression similarities. In order to understand the evolutionary significance of the GENs from multiple species, they were linked according to the orthology of each node (gene) among species. In addition to other gene expression information, functional annotation of the genes will facilitate biological comprehension. Currently we are improving the given gene annotations with natural language processing (NLP) techniques and manual curation. Here we introduce the current status of our analyses and the web database, PODC (Plant Omics Data Center;, now open to the public, providing GENs, functional annotations and additional comprehensive omics resources.
PMCID: PMC4301748  PMID: 25505034
Correspondence analysis; Database; Gene expression network; Manual curation; Natural language processing (NLP); Omics

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