Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport*

PubMed Central

Long, Wentong; Panwar, Pankaj; Witkowska, Kate; Wong, Kenneth; O'Neill, Debbie; Chen, Xing-Zhen; Lemieux, M. Joanne; Cheeseman, Chris I.

2015-01-01

High blood urate levels (hyperuricemia) have been found to be a significant risk factor for cardiovascular diseases and inflammatory arthritis, such as hypertension and gout. Human glucose transporter 9 (hSLC2A9) is an essential protein that mainly regulates urate/hexose homeostasis in human kidney and liver. hSLC2A9 is a high affinity-low capacity hexose transporter and a high capacity urate transporter. Our previous studies identified a single hydrophobic residue in trans-membrane domain 7 of class II glucose transporters as a determinant of fructose transport. A mutation of isoleucine 335 to valine (I355V) in hSLC2A9 can reduce fructose transport while not affecting glucose fluxes. This current study demonstrates that the I335V mutant transports urate similarly to the wild type hSLC2A9; however, Ile-335 is necessary for urate/fructose trans-acceleration exchange to occur. Furthermore, Trp-110 is a critical site for urate transport. Two structural models of the class II glucose transporters, hSLC2A9 and hSLC2A5, based on the crystal structure of hSLC2A1 (GLUT1), reveal that Ile-335 (or the homologous Ile-296 in hSLC2A5) is a key component for protein conformational changes when the protein translocates substrates. The hSLC2A9 model also predicted that Trp-110 is a crucial site that could directly interact with urate during transport. Together, these studies confirm that hSLC2A9 transports both urate and fructose, but it interacts with them in different ways. Therefore, this study advances our understanding of how hSLC2A9 mediates urate and fructose transport, providing further information for developing pharmacological agents to treat hyperuricemia and related diseases, such as gout, hypertension, and diabetes. PMID:25922070

DiffSLc: A graph centrality method to detect essential proteins of a protein-protein interaction network

USDA-ARS?s Scientific Manuscript database

Network centrality measures prioritize nodes and edges based on their importance to the network topology. These measures have been helpful in identifying critical genes and proteins in biomolecular networks. The proposed centrality measure DiffSLc uses the number of interactions of a protein and gen...

Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.

PubMed

Ro, Myungja; Won, Seongsik; Kang, Hyunjun; Kim, Su-Yeon; Lee, Seung Ku; Nam, Min; Bang, Hee Jung; Yang, Jae Won; Choi, Kyung-Sik; Kim, Su Kang; Chung, Joo-Ho; Kwack, Kyubum

2013-01-01

Autism spectrum disorder (ASD) is a neurobiological disorder characterized by distinctive impairments in cognitive function, language, and behavior. Linkage and population studies suggest a genetic association between solute carrier family 6 member 4 (SLC6A4) variants and ASD. Logistic regression was used to identify associations between single-nucleotide polymorphisms (SNPs) and ASD with 3 alternative models (additive, dominant, and recessive). Linear regression analysis was performed to determine the influence of SNPs on Childhood Autism Rating Scale (CARS) scores as a quantitative phenotype. In the present study, we examined the associations of SNPs in the SLC6A4 gene and the fibrinogen alpha chain (FGA) gene. Logistic regression analysis showed a significant association between the risk of ASD and rs2070025 and rs2070011 in the FGA gene. The gene-gene interaction between SLC6A4 and FGA was not significantly associated with ASD susceptibility. However, polymorphisms in both SLC6A4 and the FGA gene significantly affected the symptoms of ASD. Our findings indicate that FGA and SLC6A4 gene interactions may contribute to the phenotypes of ASD rather than the incidence of ASD. © 2013 S. Karger AG, Basel.

Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression

PubMed Central

Gardner, Katherine L.; Hale, Matthew W.; Lightman, Stafford L.; Plotsky, Paul M.; Lowry, Christopher A.

2009-01-01

Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of serotonergic systems in the brain. To evaluate the effects of early life experience, adverse experiences during adulthood, and potential interactions between these factors on serotonin transporter (slc6a4) mRNA expression, we investigated in rats the effects of maternal separation (180 min/day from days 2–14 of life; MS180), neonatal handing (15 min/day from days 2–14 of life; MS15), or normal animal facility rearing control conditions (AFR) with or without subsequent exposure to adult social defeat on slc6a4 mRNA expression in the dorsal raphe nucleus (DR) and caudal linear nucleus. At the level of specific subdivisions of the DR, there were no differences in slc6a4 mRNA expression between MS15 and AFR rats. Among rats exposed to a novel cage control condition, increased slc6a4 mRNA expression was observed in the dorsal part of the DR in MS180 rats, relative to AFR control rats. In contrast, MS180 rats exposed to social defeat as adults had increased slc6a4 mRNA expression throughout the DR compared to both MS15 and AFR controls. Social defeat increased slc6a4 mRNA expression, but only in MS180 rats and only in the “lateral wings” of the DR. Overall these data demonstrate that early life experience and stressful experience during adulthood interact to determine slc6a4 mRNA expression. These data support the hypothesis that early life experience and major stressful life events contribute to dysregulation of serotonergic systems in stress-related neuropsychiatric disorders. PMID:19781533

T7. PHARMACOGENETIC OF TARDIVE DYSKINESIA -- A FOLLOW-UP ON THE VALBENAZINE TARGET VMAT2/SLC18A2

PubMed Central

Zai, Clement; Tiwari, Arun; Mueller, Daniel; Voineskos, Aristotle; Potkin, Steven G; Lieberman, Jeffrey; Meltzer, Herbert; Remington, Gary; Kennedy, James

2018-01-01

Abstract Background Tardive dyskinesia (TD) is a motor side effect that may arise after long-term treatment of antipsychotic drugs. Its etiology is not well understood, but a number of risk factors have been associated with TD. TD occurrence appears to be familial, thus suggesting a genetic component. We previously reported on an association between the SLC18A2 gene that codes for the vesicular monoamine transporter 2 (VMAT2) that packages monoamines including dopamine from the cytoplasm into synaptic vesicles (Zai et al, 2013). In the present study, we examined the dopamine transporter gene SLC6A3 by itself and in conjunction with SLC18A2 for possible association with TD. Methods We genotyped and analyzed the variable-number tandem repeat (VNTR) polymorphism in the 3’ untranslated region of the SLC6A3 gene in our European sample of 187 schizophrenia/schizoaffective disorder patients assessed for TD occurrence based on the Abnormal Involuntary Movement Scale (AIMS). We also explored the interaction between the VNTR and the TD-associated SLC18A2 marker rs363224. Results Our preliminary analysis did not show the SLC6A3 VNTR to be associated with TD occurrence or severity. There also appeared to be no significant interaction between SLC6A3 VNTR and SLC18A2 rs363224 in TD occurrence or severity (p>0.05). Discussion Our findings did not support a major role of the dopamine transporter gene in TD risk or severity, but we will examine additional putative functional markers in this gene.

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

PubMed Central

Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire; Ucurum, Zöhre; Schlessinger, Avner; Fotiadis, Dimitrios

2018-01-01

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures (Tms) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting Tms indicated stabilization of AdiC variants upon ligand binding, in which Tms and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family. PMID:29558430

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters.

PubMed

Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire; Ucurum, Zöhre; Schlessinger, Avner; Fotiadis, Dimitrios

2018-03-20

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures ( T m s) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting T m s indicated stabilization of AdiC variants upon ligand binding, in which T m s and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family.

SLC7 family transporters control the establishment of left-right asymmetry during organogenesis in medaka by activating mTOR signaling.

PubMed

Asaoka, Yoichi; Nagai, Yoko; Namae, Misako; Furutani-Seiki, Makoto; Nishina, Hiroshi

2016-05-20

The precise government of the left-right (LR) specification of an organ is an essential aspect of its morphogenesis. Multiple signaling cascades have been implicated in the establishment of vertebrate LR asymmetry. Recently, mTOR signaling was found to critically regulate the development of LR asymmetry in zebrafish. However, the upstream factor(s) that activate mTOR signaling in the context of LR specification are as yet unknown. In this study, we identify the SLC7 amino acid transporters Slc7a7 and Slc7a8 as novel regulators of LR asymmetry development in the small fish medaka. Knockdown of Slc7a7 and/or Slc7a8 in medaka embryos disrupted LR organ asymmetries. Depletion of Slc7a7 hindered left-sided expression of the southpaw (spaw) gene, which is responsible for LR axis determination. Work at the cellular level revealed that Slc7a7 coordinates ciliogenesis in the epithelium of Kupffer's vesicle and thereby the generation of the nodal fluid flow required for LR asymmetry. Interestingly, knockdown of Slc7a7 depressed mTOR signaling activity in medaka embryos. Treatment with rapamycin, an inhibitor of mTOR signaling, together with Slc7a7 knockdown synergistically perturbed spaw expression, indicating an interaction between Slc7a7 and mTOR signaling affecting gene expression required for LR specification. Taken together, our results demonstrate that Slc7a7 governs the regulation of LR asymmetry development via the activation of mTOR signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

10. Photocopy of photograph (original photograph in possession of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. Photocopy of photograph (original photograph in possession of the Ralph M. Parsons Company, Los Angeles California). Photography by the United States Air Force, May 4, 1960. VIEW OF SOUTH FACE OF POINT ARGUELLO LAUNCH COMPLEX 1, PAD 1 (SLC-3) FROM TOP OF CONTROL CENTER (BLDG. 763). ATLAS D BOOSTER FOR THE FIRST SAMOS LAUNCH FROM POINT ARGUELLO LAUNCH COMPLEX 1 (SLC-3) ERECT IN THE SERVICE TOWER. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

MAOA Influences the Trajectory of Attentional Development

PubMed Central

Lundwall, Rebecca A.; Rasmussen, Claudia G.

2016-01-01

Attention is vital to success in all aspects of life (Meck and Benson, 2002; Erickson et al., 2015), hence it is important to identify biomarkers of later attentional problems early enough to intervene. Our objective was to determine if any of 11 genes (APOE, BDNF, HTR4, CHRNA4, COMT, DRD4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25) predicted the trajectory of attentional development within the same group of children between infancy and childhood. We recruited follow up participants from children who participated as infants in visual attention studies and used a similar task at both time points. Using multilevel modeling, we associated changes in the participant’s position in the distribution of scores in infancy to his/her position in childhood with genetic markers on each of 11 genes. While all 11 genes predicted reaction time (RT) residual scores, only Monoamine oxidase A (MAOA) had a significant interaction including time point. We conclude that the MAOA single nucleotide polymorphism (SNP) rs1137070 is useful in predicting which girls are likely to develop slower RTs on an attention task between infancy and childhood. This early identification is likely to be helpful in early intervention. PMID:27610078

Disparate bilingual experiences modulate task-switching advantages: A diffusion-model analysis of the effects of interactional context on switch costs.

PubMed

Hartanto, Andree; Yang, Hwajin

2016-05-01

Drawing on the adaptive control hypothesis (Green & Abutalebi, 2013), we investigated whether bilinguals' disparate interactional contexts modulate task-switching performance. Fifty-eight bilinguals within the single-language context (SLC) and 75 bilinguals within the dual-language context (DLC) were compared in a typical task-switching paradigm. Given that DLC bilinguals switch between languages within the same context, while SLC bilinguals speak only one language in one environment and therefore rarely switch languages, we hypothesized that the two groups' stark difference in their interactional contexts of conversational exchanges would lead to differences in switch costs. As predicted, DLC bilinguals showed smaller switch costs than SLC bilinguals. Our diffusion-model analyses suggest that DLC bilinguals' benefits in switch costs are more likely driven by task-set reconfiguration than by proactive interference. Our findings underscore the modulating role of the interactional context of conversational exchanges in task switching. Copyright © 2016 Elsevier B.V. All rights reserved.

Overexpression of SLC34A2 is an independent prognostic indicator in bladder cancer and its depletion suppresses tumor growth via decreasing c-Myc expression and transcriptional activity

PubMed Central

Ye, Wen; Chen, Cui; Gao, Ying; Zheng, Zou-Shan; Xu, Yi; Yun, Miao; Weng, Hui-Wen; Xie, Dan; Ye, Sheng; Zhang, Jia-Xing

2017-01-01

Solute carrier family 34 member 2 (SLC34A2), a pH-sensitive sodium-dependent phosphate transporter, is associated with several human cancers. In this study, we investigate the clinical significance of SLC34A2 and its function in human bladder cancer (BC). The expression dynamics of SLC34A2 were examined in two independent cohorts of BC samples by quantitative PCR, western blotting and immunohistochemical staining. In the training cohort (156 cases), we applied the X-tile program software to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (130 cases), the cutoff score derived from X-title analysis was investigated to determine the association of SLC34A2 expression with survival outcome. A series of in vitro and in vivo assays were then performed to elucidate the function of SLC34A2 in BC and its underlying mechanisms. Results showed that SLC34A2 was significantly upregulated in BC cell lines and clinical samples. In both two cohorts of BC samples, high expression of SLC34A2 was associated with large tumor size, advanced T status and poor patients' survival. The depletion of SLC34A2 in BC suppressed cellular viability, colony formation and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo, whereas overexpression of SLC34A2 had the converse effect. Simultaneously, downregulation of SLC34A2 decreased the transcriptional activity and protein expression level of c-Myc in BC cells, whereas restoration of c-Myc expression could compromise the anti-proliferation effect of SLC34A2 depletion. Furthermore, miR-214 was proved as a negative regulator of SLC34A2. Our present study illustrated that SLC34A2 has an important role in promoting proliferation and tumorigenicity of BC, and may represent a novel therapeutic target for this disease. PMID:28151475

Three cysteine residues of SLC52A1, a receptor for the porcine endogenous retrovirus-A (PERV-A), play a critical role in cell surface expression and infectivity.

PubMed

Colon-Moran, Winston; Argaw, Takele; Wilson, Carolyn A

2017-07-01

Porcine endogenous retrovirus-A (PERV-A), a gammaretrovirus, infects human cells in vitro, thus raising the potential risk of cross-species transmission in xenotransplantation. Two members of the solute carrier family 52 (SLC52A1 and SLC52A2) are PERV-A receptors. Site-directed mutagenesis of the cDNA encoding SLC52A1 identified that only one of two putative glycosylation signals is occupied by glycans. In addition, we showed that glycosylation of SLC52A1 is not necessary for PERV-A receptor function. We also identified that at a minimum, three cysteine residues are sufficient for SLC52A1 cell surface expression. Mutation of cysteine at position 365 and either of the two cysteine residues in the C-terminal tail at positions 442 or 446 reduced SLC52A1 surface expression and PERV-A infection suggesting that these residues may contribute to overall structural stability and receptor function. Understanding interactions between PERV-A and its cellular receptor may provide novel strategies to prevent zoonotic infection in the setting of xenotransplantation. Published by Elsevier Inc.

SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.

PubMed

Janer, Alexandre; Prudent, Julien; Paupe, Vincent; Fahiminiya, Somayyeh; Majewski, Jacek; Sgarioto, Nicolas; Des Rosiers, Christine; Forest, Anik; Lin, Zhen-Yuan; Gingras, Anne-Claude; Mitchell, Grant; McBride, Heidi M; Shoubridge, Eric A

2016-09-01

Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Bicarbonate transporters in corals point towards a key step in the evolution of cnidarian calcification.

