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Articles by S Lee
Total Records ( 19 ) for S Lee
  S Lee and T. L Blundell
 

Summary:BIPA is a database for protein–nucleic acid interactions in 3D structures. The database provides various physicochemical features of protein–nucleic acid interface such as size, shape, residue propensity, secondary structure composition and intermolecular interactions. The database also contains multiple structural alignments of nucleic acid-binding protein families with annotations of local environments in order to allow definition of features that influence acceptability of mutations at a particular position in a protein family. A web interface has been designed to present the results of these analyses and facilitate navigation of protein–nucleic acid interfaces.

Availability: http://www-cryst.bioc.cam.ac.uk/bipa

Contact:semin@cryst.bioc.cam.ac.uk

Supplementary information:Supplementary data are available at Bioinformatics online.

  S Lee and T. L. Blundell
 

Summary: Amino acid residues are under various kinds of local environmental restraints, which influence substitution patterns. Ulla,1 a program for calculating environment-specific substitution tables, reads protein sequence alignments and local environment annotations. The program produces a substitution table for every possible combination of environment features. Sparse data is handled using an entropy-based smoothing procedure to estimate robust substitution probabilities.

  S Salek Ardakani , G Smooha , J de Boer , N. J Sebire , M Morrow , L Rainis , S Lee , O Williams , S Izraeli and H. J.M. Brady
 

Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis. [Cancer Res 2009;69(11):4665–73]

  Y. M Yang , S Lee , C. W Nam , J. H Ha , M Jayaraman , D. N Dhanasekaran , C. H Lee , M. K Kwak and S. G. Kim
 

Bortezomib is a proteasome inhibitor approved for anticancer therapy. However, variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits. G12/13 serves modulators or signal transducers in diverse pathways. This study investigated whether cancer cells display differential sensitivity to bortezomib with reference to G12/13 expression, and if so, whether G12/13 affects the expression of proteasome subunits and their activities. Bortezomib treatment exhibited greater sensitivities in Huh7 and SNU886 cells (epithelial type) than SK-Hep1 and SNU449 cells (mesenchymal type) that exhibited higher levels of G12/13. Overexpression of an active mutant of G12 (G12QL) or G13 (G13QL) diminished the ability of bortezomib to induce cytotoxicity in Huh7 cells. Moreover, transfection with the minigene that disturbs G protein-coupled receptor-G protein coupling (CT12 or CT13) increased it in SK-Hep1 cells. Consistently, MiaPaCa2 cells transfected with CT12 or CT13 exhibited a greater sensitivity to bortezomib. Evidence of G12/13’s antagonism on the anticancer effect of bortezomib was verified in the reversal by G12QL or G13QL of the minigenes’ enhancement of cytotoxity. Real-time polymerase chain reaction assay enabled us to identify PSMB5, multicatalytic endopeptidase complex-like-1, and proteasome activator subunit-1 repression by CT12 or CT13. Furthermore, G12/13 inhibition enhanced the ability of bortezomib to repress PSMB5, as shown by immunoblotting and proteasome activity assay. Moreover, this inhibitory effect on PSMB5 was attenuated by G12QL or G13QL. In conclusion, the inhibition of G12/13 activities may enhance the anticancer effect of bortezomib through PSMB5 repression, providing insight into the G12/13 pathway for the regulation of proteasomal activity.

  S. M Ahn , T. H Kim , S Lee , D Kim , H Ghang , D. S Kim , B. C Kim , S. Y Kim , W. Y Kim , C Kim , D Park , Y. S Lee , S Kim , R Reja , S Jho , C. G Kim , J. Y Cha , K. H Kim , B Lee , J Bhak and S. J. Kim
 

We present the first Korean individual genome sequence (SJK) and analysis results. The diploid genome of a Korean male was sequenced to 28.95-fold redundancy using the Illumina paired-end sequencing method. SJK covered 99.9% of the NCBI human reference genome. We identified 420,083 novel single nucleotide polymorphisms (SNPs) that are not in the dbSNP database. Despite a close similarity, significant differences were observed between the Chinese genome (YH), the only other Asian genome available, and SJK: (1) 39.87% (1,371,239 out of 3,439,107) SNPs were SJK-specific (49.51% against Venter's, 46.94% against Watson's, and 44.17% against the Yoruba genomes); (2) 99.5% (22,495 out of 22,605) of short indels (< 4 bp) discovered on the same loci had the same size and type as YH; and (3) 11.3% (331 out of 2920) deletion structural variants were SJK-specific. Even after attempting to map unmapped reads of SJK to unanchored NCBI scaffolds, HGSV, and available personal genomes, there were still 5.77% SJK reads that could not be mapped. All these findings indicate that the overall genetic differences among individuals from closely related ethnic groups may be significant. Hence, constructing reference genomes for minor socio-ethnic groups will be useful for massive individual genome sequencing.