PubMed

Zoccola, Didier; Ganot, Philippe; Bertucci, Anthony; Caminiti-Segonds, Natacha; Techer, Nathalie; Voolstra, Christian R; Aranda, Manuel; Tambutté, Eric; Allemand, Denis; Casey, Joseph R; Tambutté, Sylvie

2015-06-04

The bicarbonate ion (HCO3(-)) is involved in two major physiological processes in corals, biomineralization and photosynthesis, yet no molecular data on bicarbonate transporters are available. Here, we characterized plasma membrane-type HCO3(-) transporters in the scleractinian coral Stylophora pistillata. Eight solute carrier (SLC) genes were found in the genome: five homologs of mammalian-type SLC4 family members, and three of mammalian-type SLC26 family members. Using relative expression analysis and immunostaining, we analyzed the cellular distribution of these transporters and conducted phylogenetic analyses to determine the extent of conservation among cnidarian model organisms. Our data suggest that the SLC4γ isoform is specific to scleractinian corals and responsible for supplying HCO3(-) to the site of calcification. Taken together, SLC4γ appears to be one of the key genes for skeleton building in corals, which bears profound implications for our understanding of coral biomineralization and the evolution of scleractinian corals within cnidarians.

A SLC4 family bicarbonate transporter is critical for intracellular pH regulation and biomineralization in sea urchin embryos.

PubMed

Hu, Marian Y; Yan, Jia-Jiun; Petersen, Inga; Himmerkus, Nina; Bleich, Markus; Stumpp, Meike

2018-05-01

Efficient pH regulation is a fundamental requisite of all calcifying systems in animals and plants but with the underlying pH regulatory mechanisms remaining largely unknown. Using the sea urchin larva, this work identified the SLC4 HCO 3 - transporter family member SpSlc4a10 to be critically involved in the formation of an elaborate calcitic endoskeleton. SpSlc4a10 is specifically expressed by calcifying primary mesenchyme cells with peak expression during de novo formation of the skeleton. Knock-down of SpSlc4a10 led to pH regulatory defects accompanied by decreased calcification rates and skeleton deformations. Reductions in seawater pH, resembling ocean acidification scenarios, led to an increase in SpSlc4a10 expression suggesting a compensatory mechanism in place to maintain calcification rates. We propose a first pH regulatory and HCO 3 - concentrating mechanism that is fundamentally linked to the biological precipitation of CaCO 3 . This knowledge will help understanding biomineralization strategies in animals and their interaction with a changing environment. © 2018, Hu et al.

A SLC4 family bicarbonate transporter is critical for intracellular pH regulation and biomineralization in sea urchin embryos

PubMed Central

Yan, Jia-Jiun; Petersen, Inga; Himmerkus, Nina; Bleich, Markus; Stumpp, Meike

2018-01-01

Efficient pH regulation is a fundamental requisite of all calcifying systems in animals and plants but with the underlying pH regulatory mechanisms remaining largely unknown. Using the sea urchin larva, this work identified the SLC4 HCO3- transporter family member SpSlc4a10 to be critically involved in the formation of an elaborate calcitic endoskeleton. SpSlc4a10 is specifically expressed by calcifying primary mesenchyme cells with peak expression during de novo formation of the skeleton. Knock-down of SpSlc4a10 led to pH regulatory defects accompanied by decreased calcification rates and skeleton deformations. Reductions in seawater pH, resembling ocean acidification scenarios, led to an increase in SpSlc4a10 expression suggesting a compensatory mechanism in place to maintain calcification rates. We propose a first pH regulatory and HCO3- concentrating mechanism that is fundamentally linked to the biological precipitation of CaCO3. This knowledge will help understanding biomineralization strategies in animals and their interaction with a changing environment. PMID:29714685

SLC12A7 alters adrenocortical carcinoma cell adhesion properties to promote an aggressive invasive behavior.

PubMed

Brown, Taylor C; Murtha, Timothy D; Rubinstein, Jill C; Korah, Reju; Carling, Tobias

2018-06-08

Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and overexpression of SLC12A7 in adrenocortical carcinoma (ACC). The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R. SW-13 cells, which express negligible amounts of SLC12A7, were enforced to express SLC12A7 constitutively, while RNAi gene silencing was performed in NCI-H295R cells, which have robust endogenous expression of SLC12A7. In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization. Further, potential alterations in transcription regulation downstream to induced SLC12A7 overexpression was explored using targeted transcription factor expression arrays. Enforced SLC12A7 overexpression in SW-13 cells robustly promoted motility and invasive characteristics (p < 0.05) without significantly altering cell viability, growth, or colony formation potential. SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction. In contrast, RNAi gene silencing of SLC12A7 stymied cell attachment strength as well as migration and invasion capacity in NCI-H295R cells. Transcription factor expression analysis identified multiple signally pathways potentially affected by SLC12A7 overexpression, including osmotic stress, bone morphogenetic protein, and Hippo signaling pathways. Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.

Zinc-Associated Variant in SLC30A8 Gene Interacts With Gestational Weight Gain on Postpartum Glycemic Changes: A Longitudinal Study in Women With Prior Gestational Diabetes Mellitus.

PubMed

Wang, Tiange; Liu, Huikun; Wang, Leishen; Huang, Tao; Li, Weiqin; Zheng, Yan; Heianza, Yoriko; Sun, Dianjianyi; Leng, Junhong; Zhang, Shuang; Li, Nan; Hu, Gang; Qi, Lu

2016-12-01

Zinc transporter 8 genetic variant SLC30A8 has been associated with postpartum risk of type 2 diabetes among women with gestational diabetes mellitus (GDM). Gestational weight gain is one of the strongest risk factors for postpartum hyperglycemia. We assessed the interaction between type 2 diabetes-associated SLC30A8 rs13266634 and gestational weight gain on 1-5 years of postpartum glycemic changes in 1,071 women with prior GDM in a longitudinal study. Compared with gestation of 26-30 weeks, postpartum levels of fasting glucose, oral glucose tolerance test 2-h glucose, and hemoglobin A 1c (HbA 1c ) increased across rs13266634 TT, CT, and CC genotypes in women with excessive gestational weight gain, whereas opposite genetic associations were found in women with inadequate or adequate gestational weight gain. Postpartum changes in fasting glucose per additional copy of the C allele were -0.18, -0.04, and 0.12 mmol/L in women with inadequate, adequate, and excessive gestational weight gain, respectively (P for interaction = 0.002). We also found similar interactions for changes in 2-h glucose and HbA 1c (P for interaction = 0.003 and 0.005, respectively). Our data indicate that gestational weight gain may modify SLC30A8 variant on long-term glycemic changes, highlighting the importance of gestational weight control in the prevention of postpartum hyperglycemia in women with GDM. © 2016 by the American Diabetes Association.

3. AERIAL VIEW FROM THE EAST OF (FOREGROUND TO BACKGROUND) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. AERIAL VIEW FROM THE EAST OF (FOREGROUND TO BACKGROUND) SLC-3 AIR FORCE BUILDING (BLDG. 761), TECHNICAL SUPPORT BUILDING (BLDG. 762/762A), ENTRY CONTROL POINT (BLDG. 768), AND LOB (BLDG. 763). EAST SIDE OF SLC-3E MOBILE SERVICE TOWER (MST) VISIBLE IN UPPER LEFT CORNER. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Human SLC4A11-C functions as a DIDS-stimulatable H+(OH−) permeation pathway: partial correction of R109H mutant transport

PubMed Central

Kao, Liyo; Azimov, Rustam; Abuladze, Natalia; Newman, Debra

2014-01-01

The SLC4A11 gene mutations cause a variety of genetic corneal diseases, including congenital hereditary endothelial dystrophy 2 (CHED2), Harboyan syndrome, some cases of Fuchs' endothelial dystrophy (FECD), and possibly familial keratoconus. Three NH2-terminal variants of the human SLC4A11 gene, named SLC4A11-A, -B, and -C are known. The SLC4A11-B variant has been the focus of previous studies. Both the expression of the SLC4A11-C variant in the cornea and its functional properties have not been characterized, and therefore its potential pathophysiological role in corneal diseases remains to be explored. In the present study, we demonstrate that SLC4A11-C is the predominant SLC4A11 variant expressed in human corneal endothelial mRNA and that the transporter functions as an electrogenic H+(OH−) permeation pathway. Disulfonic stilbenes, including 4,4′-diisothiocyano-2,2′-stilbenedisulfonate (DIDS), 4,4′-diisothiocyanatodihydrostilbene-2,2′-disulfonate (H2DIDS), and 4-acetamido-4′-isothiocyanato-stilbene-2,2′-disulfonate (SITS), which are known to bind covalently, increased SLC4A11-C-mediated H+(OH−) flux by 150–200% without having a significant effect in mock-transfected cells. Noncovalently interacting 4,4′-diaminostilbene-2,2′-disulfonate (DADS) was without effect. We tested the efficacy of DIDS on the functionally impaired R109H mutant (SLC4A11-C numbering) that causes CHED2. DIDS (1 mM) increased H+(OH−) flux through the mutant transporter by ∼40–90%. These studies provide a basis for future testing of more specific chemically modified dilsulfonic stilbenes as potential therapeutic agents to improve the functional impairment of specific SLC4A11 mutant transporters. PMID:25394471

Di- and tripeptide transport in vertebrates: the contribution of teleost fish models.

PubMed

Verri, Tiziano; Barca, Amilcare; Pisani, Paola; Piccinni, Barbara; Storelli, Carlo; Romano, Alessandro

2017-04-01

Solute Carrier 15 (SLC15) family, alias H + -coupled oligopeptide cotransporter family, is a group of membrane transporters known for their role in the cellular uptake of di- and tripeptides (di/tripeptides) and peptide-like molecules. Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from dietary protein digestion, while SLC15A2 (PEPT2) mainly allows renal tubular reabsorption of di/tripeptides from ultrafiltration, SLC15A3 (PHT2) and SLC15A4 (PHT1) possibly interact with di/tripeptides and histidine in certain immune cells, and SLC15A5 has unknown function. Our understanding of this family in vertebrates has steadily increased, also due to the surge of genomic-to-functional information from 'non-conventional' animal models, livestock, poultry, and aquaculture fish species. Here, we review the literature on the SLC15 transporters in teleost fish with emphasis on SLC15A1 (PEPT1), one of the solute carriers better studied amongst teleost fish because of its relevance in animal nutrition. We report on the operativity of the transporter, the molecular diversity, and multiplicity of structural-functional solutions of the teleost fish orthologs with respect to higher vertebrates, its relevance at the intersection of the alimentary and osmoregulative functions of the gut, its response under various physiological states and dietary solicitations, and its possible involvement in examples of total body plasticity, such as growth and compensatory growth. By a comparative approach, we also review the few studies in teleost fish on SLC15A2 (PEPT2), SLC15A4 (PHT1), and SLC15A3 (PHT2). By representing the contribution of teleost fish to the knowledge of the physiology of di/tripeptide transport and transporters, we aim to fill the gap between higher and lower vertebrates.

SLC25 Family Member Genetic Interactions Identify a Role for HEM25 in Yeast Electron Transport Chain Stability.

PubMed

Dufay, J Noelia; Fernández-Murray, J Pedro; McMaster, Christopher R

2017-06-07

The SLC25 family member SLC25A38 (Hem25 in yeast) was recently identified as a mitochondrial glycine transporter that provides substrate to initiate heme/hemoglobin synthesis. Mutations in the human SLC25A38 gene cause congenital sideroblastic anemia. The full extent to which SLC25 family members coregulate heme synthesis with other mitochondrial functions is not clear. In this study, we surveyed 29 nonessential SLC25 family members in Saccharomyces cerevisiae for their ability to support growth in the presence and absence of HEM25 Six SLC25 family members were identified that were required for growth or for heme synthesis in cells lacking Hem25 function. Importantly, we determined that loss of function of the SLC25 family member Flx1, which imports FAD into mitochondria, together with loss of function of Hem25, resulted in inability to grow on media that required yeast cells to supply energy using mitochondrial respiration. We report that specific components of complexes of the electron transport chain are decreased in the absence of Flx1 and Hem25 function. In addition, we show that mitochondria from flx1 Δ hem25 Δ cells contain uncharacterized Cox2-containing high molecular weight aggregates. The functions of Flx1 and Hem25 provide a facile explanation for the decrease in heme level, and in specific electron transport chain complex components. Copyright © 2017 Dufay et al.

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

PubMed Central

Zhong, Xi Zoë; Cao, Qi; Sun, Xue

2016-01-01

Key points SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation.P2X4 receptors act as lysosomal ion channels activated by luminal ATP.SLC17A9‐mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V‐ATPase inhibitor.SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V‐ATPase as the driving force to transport ATP into the lysosome to activate P2X4. Abstract The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling. Recently, solute carrier family 17 member 9 (SLC17A9, also known as VNUT for vesicular nucleotide transporter) proteins were suggested to function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation, and P2X4 receptors were suggested to be lysosomal ion channels that are activated by luminal ATP. However, the molecular mechanism of SLC17A9 transporting ATP and the regulatory mechanism of lysosomal P2X4 are largely unknown. In this study, we report that SLC17A9‐mediated ATP transport across lysosomal membranes is suppressed by Bafilomycin A1, the V‐ATPase inhibitor. By measuring P2X4 activity, which is indicative of ATP transport across lysosomal membranes, we further demonstrated that SLC17A9 mainly uses voltage gradient but not pH gradient as the driving force to transport ATP into lysosomes. This study provides a molecular mechanism for lysosomal ATP transport mediated by SLC17A9. It also suggests a regulatory mechanism of lysosomal P2X4 by SLC17A9. PMID:27477609

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gabrielson, Marike; Reizer, Edwin; Stål, Olle

An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclearmore » Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G{sub 1}-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G{sub 1}-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells. - Highlights: • Proposed cell cycle regulation through the mitochondrial transporter SLC25A43. • SLC25A43 alters cell proliferation rate and cell cycle progression. • Suppressed SLC25A43 influences transcription of cell cycle regulatory genes.« less

Molecular basis of interactions between mitochondrial proteins and hydroxyapatite in the presence of Triton X-100, as revealed by proteomic and recombinant techniques.

PubMed

Yamamoto, Takenori; Tamaki, Haruna; Katsuda, Chie; Nakatani, Kiwami; Terauchi, Satsuki; Terada, Hiroshi; Shinohara, Yasuo

2013-08-02

Hydroxyapatite chromatography is a very important step in the purification of voltage-dependent anion channels (VDACs) and several members of solute carrier family 25 (Slc25) from isolated mitochondria. In the presence of Triton X-100, VDACs and Slc25 members present a peculiar property, i.e., a lack of interaction with hydroxyapatite, resulting in their presence in the flow-through fraction of hydroxyapatite chromatography. This property has allowed selective isolation of VDACs and Slc25 members from a mixture of total mitochondrial proteins. However, the reason why only these few proteins are selectively obtained in the presence of Triton X-100 from the flow-though fraction of hydroxyapatite chromatography has not yet been adequately understood. In this study, when we examined the protein species in the flow-through fractions by proteomic analysis, VDAC isoforms, Slc25 members, and some other membrane proteins were identified. All the mitochondrial proteins had in common high hydrophobicity over their entire protein sequences. When the proteins were fused to soluble proteins, the fused proteins showed affinity for hydroxyapatite even in the presence of Triton X-100. Based on these results, we discussed the molecular basis of the interactions between proteins and hydroxyapatite in the presence of Triton X-100. Copyright © 2013 Elsevier B.V. All rights reserved.

Analysis of Zinc-Exporters Expression in Prostate Cancer.

PubMed

Singh, Chandra K; Malas, Kareem M; Tydrick, Caitlin; Siddiqui, Imtiaz A; Iczkowski, Kenneth A; Ahmad, Nihal

2016-11-11

Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1-10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means.

Analysis of Zinc-Exporters Expression in Prostate Cancer

PubMed Central

Singh, Chandra K.; Malas, Kareem M.; Tydrick, Caitlin; Siddiqui, Imtiaz A.; Iczkowski, Kenneth A.; Ahmad, Nihal

2016-01-01

Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1–10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means. PMID:27833104

SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction.

PubMed

Yuan, Fang-Fen; Gu, Xue; Huang, Xin; Zhong, Yan; Wu, Jing

2017-07-03

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with an estimated heritability of approximately 76%. We conducted a case-control study to explore the role of the SLC6A1 gene in ADHD. The genotypes of eight variants were determined using Sequenom MassARRAY technology. The participants in the study were 302 children with ADHD and 411 controls. ADHD symptoms were assessed using the Conners Parent Symptom Questionnaire. In our study, rs2944366 was consistently shown to be associated with the ADHD risk in the dominant model (odds ratio [OR]=0.554, 95% confidence interval [CI]=0.404-0.760), and nominally associated with Hyperactive index score (P=0.027). In addition, rs1170695 has been found to be associated with the ADHD risk in the addictive model (OR=1.457, 95%CI=1.173-1.809), while rs9990174 was associated with the Hyperactive index score (P=0.010). Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactions of rs1170695 with blood lead (P mul =0.044) to modify the ADHD risk. Expression quantitative trait loci analysis suggested that these positive single nucleotide polymorphisms (SNPs) may mediate SLC6A1 gene expression. Therefore, our results suggest that selected SLC6A1 gene variants may have a significant effect on the ADHD risk. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

NASA Technical Reports Server (NTRS)

Stewart, Patricia W.; Chapes, Stephen K.

2003-01-01

Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

slc7a6os gene plays a critical role in defined areas of the developing CNS in zebrafish.

PubMed

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes.

slc7a6os Gene Plays a Critical Role in Defined Areas of the Developing CNS in Zebrafish

PubMed Central

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes. PMID:25803583

Cation-Coupled Bicarbonate Transporters

PubMed Central

Aalkjaer, Christian; Boedtkjer, Ebbe; Choi, Inyeong; Lee, Soojung

2016-01-01

Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family. PMID:25428855

1. GENERAL VIEW OF WEST FACE OF ENTRY CONTROL POINT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF WEST FACE OF ENTRY CONTROL POINT (BLDG. 768) SHOWING RELATIVE POSITION TO TECHNICAL SUPPORT BUILDING (BLDG. 762/762A) AND SLC-3 AIR FORCE BUILDING (BLDG. 761) - Vandenberg Air Force Base, Space Launch Complex 3, Entry Control Point, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Effect of monosaccharide sugars on LH-induced differentiation and sugar transport facilitator (SLC2A) expression in sheep theca cells in vitro.

PubMed

Campbell, B K; Kendall, N R; Onions, V; Guo, L; Scaramuzzi, R J

2014-03-01

The aim of the present study was to investigate the effects of glucose, galactose and fructose on the LH-induced differentiation and mRNA expression of sugar transport facilitators (SLC2A) by sheep thecal cells derived from small antral follicles cultured under serum-free conditions for 6 days. The dose and type of monosaccharide had a significant effect on LH-induced androstenedione production by theca cells and there was a significant interaction (P<0.001). Glucose and galactose were used with equal efficiency so that cell numbers and androstenedione production at the end of the culture were comparable. Pharmacological doses of glucose (16.7 mM) inhibited steroidogenesis (P<0.05). Cell numbers and androstenedione production by cells cultured with fructose were lower than for cells cultured with either glucose or galactose (P<0.001). None of the monosaccharides resulted in the production of lactate. Expression of SLC2A1, SLC2A4 and SLC2A8, but not SLC2A5, mRNA was detected in fresh and cultured theca cells. Large doses (16.7 mM) of glucose and fructose, but not galactose, suppressed (P<0.05) SLC2A expression. The results show that glucose and galactose, but not fructose, are readily metabolised via oxidative pathways to support LH-induced differentiation of sheep theca cells. Further work is required to determine the mechanisms resulting in these differences in relation to the established effects of nutrition on reproductive function.

Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

PubMed

Villani, Vanessa; Ludmer, Jaclyn; Gonzalez, Andrea; Levitan, Robert; Kennedy, James; Masellis, Mario; Basile, Vincenzo S; Wekerle, Christine; Atkinson, Leslie

2018-05-01

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Slc45a2 and V-ATPase are regulators of melanosomal pH homeostasis in zebrafish, providing a mechanism for human pigment evolution and disease.

PubMed

Dooley, Christopher M; Schwarz, Heinz; Mueller, Kaspar P; Mongera, Alessandro; Konantz, Martina; Neuhauss, Stephan C F; Nüsslein-Volhard, Christiane; Geisler, Robert

2013-03-01

We present here the positional cloning of the Danio rerio albino mutant and show that the affected gene encodes Slc45a2. The human orthologous gene has previously been shown to be involved in human skin color variation, and mutations therein have been implicated in the disease OCA4. Through ultrastructural analysis of the melanosomes in albino alleles as well as the tyrosinase-deficient mutant sandy, we add new insights into the role of Slc45a2 in the production of melanin. To gain further understanding of the role of Slc45a2 and its possible interactions with other proteins involved in melanization, we further analyzed the role of the V-ATPase as a melanosomal acidifier. We show that it is possible to rescue the melanization potential of the albino melanosomes through genetic and chemical inhibition of V-ATPase, thereby increasing internal melanosome pH. © 2012 John Wiley & Sons A/S.

SLC9A9 Co-expression modules in autism-associated brain regions.

PubMed

Patak, Jameson; Hess, Jonathan L; Zhang-James, Yanli; Glatt, Stephen J; Faraone, Stephen V

2017-03-01

SLC9A9 is a sodium hydrogen exchanger present in the recycling endosome and highly expressed in the brain. It is implicated in neuropsychiatric disorders, including autism spectrum disorders (ASDs). Little research concerning its gene expression patterns and biological pathways has been conducted. We sought to investigate its possible biological roles in autism-associated brain regions throughout development. We conducted a weighted gene co-expression network analysis on RNA-seq data downloaded from Brainspan. We compared prenatal and postnatal gene expression networks for three ASD-associated brain regions known to have high SLC9A9 gene expression. We also performed an ASD-associated single nucleotide polymorphism enrichment analysis and a cell signature enrichment analysis. The modules showed differences in gene constituents (membership), gene number, and connectivity throughout time. SLC9A9 was highly associated with immune system functions, metabolism, apoptosis, endocytosis, and signaling cascades. Gene list comparison with co-immunoprecipitation data was significant for multiple modules. We found a disproportionately high autism risk signal among genes constituting the prenatal hippocampal module. The modules were enriched with astrocyte and oligodendrocyte markers. SLC9A9 is potentially involved in the pathophysiology of ASDs. Our investigation confirmed proposed functions for SLC9A9, such as endocytosis and immune regulation, while also revealing potential roles in mTOR signaling and cell survival.. By providing a concise molecular map and interactions, evidence of cell type and implicated brain regions we hope this will guide future research on SLC9A9. Autism Res 2017, 10: 414-429. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.

PubMed

Grabe, H J; Lange, M; Wolff, B; Völzke, H; Lucht, M; Freyberger, H J; John, U; Cascorbi, I

2005-02-01

Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

PubMed

Voyiaziakis, E; Evgrafov, O; Li, D; Yoon, H-J; Tabares, P; Samuels, J; Wang, Y; Riddle, M A; Grados, M A; Bienvenu, O J; Shugart, Y Y; Liang, K-Y; Greenberg, B D; Rasmussen, S A; Murphy, D L; Wendland, J R; McCracken, J T; Piacentini, J; Rauch, S L; Pauls, D L; Nestadt, G; Fyer, A J; Knowles, J A

2011-01-01

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption

PubMed Central

Reznicek, Josef; Ceckova, Martina; Ptackova, Zuzana; Martinec, Ondrej; Tupova, Lenka; Cerveny, Lukas

2017-01-01

ABSTRACT Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo. Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir. PMID:28696229

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice

PubMed Central

Fontes, Klaus N.; Cabanelas, Adriana; Bloise, Flavia F.; de Andrade, Cherley Borba Vieira; Souza, Luana L.; Wilieman, Marianna; Trevenzoli, Isis H.; Agra, Lais C.; Silva, Johnatas D.; Bandeira-Melo, Christianne; Silva, Pedro L.; Rocco, Patricia R. M.; Ortiga-Carvalho, Tania M.

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/Slc16a2 and MCT10/Slc16a10), metabolism (Dio1, Dio2, and Dio3) and action (Thra and Thrb) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T4) and triiodothyronine (T3), expression of Dio1, Thra, Slc16a2, and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra, and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models. PMID:29118715

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyoidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice.

PubMed

Fontes, Klaus N; Cabanelas, Adriana; Bloise, Flavia F; de Andrade, Cherley Borba Vieira; Souza, Luana L; Wilieman, Marianna; Trevenzoli, Isis H; Agra, Lais C; Silva, Johnatas D; Bandeira-Melo, Christianne; Silva, Pedro L; Rocco, Patricia R M; Ortiga-Carvalho, Tania M

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/ Slc16a2 and MCT10/ Slc16a10 ), metabolism ( Dio1, Dio2 , and Dio3 ) and action ( Thra and Thrb ) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T 4 ) and triiodothyronine (T 3 ), expression of Dio1, Thra, Slc16a2 , and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T 4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra , and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models.

Genetic variation in biotransformation enzymes, air pollution exposures, and risk of spina bifida.

PubMed

Padula, Amy M; Yang, Wei; Schultz, Kathleen; Lurmann, Fred; Hammond, S Katharine; Shaw, Gary M

2018-05-01

Spina bifida is a birth defect characterized by incomplete closure of the embryonic neural tube. Genetic factors as well as environmental factors have been observed to influence risks for spina bifida. Few studies have investigated possible gene-environment interactions that could contribute to spina bifida risk. The aim of this study is to examine the interaction between gene variants in biotransformation enzyme pathways and ambient air pollution exposures and risk of spina bifida. We evaluated the role of air pollution exposure during pregnancy and gene variants of biotransformation enzymes from bloodspots and buccal cells in a California population-based case-control (86 cases of spina bifida and 208 non-malformed controls) study. We considered race/ethnicity and folic acid vitamin use as potential effect modifiers and adjusted for those factors and smoking. We observed gene-environment interactions between each of the five pollutants and several gene variants: NO (ABCC2), NO 2 (ABCC2, SLC01B1), PM 10 (ABCC2, CYP1A1, CYP2B6, CYP2C19, CYP2D6, NAT2, SLC01B1, SLC01B3), PM 2.5 (CYP1A1 and CYP1A2). These analyses show positive interactions between air pollution exposure during early pregnancy and gene variants associated with metabolizing enzymes. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of pollution. © 2018 Wiley Periodicals, Inc.

Research progress in the genetics of hyperuricaemia and gout.

PubMed

Zheng, Min; Ma, Jun-wu

2016-04-01

Gout is one of the most common inflammatory arthritis caused by hyperuricaemia, which is affected by both genetic factors and environmental factors. Early researches show that a few of rare monogenic mutations, such as PRPS1 and HPRT1 mutations, lead to abnormal purine anabolism and then cause hyperuricaemia and gout. In recent years, genome-wide association studies (GWAS) have identified dozens of susceptibility loci and/or candidate genes associated with hyperuricemia and gout. Loss-of-function mutations in SLC2A9, SLC22A11, and SLC22A12 cause hereditary hypouricaemia, while their overexpression may increase the reabsorption of uric acid. In contrast, loss-of-function mutations in ABCG2, SLC17A1, and SLC17A3 cause urate underexcretion of renal and intestinal. These variations leading to blood uric acid excretion disorder (excess reabsorption and underexcretion) are the main genetic factors affecting hyperuicemia and gout. Moreover, to some degree, inhibins-activins growth factor system, transcription factors, cytoskeleton and gene-environment interaction can also affect the level of blood uric acid. In addition, two risk genes, RFX3 and KCNQ1, which might impair immune response and lead to functional deficiency of beta cell were recently discovered to influence hyperuiceamia and gout in Han Chinese. This paper systematically reviews genetic studies on hyperuricaemia and gout to improve our understanding of pathogenesis of hyperuricaemia and gout.

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption.

PubMed

Reznicek, Josef; Ceckova, Martina; Ptackova, Zuzana; Martinec, Ondrej; Tupova, Lenka; Cerveny, Lukas; Staud, Frantisek

2017-09-01

Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir. Copyright © 2017 American Society for Microbiology.

Solute Carriers in the Blood-Brain Barier: Safety in Abundance.

PubMed

Nałęcz, Katarzyna A

2017-03-01

Blood-brain barrier formed by brain capillary endothelial cells, being in contact with astrocytes endfeet and pericytes, separates extracellular fluid from plasma. Supply of necessary nutrients and removal of certain metabolites takes place due to the activity of transporting proteins from ABC (ATP binding cassette) and SLC (solute carrier) superfamilies. This review is focused on the SLC families involved in transport though the blood-brain barrier of energetic substrates (glucose, monocarboxylates, creatine), amino acids, neurotransmitters and their precursors, as well as organic ions. Members of SLC1, SLC2, SLC3/SLC7, SLC5, SLC6, SLC16, SLC22, SLC38, SLC44, SLC47 and SLCO (SLC21), whose presence in the blood-brain barriers has been demonstrated are characterized with a special emphasis put on polarity of transporters localization in a luminal (blood side) versus an abluminal (brain side) membrane.

The solute carrier family 10 (SLC10): beyond bile acid transport

PubMed Central

da Silva, Tatiana Claro; Polli, James E.; Swaan, Peter W.

2012-01-01

The solute carrier (SLC) family 10 (SLC10) comprises influx transporters of bile acids, steroidal hormones, various drugs, and several other substrates. Because the seminal transporters of this family, namely, sodium/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2), were primarily bile acid transporters, the term “sodium bile salt cotransporting family” was used for the SLC10 family. However, this notion became obsolete with the finding of other SLC10 members that do not transport bile acids. For example, the sodium-dependent organic anion transporter (SOAT; SLC10A6) transports primarily sulfated steroids. Moreover, NTCP was shown to also transport steroids and xenobiotics, including HMG-CoA inhibitors (statins). The SLC10 family contains four additional members, namely, P3 (SLC10A3; SLC10A3), P4 (SLC10A4; SLC10A4), P5 (SLC10A5; SLC10A5) and SLC10A7 (SLC10A7), several of which were unknown or considered hypothetical until approximately a decade ago. While their substrate specificity remains undetermined, great progress has been made towards their characterization in recent years. SLC10A4 may participate in vesicular storage or exocytosis of neurotransmitters or mastocyte mediators, whereas SLC10A5 and SLC10A7 may be involved in solute transport and SLC10A3 may have a role as a housekeeping protein. Finally, the newly found role of bile acids in glucose and energy homeostasis, via the TGR5 receptor, sheds new light on the clinical relevance of ASBT and NTCP. The present mini-review provides a brief summary of recent progress on members of the SLC10 family. PMID:23506869

An update on the genetic architecture of hyperuricemia and gout.