  Temple The MGC Project Team , D. S Gerhard , R Rasooly , E. A Feingold , P. J Good , C Robinson , A Mandich , J. G Derge , J Lewis , D Shoaf , F. S Collins , W Jang , L Wagner , C. M Shenmen , L Misquitta , C. F Schaefer , K. H Buetow , T. I Bonner , L Yankie , M Ward , L Phan , A Astashyn , G Brown , C Farrell , J Hart , M Landrum , B. L Maidak , M Murphy , T Murphy , B Rajput , L Riddick , D Webb , J Weber , W Wu , K. D Pruitt , D Maglott , A Siepel , B Brejova , M Diekhans , R Harte , R Baertsch , J Kent , D Haussler , M Brent , L Langton , C. L.G Comstock , M Stevens , C Wei , M. J van Baren , K Salehi Ashtiani , R. R Murray , L Ghamsari , E Mello , C Lin , C Pennacchio , K Schreiber , N Shapiro , A Marsh , E Pardes , T Moore , A Lebeau , M Muratet , B Simmons , D Kloske , S Sieja , J Hudson , P Sethupathy , M Brownstein , N Bhat , J Lazar , H Jacob , C. E Gruber , M. R Smith , J McPherson , A. M Garcia , P. H Gunaratne , J Wu , D Muzny , R. A Gibbs , A. C Young , G. G Bouffard , R. W Blakesley , J Mullikin , E. D Green , M. C Dickson , A. C Rodriguez , J Grimwood , J Schmutz , R. M Myers , M Hirst , T Zeng , K Tse , M Moksa , M Deng , K Ma , D Mah , J Pang , G Taylor , E Chuah , A Deng , K Fichter , A Go , S Lee , J Wang , M Griffith , R Morin , R. A Moore , M Mayo , S Munro , S Wagner , S. J.M Jones , R. A Holt , M. A Marra , S Lu , S Yang , J Hartigan , M Graf , R Wagner , S Letovksy , J. C Pulido , K Robison , D Esposito , J Hartley , V. E Wall , R. F Hopkins , O Ohara and S. Wiemann
 

Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.

  B. G Hoffman , G Robertson , B Zavaglia , M Beach , R Cullum , S Lee , G Soukhatcheva , L Li , E. D Wederell , N Thiessen , M Bilenky , T Cezard , A Tam , B Kamoh , I Birol , D Dai , Y Zhao , M Hirst , C. B Verchere , C. D Helgason , M. A Marra , S. J. M Jones and P. A. Hoodless
 

The liver and pancreas share a common origin and coexpress several transcription factors. To gain insight into the transcriptional networks regulating the function of these tissues, we globally identify binding sites for FOXA2 in adult mouse islets and liver, PDX1 in islets, and HNF4A in liver. Because most eukaryotic transcription factors bind thousands of loci, many of which are thought to be inactive, methods that can discriminate functionally active binding events are essential for the interpretation of genome-wide transcription factor binding data. To develop such a method, we also generated genome-wide H3K4me1 and H3K4me3 localization data in these tissues. By analyzing our binding and histone methylation data in combination with comprehensive gene expression data, we show that H3K4me1 enrichment profiles discriminate transcription factor occupied loci into three classes: those that are functionally active, those that are poised for activation, and those that reflect pioneer-like transcription factor activity. Furthermore, we demonstrate that the regulated presence of H3K4me1-marked nucleosomes at transcription factor occupied promoters and enhancers controls their activity, implicating both tissue-specific transcription factor binding and nucleosome remodeling complex recruitment in determining tissue-specific gene expression. Finally, we apply these approaches to generate novel insights into how FOXA2, PDX1, and HNF4A cooperate to drive islet- and liver-specific gene expression.