PubMed

Merriman, Tony R

2015-04-10

Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.

Nutritional Stress Induced by Amino Acid Starvation Results in Changes for Slc38 Transporters in Immortalized Hypothalamic Neuronal Cells and Primary Cortex Cells.

PubMed

Hellsten, Sofie V; Tripathi, Rekha; Ceder, Mikaela M; Fredriksson, Robert

2018-01-01

Amino acid sensing and signaling is vital for cells, and both gene expression and protein levels of amino acid transporters are regulated in response to amino acid availability. Here, the aim was to study the regulation of all members of the SLC38 amino acid transporter family, Slc38a1-11 , in mouse brain cells following amino acid starvation. We reanalyzed microarray data for the immortalized hypothalamic cell line N25/2 subjected to complete amino acid starvation for 1, 2, 3, 5, or 16 h, focusing specifically on the SLC38 family. All 11 Slc38 genes were expressed in the cell line, and Slc38a1, Slc38a2 , and Slc38a7 were significantly upregulated at 5 h and most strongly at 16 h. Here, protein level changes were measured for SLC38A7 and the orphan family member SLC38A11 which has not been studied under different amino acid starvation condition at protein level. At 5 h, no significant alteration on protein level for either SLC38A7 or SLC38A11 could be detected. In addition, primary embryonic cortex cells were deprived of nine amino acids, the most common amino acids transported by the SLC38 family members, for 3 h, 7 h or 12 h, and the gene expression was measured using qPCR. Slc38a1, Slc38a2, Slc38a5, Slc38a6, Slc38a9 , and Slc38a10 were upregulated, while Slc38a3 and Slc38a7 were downregulated. Slc38a8 was upregulated at 5 h and downregulated at 12 h. In conclusion, several members from the SLC38 family are regulated depending on amino acid levels and are likely to be involved in amino acid sensing and signaling in brain.

Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people.

PubMed

Lemas, Dominick J; Klimentidis, Yann C; Aslibekyan, Stella; Wiener, Howard W; O'Brien, Diane M; Hopkins, Scarlett E; Stanhope, Kimber L; Havel, Peter J; Allison, David B; Fernandez, Jose R; Tiwari, Hemant K; Boyer, Bert B

2016-12-01

n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup'ik individuals (n = 1135) and 33 polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. The results suggest that an individual's genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup'ik people. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Polymorphisms in stearoyl CoA desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people

PubMed Central

Lemas, Dominick J.; Klimentidis, Yann C.; Aslibekyan, Stella; Wiener, Howard W.; O’Brien, Diane M.; Hopkins, Scarlett E.; Stanhope, Kimber L.; Havel, Peter J.; Allison, David B.; Fernandez, Jose R.; Tiwari, Hemant K.; Boyer, Bert B.

2016-01-01

Scope n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity, however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. Materials and Methods Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup’ik individuals (n=1135) and thirty-three polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. Conclusion These results suggest that an individual’s genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup’ik people. PMID:27467133

Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine.

PubMed

Martell, Henry J; Wong, Kathie A; Martin, Juan F; Kassam, Ziyan; Thomas, Kay; Wass, Mark N

2017-08-11

Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data. Using a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions. The results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria.

Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.

PubMed

Sun, Pin; Zhu, Xiangzhu; Shrubsole, Martha J; Ness, Reid M; Hibler, Elizabeth A; Cai, Qiuyin; Long, Jirong; Chen, Zhi; Li, Guoliang; Hou, Lifang; Smalley, Walter E; Edwards, Todd L; Giovannucci, Edward; Zheng, Wei; Dai, Qi

2017-09-01

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)]. Copyright © 2017 Elsevier Inc. All rights reserved.

Sperm count and motility are quantitatively affected by functional polymorphisms of HTR2A, MAOA and SLC18A.

PubMed

Cortés-Rodriguez, Miriam; Royo, Jose-Luis; Reyes-Palomares, Arturo; Lendínez, Ana M; Ruiz-Galdón, Maximiliano; Reyes-Engel, Armando

2018-05-01

Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction. Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction

PubMed Central

Jia, Yun-Fang; Choi, YuBin; Ayers-Ringler, Jennifer R.; Biernacka, Joanna M.; Geske, Jennifer R.; Lindberg, Daniel R.; McElroy, Susan L.; Frye, Mark A.; Choi, Doo-Sup; Veldic, Marin

2017-01-01

While downregulation of excitatory amino acid transporter 2 (EAAT2), the main transporter removing glutamate from the synapse, has been recognized in bipolar disorder (BD), the underlying mechanisms of downregulation have not been elucidated. BD is influenced by environmental factors, which may, via epigenetic modulation of gene expression, differentially affect illness presentation. This study thus focused on epigenetic DNA methylation regulation of SLC1A2, encoding for EAAT2, in BD with variable environmental influences of addiction. High resolution melting PCR (HRM-PCR) and thymine–adenine (TA) cloning with sequence analysis were conducted to examine methylation of the promoter region of the SLC1A2. DNA was isolated from blood samples drawn from BD patients (N = 150) with or without addiction to alcohol, nicotine, or food, defined as binge eating, and matched controls (N = 32). In comparison to controls, the SLC1A2 promoter region was hypermethylated in BD without addiction but was hypomethylated in BD with addiction. After adjusting for age and sex, the association of methylation levels with nicotine addiction (p = 0.0009) and binge eating (p = 0.0002) remained significant. Consistent with HRM-PCR, direct sequencing revealed increased methylation in CpG site 6 in BD, but decreased methylation in three CpG sites (6, 48, 156) in BD with alcohol and nicotine addictions. These results suggest that individual point methylation within the SLC1A2 promoter region may be modified by exogenous addiction and may have a potential for developing clinically valuable epigenetic biomarkers for BD diagnosis and monitoring. PMID:28785205

Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction.

PubMed

Jia, Yun-Fang; Choi, YuBin; Ayers-Ringler, Jennifer R; Biernacka, Joanna M; Geske, Jennifer R; Lindberg, Daniel R; McElroy, Susan L; Frye, Mark A; Choi, Doo-Sup; Veldic, Marin

2017-01-01

While downregulation of excitatory amino acid transporter 2 (EAAT2), the main transporter removing glutamate from the synapse, has been recognized in bipolar disorder (BD), the underlying mechanisms of downregulation have not been elucidated. BD is influenced by environmental factors, which may, via epigenetic modulation of gene expression, differentially affect illness presentation. This study thus focused on epigenetic DNA methylation regulation of SLC1A2 , encoding for EAAT2, in BD with variable environmental influences of addiction. High resolution melting PCR (HRM-PCR) and thymine-adenine (TA) cloning with sequence analysis were conducted to examine methylation of the promoter region of the SLC1A2 . DNA was isolated from blood samples drawn from BD patients ( N = 150) with or without addiction to alcohol, nicotine, or food, defined as binge eating, and matched controls ( N = 32). In comparison to controls, the SLC1A2 promoter region was hypermethylated in BD without addiction but was hypomethylated in BD with addiction. After adjusting for age and sex, the association of methylation levels with nicotine addiction ( p = 0.0009) and binge eating ( p = 0.0002) remained significant. Consistent with HRM-PCR, direct sequencing revealed increased methylation in CpG site 6 in BD, but decreased methylation in three CpG sites (6, 48, 156) in BD with alcohol and nicotine addictions. These results suggest that individual point methylation within the SLC1A2 promoter region may be modified by exogenous addiction and may have a potential for developing clinically valuable epigenetic biomarkers for BD diagnosis and monitoring.

Natural history of SLC11 genes in vertebrates: tales from the fish world.

PubMed

Neves, João V; Wilson, Jonathan M; Kuhl, Heiner; Reinhardt, Richard; Castro, L Filipe C; Rodrigues, Pedro N S

2011-04-18

The SLC11A1/Nramp1 and SLC11A2/Nramp2 genes belong to the SLC11/Nramp family of transmembrane divalent metal transporters, with SLC11A1 being associated with resistance to pathogens and SLC11A2 involved in intestinal iron uptake and transferrin-bound iron transport. Both members of the SLC11 gene family have been clearly identified in tetrapods; however SLC11A1 has never been documented in teleost fish and is believed to have been lost in this lineage during early vertebrate evolution. In the present work we characterized the SLC11 genes in teleosts and evaluated if the roles attributed to mammalian SLC11 genes are assured by other fish specific SLC11 gene members. Two different SLC11 genes were isolated in the European sea bass (Dicentrarchus. labrax), and named slc11a2-α and slc11a2-β, since both were found to be evolutionary closer to tetrapods SLC11A2, through phylogenetic analysis and comparative genomics. Induction of slc11a2-α and slc11a2-β in sea bass, upon iron modulation or exposure to Photobacterium damselae spp. piscicida, was evaluated in in vivo or in vitro experimental models. Overall, slc11a2-α was found to respond only to iron deficiency in the intestine, whereas slc11a2-β was found to respond to iron overload and bacterial infection in several tissues and also in the leukocytes. Our data suggests that despite the absence of slc11a1, its functions have been undertaken by one of the slc11a2 duplicated paralogs in teleost fish in a case of synfunctionalization, being involved in both iron metabolism and response to bacterial infection. This study provides, to our knowledge, the first example of this type of sub-functionalization in iron metabolism genes, illustrating how conserving the various functions of the SLC11 gene family is of crucial evolutionary importance.

Knockdown of SLC41A1 magnesium transporter promotes mineralization and attenuates magnesium inhibition during osteogenesis of mesenchymal stromal cells.

PubMed

Tsao, Yu-Tzu; Shih, Ya-Yi; Liu, Yu-An; Liu, Yi-Shiuan; Lee, Oscar K

2017-02-21

Magnesium is essential for numerous physiological functions. Magnesium exists mostly in bone and the amount is dynamically regulated by skeletal remodeling. Accelerating bone mass loss occurs when magnesium intake is insufficient; whereas high magnesium could lead to mineralization defects. However, the underlying magnesium regulatory mechanisms remain elusive. In the present study, we investigated the effects of high extracellular magnesium concentration on osteogenic differentiation of mesenchymal stromal/stem cells (MSCs) and the role of magnesium transporter SLC41A1 in the mineralization process. Murine MSCs derived from the bone marrow of BALB/c mouse or commercially purchased human MSCs were treated with osteogenic induction medium containing 5.8 mM magnesium chloride and the osteogenic differentiation efficiency was compared with that of MSCs in normal differentiation medium containing 0.8 mM magnesium chloride by cell morphology, gene expression profile of osteogenic markers, and Alizarin Red staining. Slc41a1 gene knockdown in MSCs was performed by siRNA transfection using Lipofectamine RNAiMAX, and the differentiation efficiency of siRNA-treated MSCs was also assessed. High concentration of extracellular magnesium ion inhibited mineralization during osteogenic differentiation of MSCs. Early osteogenic marker genes including osterix, alkaline phosphatase, and type I collagen were significantly downregulated in MSCs under high concentration of magnesium, whereas late marker genes such as osteopontin, osteocalcin, and bone morphogenetic protein 2 were upregulated with statistical significance compared with those in normal differentiation medium containing 0.8 mM magnesium. siRNA treatment targeting SLC41A1 magnesium transporter, a member of the solute carrier family with a predominant Mg 2+ efflux system, accelerated the mineralization process and ameliorated the inhibition of mineralization caused by high concentration of magnesium. High concentration of magnesium significantly upregulated Dkk1 gene expression and the upregulation was attenuated after the Slc41a1 gene was knocked down. Immunofluorescent staining showed that Slc41a1 gene knockdown promoted the translocation of phosphorylated β-catenin into nuclei. In addition, secreted MGP protein was elevated after Slc41a1 was knocked down. High concentration of extracellular magnesium modulates gene expression of MSCs during osteogenic differentiation and inhibits the mineralization process. Additionally, we identified magnesium transporter SLC41A1 that regulates the interaction of magnesium and MSCs during osteogenic differentiation. Wnt signaling is suggested to be involved in SLC41A1-mediated regulation. Tissue-specific SLC41A1 could be a potential treatment for bone mass loss; in addition, caution should be taken regarding the role of magnesium in osteoporosis and the design of magnesium alloys for implantation.

Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants.

PubMed

Kao, Liyo; Azimov, Rustam; Shao, Xuesi M; Frausto, Ricardo F; Abuladze, Natalia; Newman, Debra; Aldave, Anthony J; Kurtz, Ira

2016-11-01

Congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (CHED with progressive sensorineural deafness), and potentially a subset of individuals with late-onset Fuchs' endothelial corneal dystrophy are caused by mutations in the SLC4A11 gene that results in corneal endothelial cell abnormalities. Originally classified as a borate transporter, the function of SLC4A11 as a transport protein remains poorly understood. Elucidating the transport function(s) of SLC4A11 is needed to better understand how its loss results in the aforementioned posterior corneal dystrophic disease processes. Quantitative PCR experiments demonstrated that, of the three known human NH 2 -terminal variants, SLC4A11-C is the major transcript expressed in human corneal endothelium. We studied the expression pattern of the three variants in mammalian HEK-293 cells and demonstrated that the SLC4A11-B and SLC4A11-C variants are plasma membrane proteins, whereas SLC4A11-A is localized intracellularly. SLC4A11-B and SLC4A11-C were shown to be multifunctional ion transporters capable of transporting H + equivalents in both a Na + -independent and Na + -coupled mode. In both transport modes, SLC4A11-C H + flux was significantly greater than SLC4A11-B. In the presence of ammonia, SLC4A11-B and SLC4A11-C generated inward currents that were comparable in magnitude. Chimera SLC4A11-C-NH 2 -terminus-SLC4A11-B experiments demonstrated that the SLC4A11-C NH 2 -terminus functions as an autoactivating domain, enhancing Na + -independent and Na + -coupled H + flux without significantly affecting the electrogenic NH 3 -H (n) + cotransport mode. All three modes of transport were significantly impaired in the presence of the CHED causing p.R109H (SLC4A11-C numbering) mutation. These complex ion transport properties need to be addressed in the context of corneal endothelial disease processes caused by mutations in SLC4A11. Copyright © 2016 the American Physiological Society.

Solute carriers (SLCs) identified and characterized from kidney transcriptome of golden mahseer (Tor putitora) (Fam: Cyprinidae).

PubMed

Barat, Ashoktaru; Sahoo, Prabhati Kumari; Kumar, Rohit; Pande, Veena

2016-10-01

The solute carriers (SLC) are trans-membrane proteins, those regulate the transport of various substances (sugars, amino acids, nucleotides, inorganic cations/anions, metals, drugs etc.) across the cell membrane. There are more than 338 solute carriers (slc) reported in fishes that play crucial role in cellular influx and efflux. The study of solute carrier families may reveal many answers regarding the function of transporter genes in the species and their effect in the existing environment. Therefore, we performed RNA sequencing of kidney tissue of the golden mahseer (Tor putitora) using Illumina platform to identify the solute carrier families and characterized 24 putative functional genes under 15 solute carrier families. Out of 24 putative functional genes, 11 genes were differentially expressed in different tissues (head kidney, trunk kidney, spleen, liver, gill, muscle, intestine and brain) using qRT-PCR assay. The slc5a1, slc5a12, slc12a3, slc13a3, slc22a13 and slc26a6 were highly expressed in kidney. The slc15a2, slc25a47, slc33a1 and slc38a2 were highly expressed in brain and slc30a5 was over-expressed in gill. The unrooted phylogenetic trees of slc2, slc5, slc13 and slc33 were constructed using amino acid sequences of Homo sapiens, Salmo salar, Danio rerio, Cyprinus carpio and Tor putitora. It appears that all the putative solute carrier families are very much conserved in human and fish species including the present fish, golden mahseer. This study provides the first hand database of solute carrier families particularly transporter encoding proteins in the species. Copyright © 2016 Elsevier Inc. All rights reserved.

Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies

PubMed Central

Loganathan, Sampath K.; Schneider, Hans-Peter; Morgan, Patricio E.; Deitmer, Joachim W.

2016-01-01

SLC4A11, a member of the SLC4 family of bicarbonate transporters, is a widely expressed integral membrane protein, abundant in kidney and cornea. Mutations of SLC4A11 cause some cases of the blinding corneal dystrophies, congenital hereditary endothelial dystrophy, and Fuchs endothelial corneal dystrophy. These diseases are marked by fluid accumulation in the corneal stroma, secondary to defective fluid reabsorption by the corneal endothelium. The role of SLC4A11 in these corneal dystrophies is not firmly established, as SLC4A11 function remains unclear. To clarify the normal function(s) of SLC4A11, we characterized the protein following expression in the simple, low-background expression system Xenopus laevis oocytes. Since plant and fungal SLC4A11 orthologs transport borate, we measured cell swelling associated with accumulation of solute borate. The plant water/borate transporter NIP5;1 manifested borate transport, whereas human SLC4A11 did not. SLC4A11 supported osmotically driven water accumulation that was electroneutral and Na+ independent. Studies in oocytes and HEK293 cells could not detect Na+-coupled HCO3− transport or Cl−/HCO3− exchange by SLC4A11. SLC4A11 mediated electroneutral NH3 transport in oocytes. Voltage-dependent OH− or H+ movement was not measurable in SLC4A11-expressing oocytes, but SLC4A11-expressing HEK293 cells manifested low-level cytosolic acidification at baseline. In mammalian cells, but not oocytes, OH−/H+ conductance may arise when SLC4A11 activates another protein or itself is activated by another protein. These data argue against a role of human SLC4A11 in bicarbonate or borate transport. This work provides additional support for water and ammonia transport by SLC4A11. When expressed in oocytes, SLC4A11 transported NH3, not NH3/H+. PMID:27558157

Slc26a6: a cardiac chloride–hydroxyl exchanger and predominant chloride–bicarbonate exchanger of the mouse heart

PubMed Central

Alvarez, Bernardo V; Kieller, Dawn M; Quon, Anita L; Markovich, Daniel; Casey, Joseph R

2004-01-01

Bicarbonate facilitate more than 50% of pH recovery in the acidotic myocardium, and have roles in cardiac hypertrophy and steady-state pH regulation. To determine which bicarbonate transporters are responsible for this activity, we measured the expression levels of all known HCO3−–anion exchange proteins in mouse heart, by quantitative real time RT-PCR. Bicarbonate–anion exchangers are members of either the SLC4A or the SLC26A gene families. In neonatal and adult myocardium, AE1 (Slc4a1), AE2 (Slc4a2), AE3 (Slc4a3) (AE3fl and AE3c variants), Slc26a3 and Slc26a6 were expressed. Adult hearts expressed Slc26a3 and Slc4a1–3 mRNAs at similar levels, while Slc26a6 mRNA was about seven-fold higher than AE3, which was more abundant than any other. Immunohistochemistry revealed that Slc26a6 and AE3 are present in the plasma membrane of ventricular myocytes. Slc26a6 expression levels were higher in ventricle than atrium, whereas AE3 was detected only in ventricle. Cl−–HCO3− and Cl−–OH− exchange activity of SLC26A6 and AE3 were investigated in transfected HEK293 cells, using intracellular fluorescence measurements of 2′,7′-bis (2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), to monitor intracellular pH (pHi). Rates of pHi change were measured under HCO3−-containing (Cl−–HCO3−) or nominally HCO3−-free (Cl−–OH−) conditions. HCO3− fluxes were similar for cells expressing AE3fl, SLC26A6 or Slc26a3, suggesting that they have similar transport activity. However, only SLC26A6 and Slc26a3 functioned as Cl−–OH− exchangers. Activation of α-adrenergic receptors, which stimulates protein kinase C, inhibited SLC26A6 Cl−–HCO3− exchange activity. We conclude that Slc26a6 is the predominant Cl−–HCO3− and Cl−–OH− exchanger of the myocardium and that Slc26a6 is negatively regulated upon α-adrenergic stimulation. PMID:15498800

Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52.

PubMed

Yonezawa, Atsushi; Inui, Ken-ichi

2013-01-01

Riboflavin, a water-soluble vitamin also known as vitamin B2, is essential for normal cellular functions. Riboflavin transporters play important roles in its homeostasis. Recently, three novel riboflavin transporters were identified, and designated as RFT1, RFT2 and RFT3. Because the RFTs did not show similarity to other SLC transporters, and RFT1 and RFT3 are similar in sequence and function, they were assigned into a new SLC family, SLC52. Subsequently, RFT1/GPR172B, RFT3/GPR172A and RFT2/C20orf54 were renamed as RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3, respectively. In this review, we summarize recent findings on the cloning, nomenclature, functional characterization and genetic diseases of RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Combined Study of SLC6A15 Gene Polymorphism and the Resting-State Functional Magnetic Resonance Imaging in First-Episode Drug-Naive Major Depressive Disorder.

PubMed

Wang, Lijuan; Liu, Zhifen; Cao, Xiaohua; Li, Jianying; Zhang, Aixia; Sun, Ning; Yang, Chunxia; Zhang, Kerang

2017-09-01

The SLC6A15 gene has been identified as a novel candidate gene for major depressive disorder (MDD). However, the mechanism underlying the effects of how the SLC6A15 gene affects functional brain activity of patients with MDD remains unknown. In the present study, we investigated the effect of the SLC6A15 gene polymorphism, rs1545843, on resting-state brain function in MDD with the imaging genomic technology and the regional homogeneity (ReHo) method. Sixty-seven MDD patients and 44 healthy controls underwent functional magnetic resonance imaging scans and genotyping. The differences in ReHo between genotypes were initially tested using the student's t test. We then performed a 2 × 2 (genotypes × disease status) analysis of variance to identify the main effects of genotypes, disease status, and their interactions in MDD. MDD patients with A+ genotypes showed decreased ReHo in the medial cingulum compared with MDD patients with the GG genotype. This was in contrast to normal controls with A+ genotypes who showed increased ReHo in the posterior cingulum and the frontal, temporal, and parietal lobes and decreased ReHo in the left corpus callosum, compared with controls with the GG genotypes. The main effect of disease was found in the frontal, parietal, and temporal lobes. The main effect of genotypes was found in the left corpus callosum and the frontal lobe. There was no interaction between rs1545843 genotypes and disease status. We found that the left corpus callosum ReHo was positively correlated with total scores of the Hamilton Depression Scale (HAMD) (p = 0.021), so as was the left inferior parietal gyrus ReHo with cognitive disorder (p = 0.02). In addition, the right middle temporal gyrus had a negative correlation with retardation (p = 0.049). We observed an association between the SLC6A15 rs1545843 and resting-state brain function of the corpus callosum, cingulum and the frontal, parietal, and temporal lobes in MDD patients, which may be involved in the pathogenesis of MDD.

Garnet Pyroxenites from Kaula, Hawaii: Implications for Plume-Lithosphere Interaction

NASA Astrophysics Data System (ADS)

Bizimis, M.; Garcia, M. O.; Norman, M. D.

2006-12-01

The presence of garnet pyroxenite xenoliths on Oahu and Kaula Islands, Hawaii, provides the rare opportunity to investigate the composition of the deeper oceanic mantle lithosphere and the nature of plume-lithosphere interaction in two dimensions, downstream from the center of the Hawaiian plume. Kaula (60 miles SW of Kauai) is on the same bathymetric shallow as Kauai and the Kaula-Niihau-Kauai islands form a cross-trend relationship to the Hawaiian Island ridge. Here, we present the first Sr-Nd isotope data on clinopyroxenes (cpx) from Kaula pyroxenites, and we compare them with the Salt Lake Crater (SLC) pyroxenites from Oahu. The Kaula cpx major element compositions overlap those of the (more variable) SLC pyroxenites (e.g. Mg# = 0.79-0.83), except for their higher Al2O3 contents (9% vs. 5-8%) than the SLC. The Kaula cpx are LREE enriched with elevated Dy/Yb ratios, similar to the SLC pyroxenites and characteristic of the presence of garnet that preferentially incorporates the HREE. In Sr-Nd isotope space, the Kaula pyroxenite compositions (87Sr/86Sr= 0.70312-0.70326, ɛNd= 7.2-8.6) overlap those of both the Oahu-Kauai post erosional lavas and the SLC pyroxenites, falling at the isotopically depleted end of the Hawaiian lava compositions. The depleted Sr-Nd isotope compositions of the Kaula pyroxenites suggest that they are not related to the isotopically enriched shield stage Hawaiian lavas, either as a source material (i.e. recycled eclogite) or as cumulates. Their elevated 87Sr/86Sr ratios relative to MORB also suggests that they are not likely MORB-related cumulates. The similarities between the Oahu and Kaula pyroxenites, some 200 km apart, suggest the widespread presence of pyroxenitic material in the deeper (>60km) Pacific lithosphere between Oahu and Kaula-Kauai, as high pressure cumulates from melts isotopically similar to the secondary Hawaiian volcanism. The presence of this material within the lower lithosphere is consistent with seismic observations suggesting erosion and replacement of the deeper Pacific lithosphere by plume material, downstream from the center of the plume.

Conformational state interactions provide clues to the pharmacochaperone potential of serotonin transporter partial substrates

PubMed Central

Bhat, Shreyas; Hasenhuetl, Peter S.; Kasture, Ameya; El-Kasaby, Ali; Baumann, Michael H.; Blough, Bruce E.; Sucic, Sonja; Sandtner, Walter; Freissmuth, Michael

2017-01-01

Point mutations in SLC6 transporters cause misfolding, which can be remedied by pharmacochaperones. The serotonin transporter (SERT/SLC6A4) has a rich pharmacology including inhibitors, releasers (amphetamines, which promote the exchange mode), and more recently, discovered partial substrates. We hypothesized that partial substrates trapped the transporter in one or several states of the transport cycle. This conformational trapping may also be conducive to folding. We selected naphthylpropane-2-amines of the phenethylamine library (PAL) including the partial substrate PAL1045 and its congeners PAL287 and PAL1046. We analyzed their impact on the transport cycle of SERT by biochemical approaches and by electrophysiological recordings; substrate-induced peak currents and steady-state currents monitored the translocation of substrate and co-substrate Na+ across the lipid bilayer and the transport cycle, respectively. These experiments showed that PAL1045 and its congeners bound with different affinities (ranging from nm to μm) to various conformational intermediates of SERT during the transport cycle. Consistent with the working hypothesis, PAL1045 was the most efficacious compound in restoring surface expression and transport activity to the folding-deficient mutant SERT-601PG602-AA. These experiments provide a proof-of-principle for a rational search for pharmacochaperones, which may be useful to restore function to clinically relevant folding-deficient transporter mutants. PMID:28842491

Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition-metal ion transport.

PubMed

Ehrnstorfer, Ines A; Geertsma, Eric R; Pardon, Els; Steyaert, Jan; Dutzler, Raimund

2014-11-01

Members of the SLC11 (NRAMP) family transport iron and other transition-metal ions across cellular membranes. These membrane proteins are present in all kingdoms of life with a high degree of sequence conservation. To gain insight into the determinants of ion selectivity, we have determined the crystal structure of Staphylococcus capitis DMT (ScaDMT), a close prokaryotic homolog of the family. ScaDMT shows a familiar architecture that was previously identified in the amino acid permease LeuT. The protein adopts an inward-facing conformation with a substrate-binding site located in the center of the transporter. This site is composed of conserved residues, which coordinate Mn2+, Fe2+ and Cd2+ but not Ca2+. Mutations of interacting residues affect ion binding and transport in both ScaDMT and human DMT1. Our study thus reveals a conserved mechanism for transition-metal ion selectivity within the SLC11 family.

Association between SLC11A1 (NRAMP1) polymorphisms and susceptibility to tuberculosis in Chinese Holstein cattle.

PubMed

Liu, Kaihua; Zhang, Bin; Teng, Zhaochun; Wang, Youtao; Dong, Guodong; Xu, Cong; Qin, Bo; Song, Chunlian; Chai, Jun; Li, Yang; Shi, Xianwei; Shu, Xianghua; Zhang, Yifang

2017-03-01

We investigated the associations between SLC11A1 polymorphisms and susceptibility to tuberculosis (TB) in Chinese Holstein cattle, using a case-control study of 136 animals that had positive reactions to TB tests and showed symptoms and 96 animals that had negative reactions to tests and showed no symptoms. Polymerase chain reaction (PCR) sequencing and the restriction fragment length polymorphism (RFLP) technique were used to detect and determine SLC11A1 polymorphisms. Association analysis identified significant correlations between SLC11A1 polymorphisms and susceptibility/resistance to TB, and two genetic markers for SLC11A1 were established using PCR-RFLP. Sequence alignment of SLC11A1 revealed seven single-nucleotide polymorphisms (SNPs). This is the first report of MaeII PCR-RFLP markers for the SLC11A1-SNP3 site and PstI PCR-RFLP markers for the SLC11A1-SNP5 and SLC11A1-SNP6 sites in Chinese Holstein cattle. Logistic regression analysis indicated that SLC11A1-SNP1, SLC11A1-SNP3, and SLC11A1-SNP5 were significantly associated with susceptibility/resistance to TB. Two genotypes of SLC11A1-SNP3 were susceptible to TB, whereas one genotype of SLC11A1-SNP1 and two genotypes of SLC11A1-SNP5 were resistant. Haplotype analysis showed that nine haplotypes were potentially resistant to TB. After Bonferroni correction, three of the haplotypes remained significantly associated with TB resistance. SLC11A1 is a useful candidate gene related to TB in Chinese Holstein cattle. Copyright © 2016 Elsevier Ltd. All rights reserved.

Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model.

PubMed

Zhang, Wenlin; Ogando, Diego G; Kim, Edward T; Choi, Moon-Jung; Li, Hongde; Tenessen, Jason M; Bonanno, Joseph A

2017-07-01

To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11-/- mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-γ dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11-/- C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC-MS). The immortalized Slc4a11+/+ and Slc4a11-/- mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-γ dependent. Slc4a11-/- MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11-/- mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11-/- MCECs. Furthermore, Slc4a11-/- MCECs recapitulate the glutaminolysis defects observed in Slc4a11-/- mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents.

Sodium-dependent bile salt transporters of the SCL10A Transporter Family: More than solute transporters

PubMed Central

Anwer, M. Sawkat; Stieger, Bruno

2013-01-01

Summary The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na+-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide or NTCP) and SLC10A2 (apical sodium-dependent bile salt transporter or ASBT) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes. PMID:24196564

Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib.

PubMed

Carlin, Marcelo Paschoalete; Scherrer, Daniel Zanetti; De Tommaso, Adriana Maria Alves; Bertuzzo, Carmen Silvia; Steiner, Carlos Eduardo

2013-12-01

Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.