  H. S Eom , C. K Min , B. S Cho , S Lee , J. W Lee , W. S Min , C. C Kim , M Kim and Y. Kim
  Objective

Patients with multiple myeloma (MM) achieving high-quality responses, defined as a complete response (CR) and a very good partial response (VGPR) after transplant, benefit from high-dose therapy followed by autologous stem cell transplantation (ASCT). Induction pre-transplantation treatment with vincristine, doxorubicin and dexamethasone (VAD) is currently being replaced by new targeted agents with high anti-myeloma activity. The use of these novel agents may increase the CR + VGPR rate before ASCT, which may improve post-transplantation responses and survival.

Methods

We performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or VAD (n = 39) before collection of peripheral blood stem cells and ASCT.

Results

Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90%) of 30 and 31 (81.6%) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (P = 0.494). However, the high-quality response rate with VGPR or more in the bortezomib group was significantly higher compared with the VAD group (66.7% vs. 34.2%, respectively, P = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, P = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival (P = 0.498 and 0.835, respectively).

Conclusions

The results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.

  J. J Carter , K. G Paulson , G. C Wipf , D Miranda , M. M Madeleine , L. G Johnson , B. D Lemos , S Lee , A. H Warcola , J. G Iyer , P Nghiem and D. A. Galloway
  Background

Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma.

Methods

Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain–specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162.

Results

We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval [CI] = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162.

Conclusion

Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma.

  S. Y Kim , S Lee , S. W Hong , B. H Min , K. U Lee , M Bendayan and I. S. Park
 

Nestin, which was initially identified as a marker of neural stem cells, has been reported in regenerating pancreas as well as in early embryonic stem (ES) cell derivatives. However, little is known about its specific roles in stem cells as a functional regulator. We investigated the source of the action of nestin in ES and adult pancreatic ductal stem (PDS) cells in regard to the neogenesis of insulin-secreting β-cells. In ES cells, suppression of nestin by gene silencing led to an increased expression of the pluripotency-associated genes, including Oct 4, Nanog, and SSEA-1, before embryoid body (EB) formation, whereas it reduced endodermal and pancreatic transcription factors in EBs. Inhibition of nestin expression in adult PDS cells caused a low expression of pancreatic transcription factors and islet hormones, leading to poor β-cell development and insulin secretion. These data may indicate not only that nestin is a simple stem cell marker, but also that it constitutes a functional factor at the time of stem cell differentiation. We suggest that nestin plays pivotal roles as an intermediate regulator governing both stemness and differentiation of stem cells in the process of their differentiation into insulin-secreting cells. (J Histochem Cytochem 58:567–576, 2010)

  H. J Park , I Rajbhandari , H. S Yang , S Lee , D Cucoranu , D. S Cooper , J. D Klein , J. M Sands and I. Choi
 

The sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an acid-base transporter that normally moves Na+ and HCO3 into the cell. This membrane protein is sensitive to cellular and systemic pH changes. We examined NBCn1 expression and localization in the brain and its response to chronic metabolic acidosis. Two new NBCn1 antibodies were generated by immunizing a rabbit and a guinea pig. The antibodies stained neurons in a variety of rat brain regions, including hippocampal pyramidal neurons, dentate gyrus granular neurons, posterior cortical neurons, and cerebellar Purkinje neurons. Choroid plexus epithelia were also stained. Double immunofluorescence labeling showed that NBCn1 and the postsynaptic density protein PSD-95 were found in the same hippocampal CA3 neurons and partially colocalized in dendrites. PSD-95 was pulled down from rat brain lysates with the GST/NBCn1 fusion protein and was also coimmunoprecipitated with NBCn1. Chronic metabolic acidosis was induced by feeding rats with normal chow or 0.4 M HCl-containing chow for 7 days. Real-time PCR and immunoblot showed upregulation of NBCn1 mRNA and protein in the hippocampus of acidotic rats. NBCn1 immunostaining was enhanced in CA3 neurons, posterior cortical neurons, and cerebellar granular cells. Intraperitoneal administration of N-methyl-d-aspartate caused neuronal death determined by caspase-3 activity, and this effect was more severe in acidotic rats. Administering N-methyl-d-aspartate also inhibited NBCn1 upregulation in acidotic rats. We conclude that NBCn1 in neurons is upregulated by chronic acid loads, and this upregulation is associated with glutamate excitotoxicity.