Differential expression of the Slc4 bicarbonate transporter family in murine corneal endothelium and cell culture.

PubMed

Shei, William; Liu, Jun; Htoon, Hla M; Aung, Tin; Vithana, Eranga N

2013-01-01

To characterize the relative expression levels of all the solute carrier 4 (Slc4) transporter family members (Slc4a1-Slc4a11) in murine corneal endothelium using real-time quantitative (qPCR), to identify further important members besides Slc4a11 and Slc4a4, and to explore how close to the baseline levels the gene expressions remain after cells have been subjected to expansion and culture. Descemet's membrane-endothelial layers of 8-10-week-old C57BL6 mice were stripped from corneas and used for both primary cell culture and direct RNA extraction. Total RNA (from uncultured cells as well as cultured cells at passages 2 and 7) was reverse transcribed, and the cDNA was used for real time qPCR using specific primers for all the Slc4 family members. The geNorm method was applied to determine the most stable housekeeping genes and normalization factor, which was calculated from multiple housekeeping genes for more accurate and robust quantification. qPCR analyses revealed that all Slc4 bicarbonate transporter family members were expressed in mouse corneal endothelium. Slc4a11 showed the highest expression, which was approximately three times higher than that of Slc4a4 (3.4±0.3; p=0.004). All Slc4 genes were also expressed in cultured cells, and interestingly, the expression of Slc4a11 in cultured cells was significantly reduced by approximately 20-fold (0.05±0.001; p=0.000001) in early passage and by approximately sevenfold (0.14±0.002; p=0.000002) in late passage cells. Given the known involvement of SLC4A4 and SLC4A11 in corneal dystrophies, we speculate that the other two highly expressed genes in the uncultured corneal endothelium, SLC4A2 and SLC4A7, are worthy of being considered as potential candidate genes for corneal endothelial diseases. Moreover, as cell culture can affect expression levels of Slc4 genes, caution and careful design of experiments are necessary when undertaking studies of Slc4-mediated ion transport in cultured cells.

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

PubMed Central

Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, Matthias

2011-01-01

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. PMID:21779389

Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion

PubMed Central

Syring, Kristen E.; Boortz, Kayla A.; Oeser, James K.; Ustione, Alessandro; Platt, Kenneth A.; Shadoan, Melanie K.; McGuinness, Owen P.; Piston, David W.; Powell, David R.

2016-01-01

Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function. PMID:27754787

Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6.

PubMed

Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy; Thai, Phung N; Ren, Lu; Kim, Hyo Jeong; Park, Seojin; Lee, Jeong Han; Dai, Gu; Moshref, Maryam; Sihn, Choong-Ryoul; Chen, Wei Chun; Timofeyeva, Maria Valeryevna; Jian, Zhong; Shimkunas, Rafael; Izu, Leighton T; Chiamvimonvat, Nipavan; Chen-Izu, Ye; Yamoah, Ebenezer N; Zhang, Xiao-Dong

2017-10-01

Intracellular pH (pH i ) is critical to cardiac excitation and contraction; uncompensated changes in pH i impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH i regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl - /HCO 3 - exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH i , but also cardiac excitability. To test the mechanistic role of Slc26a6 in the heart, we took advantage of Slc26a6 knockout ( Slc26a6 -/ - ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of Slc26a6 results in action potential shortening. There are reduced Ca 2+ transient and sarcoplasmic reticulum Ca 2+ load, together with decreased sarcomere shortening in Slc26a6 -/ - cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH i is elevated in Slc26a6 -/ - cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl - /HCO 3 - exchange activities of Slc26a6. Moreover, Slc26a6 -/ - mice show evidence of sinus bradycardia and fragmented QRS complex, supporting the critical role of Slc26a6 in cardiac conduction system. Our study provides mechanistic insights into Slc26a6, a unique cardiac electrogenic Cl - /HCO 3 - transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH i , excitability, and contractility. pH i is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6 -/ - mice. © 2017 American Heart Association, Inc.

Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant

PubMed Central

Kanoni, Stavroula; Nettleton, Jennifer A.; Hivert, Marie-France; Ye, Zheng; van Rooij, Frank J.A.; Shungin, Dmitry; Sonestedt, Emily; Ngwa, Julius S.; Wojczynski, Mary K.; Lemaitre, Rozenn N.; Gustafsson, Stefan; Anderson, Jennifer S.; Tanaka, Toshiko; Hindy, George; Saylor, Georgia; Renstrom, Frida; Bennett, Amanda J.; van Duijn, Cornelia M.; Florez, Jose C.; Fox, Caroline S.; Hofman, Albert; Hoogeveen, Ron C.; Houston, Denise K.; Hu, Frank B.; Jacques, Paul F.; Johansson, Ingegerd; Lind, Lars; Liu, Yongmei; McKeown, Nicola; Ordovas, Jose; Pankow, James S.; Sijbrands, Eric J.G.; Syvänen, Ann-Christine; Uitterlinden, André G.; Yannakoulia, Mary; Zillikens, M. Carola; Wareham, Nick J.; Prokopenko, Inga; Bandinelli, Stefania; Forouhi, Nita G.; Cupples, L. Adrienne; Loos, Ruth J.; Hallmans, Goran; Dupuis, Josée; Langenberg, Claudia; Ferrucci, Luigi; Kritchevsky, Stephen B.; McCarthy, Mark I.; Ingelsson, Erik; Borecki, Ingrid B.; Witteman, Jacqueline C.M.; Orho-Melander, Marju; Siscovick, David S.; Meigs, James B.; Franks, Paul W.; Dedoussis, George V.

2011-01-01

OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels. PMID:21810599

Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression

PubMed Central

Traurig, Michael; Hanson, Robert L.; Marinelarena, Alejandra; Kobes, Sayuko; Piaggi, Paolo; Cole, Shelley; Curran, Joanne E.; Blangero, John; Göring, Harald; Kumar, Satish; Nelson, Robert G.; Howard, Barbara V.; Knowler, William C.; Baier, Leslie J.

2016-01-01

Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10−7) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10−15) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. PMID:26487785

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

PubMed

Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

2015-11-09

The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism

PubMed Central

Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

2015-01-01

The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2.

PubMed

Kommareddi, Pavan; Nair, Thankam; Kakaraparthi, Bala Naveen; Galano, Maria M; Miller, Danielle; Laczkovich, Irina; Thomas, Trey; Lu, Lillian; Rule, Kelli; Kabara, Lisa; Kanicki, Ariane; Hughes, Elizabeth D; Jones, Julie M; Hoenerhoff, Mark; Fisher, Susan G; Altschuler, Richard A; Dolan, David; Kohrman, David C; Saunders, Thomas L; Carey, Thomas E

2015-12-01

SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like protein 2), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3–10 (Slc44a2(Δ/Δ)resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2Δ allele were backcrossed to the ARHL-resistant FVB/NJ strain and evaluated after backcross seven(N7) (99 % FVB). Slc44a2(Δ/Δ) mice produced abnormally spliced Slc44a2 transcripts that contain a frame shift and premature stop codons. Neither full-length SLC44A2 nor a putative truncated protein could be detected in Slc44a2(Δ/Δ) mice, suggesting a likely null allele. Auditory brain stem responses (ABRs) of mice carrying the Slc44a2Δ allele on an FVB/NJ genetic background were tested longitudinally between the ages of 2 and 10 months. By 6 months of age,Slc44a2(Δ/Δ) mice exhibited hearing loss at 32 kHz,but at 12 and 24 kHz had sound thresholds similar to those of wild-type Slc44a2(+/+) and heterozygous +/Slc44a2Δ mice. After 6 months of age, Slc44a2(Δ/Δ) mutants exhibited progressive hearing loss at all frequencies and +/Slc44a2(Δ) mice exhibited moderate threshold elevations at high frequency. Histologic evaluation of Slc44a2(Δ/Δ) mice revealed extensive hair cell and spiral ganglion cell loss, especially in the basal turn of the cochlea. We conclude that Slc44a2 function is required for long-term hair cell survival and maintenance of hearing.

Conditionally Immortal Slc4a11−/− Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11−/− Mouse Model

PubMed Central

Zhang, Wenlin; Ogando, Diego G.; Kim, Edward T.; Choi, Moon-Jung; Li, Hongde; Tenessen, Jason M.; Bonanno, Joseph A.

2017-01-01

Purpose To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11−/− mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. Methods We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-γ dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11−/− C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC-MS). Results The immortalized Slc4a11+/+ and Slc4a11−/− mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-γ dependent. Slc4a11−/− MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11−/− mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. Conclusions This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11−/− MCECs. Furthermore, Slc4a11−/− MCECs recapitulate the glutaminolysis defects observed in Slc4a11−/− mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents. PMID:28738416

Drosophila SLC5A11 Mediates Hunger by Regulating K(+) Channel Activity.

PubMed

Park, Jin-Yong; Dus, Monica; Kim, Seonil; Abu, Farhan; Kanai, Makoto I; Rudy, Bernardo; Suh, Greg S B

2016-08-08

Hunger is a powerful drive that stimulates food intake. Yet, the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11-a sodium/solute co-transporter-like-(or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sugar after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain increase significantly when flies are starved and decrease shortly after starved flies are refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of the Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knockdown of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state. Copyright © 2016 Elsevier Ltd. All rights reserved.

The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38.

PubMed

Sundberg, Björn E; Wååg, Elin; Jacobsson, Josefin A; Stephansson, Olga; Rumaks, Juris; Svirskis, Simons; Alsiö, Johan; Roman, Erika; Ebendal, Ted; Klusa, Vija; Fredriksson, Robert

2008-06-01

Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the beta-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian beta-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the beta-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.

Reducing Emergency Department Utilization Through Engagement in Telemedicine by Senior Living Communities.

PubMed

Gillespie, Suzanne M; Shah, Manish N; Wasserman, Erin B; Wood, Nancy E; Wang, Hongyue; Noyes, Katia; Nelson, Dallas; Dozier, Ann; McConnochie, Kenneth M

2016-06-01

High-intensity telemedicine has been shown to reduce the need for emergency department (ED) care for older adult senior living community (SLC) residents with acute illnesses. We evaluated the effect of SLC engagement in the telemedicine program on ED use rates. We performed a secondary analysis of data from a prospective cohort study evaluating the effectiveness of high-intensity telemedicine for SLC residents. We compared the annual rate of change in ED use among subjects who resided in SLC units that were more engaged in telemedicine services with that among subjects who resided in SLC units that were less engaged in telemedicine and control subjects who lived at facilities without access to telemedicine services. During the study, subjects had 503 telemedicine visits, with 362 (72.0%) in the more engaged SLCs and 141 (28.0%) in the less engaged SLCs. For subjects residing in more engaged SLCs, ED use decreased at an annualized rate of 28% (rate ratio [RR] = 0.72; 95% confidence interval [CI], 0.58-0.89), whereas in the less engaged (RR = 0.962; 95% CI, 0.776-1.19) and control (RR = 0.909, 95% CI, 0.822-1.07) groups there was no significant change in ED use (p = 0.036 for group × time interaction). Individuals residing in more engaged SLCs experienced a greater decrease in ED use compared with subjects residing in less engaged SLCs or those without access to high-intensity telemedicine for acute illnesses. We identified potential factors associated with more engaged SLCs, but further research is needed to understand resident and staff engagement and how to increase it.

Human Sodium Phosphate Transporter 4 (hNPT4/SLC17A3) as a Common Renal Secretory Pathway for Drugs and Urate*

PubMed Central

Jutabha, Promsuk; Anzai, Naohiko; Kitamura, Kenichiro; Taniguchi, Atsuo; Kaneko, Shuji; Yan, Kunimasa; Yamada, Hideomi; Shimada, Hidetaka; Kimura, Toru; Katada, Tomohisa; Fukutomi, Toshiyuki; Tomita, Kimio; Urano, Wako; Yamanaka, Hisashi; Seki, George; Fujita, Toshiro; Moriyama, Yoshinori; Yamada, Akira; Uchida, Shunya; Wempe, Michael F.; Endou, Hitoshi; Sakurai, Hiroyuki

2010-01-01

The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4. PMID:20810651

Image-based RNA interference screening reveals an individual dependence of acute lymphoblastic leukemia on stromal cysteine support

PubMed Central

Marovca, Blerim; Vonderheit, Andreas; Grotzer, Michael A.; Eckert, Cornelia; Cario, Gunnar; Wollscheid, Bernd; Horvath, Peter

2014-01-01

Interactions with the bone marrow microenvironment are essential for leukemia survival and disease progression. We developed an imaging-based RNAi platform to identify protective cues from bone marrow derived mesenchymal stromal cells (MSC) that promote survival of primary acute lymphoblastic leukemia (ALL) cells. Using a candidate gene approach, we detected distinct responses of individual ALL cases to RNA interference with stromal targets. The strongest effects were observed when interfering with solute carrier family 3 member 2 (SLC3A2) expression, which forms the cystine transporter xc− when associated with SLC7A11. Import of cystine and metabolism to cysteine by stromal cells provides the limiting substrate to generate and maintain glutathione in ALL. This metabolic interaction reduces oxidative stress in ALL cells that depend on stromal xc−. Indeed, cysteine depletion using cysteine dioxygenase resulted in leukemia cell death. Thus, functional evaluation of intercellular interactions between leukemia cells and their microenvironment identifies a selective dependency of ALL cells on stromal metabolism for a relevant subgroup of cases, providing new opportunities to develop more personalized approaches to leukemia treatment. PMID:25415224

Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3.

PubMed

Uwai, Yuichi; Taniguchi, Risa; Motohashi, Hideyuki; Saito, Hideyuki; Okuda, Masahiro; Inui, Ken-ichi

2004-10-01

Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters*

PubMed Central

Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

2014-01-01

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. PMID:25320081

The Physiopathological Role of the Exchangers Belonging to the SLC37 Family

NASA Astrophysics Data System (ADS)

Cappello, Anna Rita; Curcio, Rosita; Lappano, Rosamaria; Maggiolini, Marcello; Dolce, Vincenza

2018-04-01

The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.

The novel putative bile acid transporter SLC10A5 is highly expressed in liver and kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernandes, Carla F.; Godoy, Jose R.; Doering, Barbara

2007-09-14

Here we report the identification, cloning, and characterization of SLC10A5, which is a new member of Solute Carrier Family 10 (SLC10), also known as the 'sodium/bile acid cotransporter family'. Expression of SLC10A5/Slc10a5 was examined by quantitative real-time PCR and revealed its highest expression levels in liver and kidney in humans, rat and mouse. In rat liver and kidney, Slc10a5 expression was localized by in situ hybridization to hepatocytes and proximal tubules, respectively. A SLC10A5-FLAG fusion protein was expressed in HEK293 cells and showed an apparent molecular weight of 42 kDa after immunoprecipitation. When expressed in Xenopus laevis oocytes, the SLC10A5-FLAGmore » protein was detected in the oocyte's plasma membrane but showed no transport activity for taurocholate, cholate, estrone-3-sulfate, or dehydroepiandrosterone sulfate. As bile acid carriers are the most related carriers to SLC10A5 though, we strongly suppose that SLC10A5 is an orphan carrier with yet non-identified substrates.« less

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

PubMed Central

Corpe, Christopher P.; Tu, Hongbin; Eck, Peter; Wang, Jin; Faulhaber-Walter, Robert; Schnermann, Jurgen; Margolis, Sam; Padayatty, Sebastian; Sun, He; Wang, Yaohui; Nussbaum, Robert L.; Espey, Michael Graham; Levine, Mark

2010-01-01

Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1–/– mice. Compared with wild-type mice, Slc23a1–/– mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1–/– dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1–/– pups born to Slc23a1–/– dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1–/– mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice. PMID:20200446

The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters.

PubMed

Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

2014-11-28

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

2. AERIAL VIEW OF SLC3 FROM THE NORTH. SLC3W IN ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. AERIAL VIEW OF SLC-3 FROM THE NORTH. SLC-3W IN FOREGROUND; SLC-3E IN BACKGROUND. LAUNCH OPERATIONS BUILDING (LOB; BLDG. 763) AND CABLE TRAYS BETWEEN LOB AND THE PADS VISIBLE IMMEDIATELY EAST (LEFT) OF THE PADS. VEHICLE SUPPORT BUILDING (BLDG. 766) LOCATED EAST OF ROAD IN LEFT FOREGROUND. TECHNICAL SUPPORT BUILDING (BLDG. 762/762A) AND SLC-3 AIR FORCE BUILDING (BLDG. 761) VISIBLE EAST OF LOG IN LEFT BACKGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Acute and Chronic Plasma Metabalomic and Liver Transcriptomic Stress Effects in a Mouse Model with Features of Post-Traumatic Stress Disorder

DTIC Science & Technology

2015-01-28

trends is that at both 24 hr time points and the 1.5 wks time point, the HPA had already become desensitized , potentially involving attenuated release...points To explore metabolic alterations occurring at 24 hrs that potentially persisted out to 1.5 and 4 wks, we used random forests (RF) to classify...NR0B2, SLC27A3, SREBF1) Inhibition of cholesterol and lipid metabolism and transport; activation of Phase I metabolizing enzymes ->lipid and xenobiotic

The Pharmacogenetics of Type 2 Diabetes: A Systematic Review

PubMed Central

Maruthur, Nisa M.; Gribble, Matthew O.; Bennett, Wendy L.; Bolen, Shari; Wilson, Lisa M.; Balakrishnan, Poojitha; Sahu, Anita; Bass, Eric; Kao, W.H. Linda; Clark, Jeanne M.

2014-01-01

OBJECTIVE We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition. PMID:24558078

Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport.

PubMed

Kim, Hye In; Raffler, Johannes; Lu, Wenyun; Lee, Jung-Jin; Abbey, Deepti; Saleheen, Danish; Rabinowitz, Joshua D; Bennett, Michael J; Hand, Nicholas J; Brown, Christopher; Rader, Daniel J

2017-10-05

Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport. Copyright © 2017. Published by Elsevier Inc.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis

PubMed Central

Miller, Melissa R.; Soave, David; Li, Weili; Gong, Jiafen; Pace, Rhonda G.; Boëlle, Pierre-Yves; Cutting, Garry R.; Drumm, Mitchell L.; Knowles, Michael R.; Sun, Lei; Rommens, Johanna M.; Accurso, Frank; Durie, Peter R.; Corvol, Harriet; Levy, Hara; Sontag, Marci K.; Strug, Lisa J.

2015-01-01

Objectives To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal CF Transmembrane Conductance Regulator (CFTR) protein, including known cystic fibrosis (CF) modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) IRT levels. Study design NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of eight SNPs in SLC26A9, SLC6A14 and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT. Results In the Colorado sample, three SLC26A9 SNPs were associated with NBS IRT (min P = 1.16 × 10−3; rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P > 0.05). The rs7512462 association replicated in the Wisconsin sample (P = 0.03) but not in the French sample (P = 0.76). Furthermore, rs7512462 was the top ranked apical membrane constituent in the combined Colorado and Wisconsin sample. Conclusions NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease. PMID:25771386

The choline transporter-like family SLC44: properties and roles in human diseases.

PubMed

Traiffort, Elisabeth; O'Regan, Seana; Ruat, Martial

2013-01-01

The Na(+)-independent, high affinity choline carrier system proposed to supply choline for the synthesis of cell membrane phospholipids was recently associated with SLC44 family members (SLC44A1-5) also called choline-like transporter family. SLC44A1 is widely expressed throughout the nervous system in both neurons and oligodendrocytes, while SLC44A2-4 are mainly detected in peripheral tissues. The subcellular localization of the proteins was mainly addressed for SLC44A1 through the development of specific antibodies. SLC44A1 is detected in both the plasma and mitochondrial membranes where the protein is able to transport choline at high affinity and in a Na(+)-independent manner. The physiological relevance of SLC44A1 as a choline carrier is indicated by its likely involvement in membrane synthesis for cell growth or repair, and also by its role in phospholipid production for the generation of lung surfactant. Moreover, an autoimmune disease has been related to the blockade of SLC44A2 function, which results in the alteration of hair cells in the inner ear and leads to autoimmune hearing loss. In the alloimmune syndrome called transfusion-related acute lung injury, antibodies to SLC44A2 cause a deleterious aggregation of granulocytes. Therefore transporters of the SLC44 family represent attractive and promising targets for therapeutic and diagnostic applications regarding both immune and degenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

Molecular transport machinery involved in orchestrating luminal acid-induced duodenal bicarbonate secretion in vivo

PubMed Central

Singh, Anurag Kumar; Liu, Yongjian; Riederer, Brigitte; Engelhardt, Regina; Thakur, Basant Kumar; Soleimani, Manoocher; Seidler, Ursula

2013-01-01

The duodenal villus brush border membrane expresses several ion transporters and/or channels, including the solute carrier 26 anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1), the Na+/H+ exchanger isoform 3 (NHE3), as well as the anion channels cystic fibrosis transmembrane conductance regulator (CFTR) and Slc26a9. Using genetically engineered mouse models lacking Scl26a3, Slc26a6, Slc26a9 or Slc9a3 (NHE3), the study was carried out to assess the role of these transporters in mediating the protective duodenal bicarbonate secretory response (DBS-R) to luminal acid; and to compare it to their role in DBS-R elicited by the adenylyl cyclase agonist forskolin. While basal DBS was reduced in the absence of any of the three Slc26 isoforms, the DBS-R to forskolin was not altered. In contrast, the DBS-R to a 5 min exposure to luminal acid (pH 2.5) was strongly reduced in the absence of Slc26a3 or Slc26a9, but not Slc26a6. CFTR inhibitor [CFTR(Inh)-172] reduced the first phase of the acid-induced DBS-R, while NHE3 inhibition (or knockout) abolished the sustained phase of the DBS-R. Luminal acid exposure resulted in the activation of multiple intracellular signalling pathways, including SPAK, AKT and p38 phosphorylation. It induced a biphasic trafficking of NHE3, first rapidly into the brush border membrane, followed by endocytosis in the later stage. We conclude that the long-lasting DBS-R to luminal acid exposure activates multiple duodenocyte signalling pathways and involves changes in trafficking and/or activity of CFTR, Slc26 isoforms Slc26a3 and Slc26a9, and NHE3. PMID:24018950

Knockdown of SLC39A7 inhibits cell growth and induces apoptosis in human colorectal cancer cells.

PubMed

Sheng, Nengquan; Yan, Li; You, Weiqiang; Tan, Gewen; Gong, Jianfeng; Chen, Hongqi; Yang, Yi; Hu, Landian; Wang, Zhigang

2017-10-01

SLC39A7 (zip7) is a zinc transporter that plays a key role in intestinal epithelial self-renewal. However, little is known about SLC39A7 in colorectal cancer. To assess the biological function of SLC39A7 in colorectal cancer, the expression of SLC39A7 in human colorectal tumors and five colorectal cancer cell lines were evaluated by Oncomine Cancer Microarray Database and western blot analysis. In addition, short hairpin RNAs specifically targeting SLC39A7 were transfected into HCT116 and SW1116 cells to knockdown SLC39A7 expression. Then, the effects of SLC39A7 knockdown on colorectal cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide, colony-forming assay and flow cytometry. Our results showed that colorectal tumors have higher expression levels of SLC39A7 than normal colon tissues. Knockdown of SLC39A7 exhibited a significant decrease in cell viability and proliferation of colorectal cancer cells. It was also shown that knockdown of SLC39A7 interfered with cell cycle progression and induced G2/M cell cycle arrest, as well as boosted early and late apoptosis in colorectal cancer cells. Furthermore, downregulation of SLC39A7 promoted the cleavage of PARP and enhanced the expression of Bad, Caspase-9, and cleaved-Caspase-3, as well as suppressed Bcl-2 expression. In conclusion, our results suggest that SLC39A7 plays a crucial role in the proliferation and survival of colorectal cancer cells, which associates with colorectal tumorigenesis. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects.

PubMed

González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A

2015-01-01

Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world.

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

PubMed

Liang, Xiaomin; Chien, Huan-Chieh; Yee, Sook Wah; Giacomini, Marilyn M; Chen, Eugene C; Piao, Meiling; Hao, Jia; Twelves, Jolyn; Lepist, Eve-Irene; Ray, Adrian S; Giacomini, Kathleen M

2015-12-07

The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

PubMed Central

Murillo-Cuesta, Silvia; Errasti- Murugarren, Ekaitz; Celaya, Adelaida M; Girotto, Giorgia; Vuckovic, Dragana; Mezzavilla, Massimo; Vilches, Clara; Bodoy, Susanna; Sahún, Ignasi; González, Laura; Prat, Esther; Zorzano, Antonio; Dierssen, Mara

2018-01-01

Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations. PMID:29355479

Slc10A4 - what do we know about the function of this "secret ligand carrier" protein?

PubMed

Borges, Karin

2013-10-01

This commentary discusses the possible functions of a relatively newly described solute carrier protein, Slc10a4, in regards to a recent article by Zelano et al. (2013) published in the January issue of Experimental Neurology, 239, 73-81. Slc10a4 belongs to the sodium-bile acid cotransporter family (Slc10), but does not show plasma membrane transport activity of bile acids and related molecules. It is co-localized with synaptic vesicle transporters for acetylcholine and dopamine. In Slc10a4 lacking mice, Zelano et al. found increased excitability in hippocampal slices and in vivo responses to pilocarpine, but not kainate. These findings are critically examined here. This author speculates on the possible function of Slc10a4, but remains partial about "specific effects of Slc10a4 in cholinergic systems". It is hoped that approaches targeting human SLC10A4 can be discovered for potential clinical use in neurological disorders, such as Alzheimer's and Parkinson's disease, schizophrenia and addiction. Conversely, some side effects are expected due to peripheral Slc10a4 localization in sympathetic and parasympathetic nerves, as well as mast cells. © 2013.

Developmental expression of SLC26A4 (Pendrin) during amelogenesis in developing rodent teeth

PubMed Central

Bronckers, Antonius LJJ; Guo, Jing; Zandieh-Doulabi, Behrouz; Bervoets, Theodore J; Lyaruu, Donacian M.; Li, Xiangming; Wangemann, Philine; DenBesten, Pamela

2012-01-01

Ameloblasts need to regulate pH during formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT-PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as pH regulator. SLC26A4 does not appear critical for ameloblast functioning and is likely compensated by other pH regulators. PMID:22243245

15. Photocopy of drawing (1958 architectural drawing by Ralph M. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

15. Photocopy of drawing (1958 architectural drawing by Ralph M. Parsons Company. Original drawing in possession of Vandenberg Air Force Base Civil Engineering Office). SITE PLAN FOR POINT ARGUELLO LAUNCH COMPLEX 1 (SLC-3) SHOWING POTENTIAL SITES OF FUTURE PADS. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Riboflavin uptake transporter Slc52a2 (RFVT2) is upregulated in the mouse mammary gland during lactation.

PubMed

Wu, Alex Man Lai; Dedina, Liana; Dalvi, Pooja; Yang, Mingdong; Leon-Cheon, John; Earl, Brian; Harper, Patricia A; Ito, Shinya

2016-04-01

While it is well recognized that riboflavin accumulates in breast milk as an essential vitamin for neonates, transport mechanisms for its milk excretion are not well characterized. The multidrug efflux transporter ABCG2 in the apical membrane of milk-producing mammary epithelial cells (MECs) is involved with riboflavin excretion. However, it is not clear whether MECs possess other riboflavin transport systems, which may facilitate its basolateral uptake into MECs. We report here that transcripts encoding the second (SLC52A2) and third (SLC52A3) member of the recently discovered family of SLC52A riboflavin uptake transporters are expressed in milk fat globules from human breast milk. Furthermore, Slc52a2 and Slc52a3 mRNA are upregulated in the mouse mammary gland during lactation. Importantly, the induction ofSlc52a2, which was the major Slc52a riboflavin transporter in the lactating mammary gland, was also observed at the protein level. Subcellular localization studies showed that green fluorescent protein-tagged mouse SLC52A2 mainly localized to the cell membrane, with no preferential distribution to the apical or basolateral membrane in polarized kidney MDCK cells. These results strongly implicate a potential role for SLC52A2 in riboflavin uptake by milk-producing MECs, a critical step in the transfer of riboflavin into breast milk. Copyright © 2016 the American Physiological Society.

Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia

PubMed Central

Scarr, Elizabeth; Udawela, Madhara; Greenough, Mark A; Neo, Jaclyn; Suk Seo, Myoung; Money, Tammie T; Upadhyay, Aradhana; Bush, Ashley I; Everall, Ian P; Thomas, Elizabeth A; Dean, Brian

2016-01-01

Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 (SLC39A12) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmann’s area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a12 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12. PMID:27336053

Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

PubMed

Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

2002-06-15

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional.

Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

PubMed Central

Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

2002-01-01

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional. PMID:12049641

Molecular pathophysiology of SLC4 bicarbonate transporters.

PubMed

Romero, Michael F

2005-09-01

Acid-base (H and HCO3) transport in the kidney is crucial for maintaining blood pH, cellular pH and excreting metabolic acid. HCO3 transport in the kidney is mediated by HCO3 transporter proteins which occur in two gene families in humans, vertebrates and invertebrates (SLC4 and SLC26). Since SLC26 transporters have other, non-HCO3 transport functions, this review highlights the history and recent advances in the SLC4 transporters in the kidney. The SLC4 gene and protein family (10 genes) contains three types of HCO3 transporters: Cl-HCO3 exchangers, Na/HCO3 cotransporters and Na-driven Cl-HCO3 exchangers. Function and human chromosomal location have been determined for most members. Human mutations in AE1 (SLC4A1) and NBCe1 (SLC4A4) are associated with distal and proximal renal tubular acidosis, respectively. Recent advances include the cellular and biophysical mechanisms by which AE1 and NBCe1 mutations lead to renal disease. Mutational and cellular trafficking studies have begun to elucidate the membrane topology and functional domains of AE1 and NBCe1. Knockout mice for AE2 and NBCn1 do not have obvious renal phenotypes. Recently, SLC4A11 (bicarbonate transporter 1) was shown to function as an electrogenic Na/borate cotransporter unable to transport HCO3 but involved in cell cycle control. SLC4 HCO3 transporters play critical roles in systemic and cellular pH homeostasis. Most of the SLC4 members are present at some level in the kidney. Future studies will likely continue to make use of knockout animals, for example mice and zebrafish, human mutations or polymorphisms to elucidate the normal and pathophysiologic roles of these proteins.