  D. E Conway , S Lee , S. G Eskin , A. K Shah , H Jo and L. V. McIntire
 

We examined the effects of fluid shear stress on metallothionein (MT) gene and protein expression and intracellular free zinc in mouse aorta and in human umbilical vein endothelial cells (HUVECs). Immunostaining of the endothelial surface of mouse aorta revealed increased expression of MT protein in the lesser curvature of the aorta relative to the descending thoracic aorta. HUVECs were exposed to high steady shear stress (15 dyn/cm2), low steady shear stress (1 dyn/cm2), or reversing shear stress (mean of 1 dyn/cm2, 1 Hz) for 24 h. Gene expression of three MT-1 isoforms, MT-2A, and zinc transporter-1 was upregulated by low steady shear stress and reversing shear stress. HUVECs exposed to 15 dyn/cm2 had increased levels of free zinc compared with cells under other shear stress regimes and static conditions. The increase in free zinc was partially blocked with an inhibitor of nitric oxide synthesis, suggesting a role for shear stress-induced endothelial nitric oxide synthase activity. Cells subjected to reversing shear stress in zinc-supplemented media (50 µM ZnSO4) had increased intracellular free zinc, reduced surface intercellular adhesion molecule-1 expression, and reduced monocyte adhesion compared with cells exposed to reversing shear stress in normal media. The sensitivity of intracellular free zinc to differences in shear stress suggests that intracellular zinc levels are important in the regulation of the endothelium and in the progression of vascular disease.

  Y Huang , R Kotov , G de Girolamo , A Preti , M Angermeyer , C Benjet , K Demyttenaere , R de Graaf , O Gureje , A. N Karam , S Lee , J. P Lepine , H Matschinger , J Posada Villa , S Suliman , G Vilagut and R. C. Kessler
 

Background

Little is known about the cross-national population prevalence or correlates of personality disorders.

Aims

To estimate prevalence and correlates of DSM–IV personality disorder clusters in the World Health Organization World Mental Health (WMH) Surveys.

Method

International Personality Disorder Examination (IPDE) screening questions in 13 countries (n = 21 162) were calibrated to masked IPDE clinical diagnoses. Prevalence and correlates were estimated using multiple imputation.

Results

Prevalence estimates are 6.1% (s.e. = 0.3) for any personality disorder and 3.6% (s.e. = 0.3), 1.5% (s.e. = 0.1) and 2.7% (s.e. = 0.2) for Clusters A, B and C respectively. Personality disorders are significantly elevated among males, the previously married (Cluster C), unemployed (Cluster C), the young (Clusters A and B) and the poorly educated. Personality disorders are highly comorbid with Axis I disorders. Impairments associated with personality disorders are only partially explained by comorbidity.

Conclusions

Personality disorders are relatively common disorders that often co-occur with Axis I disorders and are associated with significant role impairments beyond those due to comorbidity.

  S Lee , A Tsang , R. C Kessler , R Jin , N Sampson , L Andrade , E. G Karam , M. E. M Mora , K Merikangas , Y Nakane , D. G Popovici , J Posada Villa , R Sagar , J. E Wells , Z Zarkov and M. Petukhova
 

Background

The epidemiology of rapid-cycling bipolar disorder in the community is largely unknown.

Aims

To investigate the epidemiological characteristics of rapid-cycling and non-rapid-cycling bipolar disorder in a large cross-national community sample.

Method

The Composite International Diagnostic Interview (CIDI version 3.0) was used to examine the prevalence, severity, comorbidity, impairment, suicidality, sociodemographics, childhood adversity and treatment of rapid-cycling and non-rapid-cycling bipolar disorder in ten countries (n = 54 257).

Results

The 12-month prevalence of rapid-cycling bipolar disorder was 0.3%. Roughly a third and two-fifths of participants with lifetime and 12-month bipolar disorder respectively met criteria for rapid cycling. Compared with the non-rapid-cycling, rapid-cycling bipolar disorder was associated with younger age at onset, higher persistence, more severe depressive symptoms, greater impairment from depressive symptoms, more out-of-role days from mania/hypomania, more anxiety disorders and an increased likelihood of using health services. Associations regarding childhood, family and other sociodemographic correlates were less clear cut.

Conclusions

The community epidemiological profile of rapid-cycling bipolar disorder confirms most but not all current clinically based knowledge about the illness.

  D Levinson , M. D Lakoma , M Petukhova , M Schoenbaum , A. M Zaslavsky , M Angermeyer , G Borges , R Bruffaerts , G de Girolamo , R de Graaf , O Gureje , J. M Haro , C Hu , A. N Karam , N Kawakami , S Lee , J. P Lepine , M. O Browne , M Okoliyski , J Posada Villa , R Sagar , M. C Viana , D. R Williams and R. C. Kessler
 

Background

Burden-of-illness data, which are often used in setting healthcare policy-spending priorities, are unavailable for mental disorders in most countries.

Aims

To examine one central aspect of illness burden, the association of serious mental illness with earnings, in the World Health Organization (WHO) World Mental Health (WMH) Surveys.

Method

The WMH Surveys were carried out in 10 high-income and 9 low- and middle-income countries. The associations of personal earnings with serious mental illness were estimated.

Results

Respondents with serious mental illness earned on average a third less than median earnings, with no significant between-country differences (2(9) = 5.5–8.1, P = 0.52–0.79). These losses are equivalent to 0.3–0.8% of total national earnings. Reduced earnings among those with earnings and the increased probability of not earning are both important components of these associations.

Conclusions

These results add to a growing body of evidence that mental disorders have high societal costs. Decisions about healthcare resource allocation should take these costs into consideration.

  R. C Kessler , K. A McLaughlin , J. G Green , M. J Gruber , N. A Sampson , A. M Zaslavsky , S Aguilar Gaxiola , A. O Alhamzawi , J Alonso , M Angermeyer , C Benjet , E Bromet , S Chatterji , G de Girolamo , K Demyttenaere , J Fayyad , S Florescu , G Gal , O Gureje , J. M Haro , C. y Hu , E. G Karam , N Kawakami , S Lee , J. P Lepine , J Ormel , J Posada Villa , R Sagar , A Tsang , T. B Ustun , S Vassilev , M. C Viana and D. R. Williams
 

Background

Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders.

Aims

To examine joint associations of 12 childhood adversities with first onset of 20 DSM–IV disorders in World Mental Health (WMH) Surveys in 21 countries.

Method

Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM–IV disorders with the WHO Composite International Diagnostic Interview (CIDI).

Results

Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries.

Conclusions

Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.

  H. S Yang , E Kim , S Lee , H. J Park , D. S Cooper , I Rajbhandari and I. Choi
 

To understand the mechanism for ion transport through the sodium/bicarbonate transporter SLC4A4 (NBCe1), we examined amino acid residues, within transmembrane domains, that are conserved among electrogenic Na/HCO3 transporters but are substituted with residues at the corresponding site of all electroneutral Na/HCO3 transporters. Point mutants were constructed and expressed in Xenopus oocytes to assess function using two-electrode voltage clamp. Among the mutants, D555E (charge-conserved substitution of the aspartate at position 555 with a glutamate) produced decreasing HCO3 currents at more positive membrane voltages. Immunohistochemistry showed D555E protein expression in oocyte membranes. D555E induced Na/HCO3-dependent pH recovery from a CO2-induced acidification. Current-voltage relationships revealed that D555E produced an outwardly rectifying current in the nominally CO2/HCO3-free solution that was abolished by Cl removal from the bath. In the presence of CO2/HCO3, however, the outward current produced by D555E decreased only slightly after Cl removal. Starting from a Cl-free condition, D555E produced dose-dependent outward currents in response to a series of chloride additions. The D555E-mediated chloride current decreased by 70% in the presence of CO2/HCO3. The substitution of Asp555 with an asparagine also produced a Cl current. Anion selectivity experiments revealed that D555E was broadly permissive to other anions including NO3. Fluorescence measurements of chloride transport were done with human embryonic kidney HEK 293 cells expressing NBCe1 and D555E. A marked increase in chloride transport was detected in cells expressing D555E. We conclude that Asp555 plays a role in HCO3 selectivity.

  T. T Chen , A Luque , S Lee , S. M Anderson , T Segura and M. L. Iruela Arispe
 

Matrix-bound VEGF elicits more distinct vascular effects than soluble VEGF, including prolonged VEGFR2 activation with altered patterns of tyrosine activation and downstream enhancement of the p38/MAPK pathway.

 
 
 
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