Molecular analysis of the human SLC13A4 sulfate transporter gene promoter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jefferis, J.; Rakoczy, J.; School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland

2013-03-29

Highlights: ► Basal promoter activity of SLC13A4 −57 to −192 nt upstream of transcription initiation site. ► Human SLC13A4 5′-flanking region has conserved motifs with other placental species. ► Putative NFY, SP1 and KLF7 motifs in SLC13A4 5′-flanking region enhance transcription. -- Abstract: The human solute linked carrier (SLC) 13A4 gene is primarily expressed in the placenta where it is proposed to mediate the transport of nutrient sulfate from mother to fetus. The molecular mechanisms involved in the regulation of SLC13A4 expression remain unknown. To investigate the regulation of SLC13A4 gene expression, we analysed the transcriptional activity of the humanmore » SLC13A4 5′-flanking region in the JEG-3 placental cell line using luciferase reporter assays. Basal transcriptional activity was identified in the region −57 to −192 nucleotides upstream of the SLC13A4 transcription initiation site. Mutational analysis of the minimal promoter region identified Nuclear factor Y (NFY), Specificity protein 1 (SP1) and Krüppel like factor 7 (KLF7) motifs which conferred positive transcriptional activity, as well as Zinc finger protein of the cerebellum 2 (ZIC2) and helix–loop–helix protein 1 (HEN1) motifs that repressed transcription. The conserved NFY, SP1, KLF7, ZIC2 and HEN1 motifs in the SLC13A4 promoter of placental species but not in non-placental species, suggests a potential role for these putative transcriptional factor binding motifs in the physiological control of SLC13A4 mRNA expression.« less

The systems biology of uric acid transporters: the role of remote sensing and signaling.

PubMed

Nigam, Sanjay K; Bhatnagar, Vibha

2018-07-01

Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific 'drug' transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a 'systems biology' problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the 'Remote Sensing and Signaling Hypothesis.' This hypothesis explains how SLC and ABC 'drug' and other transporters mediate interorgan and interorganismal communication (e.g., gut microbiome and host) via small molecules (e.g., metabolites, antioxidants signaling molecules) through transporters expressed in tissues lining body fluid compartments (e.g., blood, urine, cerebrospinal fluid). The list of uric acid transporters includes: SLC2A9, ABCG2, URAT1 (SLC22A12), OAT1 (SLC22A6), OAT3 (SLC22A8), OAT4 (SLC22A11), OAT10 (SLC22A13), NPT1 (SLC17A1), NPT4 (SLC17A3), MRP2 (ABCC2), MRP4 (ABCC4). Normally, SLC2A9, - along with URAT1, OAT1 and OAT3, - appear to be the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport. In chronic kidney disease (CKD), intestinal ABCG2 becomes much more important, suggesting remote organ communication between the injured kidney and the intestine. The remote sensing and signaling hypothesis provides a useful systems-level framework for understanding the complex interplay of uric acid transporters expressed in different tissues involved in optimizing uric acid levels under normal and diseased (e.g., CKD, gut microflora dysbiosis) conditions.

Polymorphic Imprinting of SLC38A4 Gene in Bovine Placenta.

PubMed

Xu, Da; Zhang, Cui; Li, Junliang; Wang, Guannan; Chen, Weina; Li, Dongjie; Li, Shijie

2018-05-21

Imprinted genes are characterized by monoallelic expression that is dependent on parental origin. Comparative analysis of imprinted genes between species is a powerful tool for understanding the biological significance of genomic imprinting. The slc38a4 gene encodes a neutral amino acid transporter and is identified as imprinted in mice. In this study, the imprinting status of SLC38A4 was assessed in bovine adult tissues and placenta using a polymorphism-based approach. Results indicate that SLC38A4 is not imprinted in eight adult bovine tissues including heart, liver, spleen, lung, kidney, muscle, fat, and brain. It was interesting to note that SLC38A4 showed polymorphic status in five heterogeneous placentas, with three exhibiting paternal monoallelic expression and two exhibiting biallelic expression. Monoallelic expression of imprinted genes is generally associated with allele-specific differentially methylation regions (DMRs) of CpG islands (CGIs)-encompassed promoter; therefore, the DNA methylation statuses of three CGIs in the SLC38A4 promoter and exon 1 region were tested in three placentas (two exhibiting paternal monoallelic and one showing biallelic expression of SLC38A4) and their corresponding paternal sperms. Unexpectedly, extreme hypomethylation (< 3%) of the DNA was observed in all the three detected placentas and their corresponding paternal sperms. The absence of DMR in bovine SLC38A4 promoter region implied that DNA methylation of these three CGIs does not directly or indirectly affect the polymorphic imprinting of SLC38A4 in bovine placenta. This suggested other epigenetic features other than DNA methylation are needed in regulating the imprinting of bovine SLC38A4, which is different from that of mouse with respect to a DMR existence at the mouse's slc38a4 promoter region. Although further work is needed, this first characterization of polymorphic imprinting status of SLC38A4 in cattle placenta provides valuable information on investigating the genomic imprinting phenomenon itself.

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

PubMed Central

Stewart, Andrew K.; Shmukler, Boris E.; Vandorpe, David H.; Reimold, Fabian; Heneghan, John F.; Nakakuki, M.; Akhavein, Arash; Ko, Shigeru; Ishiguro, Hiroshi

2011-01-01

The secretin-stimulated human pancreatic duct secretes HCO3−-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3− secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl−/HCO3− exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼40–70 mM HCO3−. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3− secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl−/Cl− exchange and electroneutral Cl−/HCO3− exchange. gpSlc26a6 in Xenopus oocytes mediated Cl−/Cl− exchange and bidirectional exchange of Cl− for oxalate and sulfate, but Cl−/HCO3− exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl−, oxalate, and sulfate transport but no detectable Cl−/HCO3− exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of 36Cl− influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3− secretion in species that share a high HCO3− secretory output. PMID:21593449

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter

PubMed Central

Yu, Dongke; Zhang, Han; Lionarons, Daniel A.; Boyer, James L.

2017-01-01

The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea. The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA (Km = 92.4 µM) and scymnol sulfate (Ki = 31 µM), compared with hNTCP (TCA, Km = 5.4 µM; Scymnol sulfate, Ki = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. PMID:28077388

Increased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer

PubMed Central

Xu, Lixia; Li, Xiaoxing; Cai, Muyan; Chen, Jinna; Li, Xiangchun; Wu, William K K; Kang, Wei; Tong, Joanna; To, Ka-Fai; Guan, Xin-Yuan; Sung, Joseph J Y; Chan, Francis K L; Yu, Jun

2016-01-01

Objective Using whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC. Design SLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC. Results Amplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan–Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC. Conclusions SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC. PMID:25947013

SLC4A11 is an EIPA-sensitive Na+ permeable pHi regulator

PubMed Central

Ogando, Diego G.; Jalimarada, Supriya S.; Zhang, Wenlin; Vithana, Eranga N.

2013-01-01

Slc4a11, a member of the solute linked cotransporter 4 family that is comprised predominantly of bicarbonate transporters, was described as an electrogenic 2Na+-B(OH)4− (borate) cotransporter and a Na+-2OH− cotransporter. The goal of the current study was to confirm and/or clarify the function of SLC4A11. In HEK293 cells transfected with SLC4A11 we tested if SLC4A11 is a: 1) Na+-HCO3− cotransporter, 2) Na+-OH−(H+) transporter, and/or 3) Na+-B(OH)4− cotransporter. CO2/HCO3− perfusion yielded no significant differences in rate or extent of pHi changes or Na+ flux in SLC4A11-transfected compared with control cells. Similarly, in CO2/HCO3−, acidification on removal of Na+ and alkalinization on Na+ add back were not significantly different between control and transfected indicating that SLC4A11 does not have Na+-HCO3− cotransport activity. In the absence of CO2/HCO3−, SLC4A11-transfected cells showed higher resting intracelllular Na+ concentration ([Na+]i; 25 vs. 17 mM), increased NH4+-induced acidification and increased acid recovery rate (160%) after an NH4 pulse. Na+ efflux and influx were faster (80%) following Na+ removal and add back, respectively, indicative of Na+-OH−(H+) transport by SLC4A11. The increased alkalinization recovery was confirmed in NHE-deficient PS120 cells demonstrating that SLC4A11 is a bonafide Na+-OH−(H+) transporter and not an activator of NHEs. SLC4A11-mediated H+ efflux is inhibited by 5-(N-ethyl-N-isopropyl) amiloride (EIPA; EC50: 0.1 μM). The presence of 10 mM borate did not alter dpHi/dt or ΔpH during a Na+-free pulse in SLC4A11-transfected cells. In summary our results show that SLC4A11 is not a bicarbonate or borate-linked transporter but has significant EIPA-sensitive Na+-OH−(H+) and NH4+ permeability. PMID:23864606

Ion Transport Function of SLC4A11 in Corneal Endothelium

PubMed Central

Jalimarada, Supriya S.; Ogando, Diego G.; Vithana, Eranga N.; Bonanno, Joseph A.

2013-01-01

Purpose. Mutations in SLC4A11, a member of the SLC4 superfamily of bicarbonate transporters, give rise to corneal endothelial cell dystrophies. SLC4A11 is a putative Na+ borate and Na+:OH− transporter. Therefore we ask whether SLC4A11 in corneal endothelium transports borate (B[OH]4−), bicarbonate (HCO3−), or hydroxyl (OH−) anions coupled to Na+. Methods. SLC4A11 expression in cultured primary bovine corneal endothelial cells (BCECs) was determined by semiquantitative PCR, SDS-PAGE/Western blotting, and immunofluorescence staining. Ion transport function was examined by measuring intracellular pH (pHi) or Na+ ([Na+]i) in response to Ringer solutions with/without B(OH)4− or HCO3− after overexpressing or small interfering RNA (siRNA) silencing of SLC4A11. Results. SLC4A11 is localized to the basolateral membrane in BCEC. B(OH)4− (2.5–10 mM) in bicarbonate-free Ringer induced a rapid small acidification (0.01 pH unit) followed by alkalinization (0.05–0.1 pH unit), consistent with diffusion of boric acid into the cell followed by B(OH)4−. However, the rate of B(OH)4−-induced pHi change was unaffected by overexpression of SLC4A11. B(OH)4− did not induce significant changes in resting [Na+i] or the amplitude and rate of acidification caused by Na+ removal. siRNA-mediated knockdown of SLC4A11 (∼70%) did not alter pHi responses to CO2/HCO3−-rich Ringer, Na+-free induced acidification, or the rate of Na+ influx in the presence of bicarbonate. However, in the absence of bicarbonate, siSLC4A11 knockdown significantly decreased the rate (43%) and amplitude (48%) of acidification due to Na+ removal and recovery (53%) upon add-back. Additionally, the rate of acid recovery following NH4+ prepulse was decreased significantly (27%) by SLC4A11 silencing. Conclusions. In corneal endothelium, SLC4A11 displays robust Na+-coupled OH− transport, but does not transport B(OH)4− or HCO3−. PMID:23745003

Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs.

PubMed

Nies, Anne T; Damme, Katja; Schaeffeler, Elke; Schwab, Matthias

2012-12-01

Antimicrobial drugs are essential in the treatment of infectious diseases. A better understanding of transport processes involved in drug disposition will improve the predictability of drug-drug interactions with consequences for drug response. Multidrug And Toxin Extrusion (MATE; SLC47A) proteins are efflux transporters mediating the excretion of several antimicrobial drugs as well as other organic compounds into bile and urine, thereby contributing to drug disposition. This review summarizes current knowledge of the structural and molecular features of human MATE transporters including their functional role in drug transport with a specific focus on antimicrobial drugs. The PubMed database was searched using the terms "MATE1," "MATE-2K," "MATE2," "SLC47A1," "SLC47A2," and "toxin extrusion protein" (up to June 2012). MATE proteins have been recognized as important transporters mediating the final excretion step of cationic drugs into bile and urine. These include the antiviral drugs acyclovir, amprenavir, and ganciclovir, the antibiotics cephalexin, cephradine and levofloxacin, as well as the antimalarial agents chloroquine and quinine. It is therefore important to enhance our understanding of the role of MATEs in drug extrusion with particular emphasis on the functional consequences of genetic variants on disposition of these antimicrobial drugs.

Yogurt fermentation in the presence of starch-lipid composite.

PubMed

Singh, M; Kim, S

2009-03-01

The fermentation of yogurt in the presence of 0.5%, 1.0%, 1.5%, and 2.0% starch-lipid composite (SLC) was investigated. The pH, viscosity, and morphology of the mix were monitored during the fermentation process. The rate of drop in pH with time during incubation was not affected by the addition of SLC. However, it was found that the presence of SLC caused faster aggregation, which was clearly evidenced by the viscosity variation during the process of fermentation. An examination of the morphologies confirmed that aggregation occurred earlier in the presence of SLC and SLC did not form phase-separated domains. This study concludes that SLC would serve as a good additive (fat replacer and stabilizer) for the production of yogurt.

Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.

PubMed

Traurig, Michael; Hanson, Robert L; Marinelarena, Alejandra; Kobes, Sayuko; Piaggi, Paolo; Cole, Shelley; Curran, Joanne E; Blangero, John; Göring, Harald; Kumar, Satish; Nelson, Robert G; Howard, Barbara V; Knowler, William C; Baier, Leslie J; Bogardus, Clifton

2016-02-01

Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10(-7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters

PubMed Central

Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor; Gowda, Vykuntaraju K; Raghavan, Varun S; Varalakshmi, Perumal; Said, Hamid M; Ashokkumar, Balasubramaniem

2017-01-01

Background Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Methods Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Results Functional characterization based on 3H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. Conclusions This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2. PMID:27702554

Large-scale identification of differentially expressed genes during pupa development reveals solute carrier gene is essential for pupal pigmentation in Chilo suppressalis.

PubMed

Sun, Yang; Huang, Shuijin; Wang, Shuping; Guo, Dianhao; Ge, Chang; Xiao, Huamei; Jie, Wencai; Yang, Qiupu; Teng, Xiaolu; Li, Fei

2017-04-01

Insects undergo metamorphosis, involving an abrupt change in body structure through cell growth and differentiation. Rice stem stripped borer (SSB), Chilo suppressalis, is one of the most destructive rice pests. However, little is known about the regulation mechanism of metamorphosis development in this notorious insect pest. Here, we studied the expression of 22,197 SSB genes at seven time points during pupa development with a customized microarray, identifying 622 differentially expressed genes (DEG) during pupa development. Gene ontology (GO) analysis of these DEGs indicated that the genes related to substance metabolism were highly expressed in the early pupa, which participate in the physiological processes of larval tissue disintegration at these stages. In comparison, highly expressed genes in the late pupal stages were mainly associated with substance biosynthesis, consistent with adult organ formation at these stages. There were 27 solute carrier (SLC) genes that were highly expressed during pupa development. We knocked down SLC22A3 at the prepupal stage, demonstrating that silencing SLC22A3 induced a deficiency in pupa stiffness and pigmentation. The RNAi-treated individuals had white and soft pupa, suggesting that this gene has an essential role in pupal development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Developmental expression of solute carrier family 26A member 4 (SLC26A4/pendrin) during amelogenesis in developing rodent teeth.

PubMed

Bronckers, Antonius L J J; Guo, Jing; Zandieh-Doulabi, Behrouz; Bervoets, Theodore J; Lyaruu, Donacian M; Li, Xiangming; Wangemann, Philine; DenBesten, Pamela

2011-12-01

Ameloblasts need to regulate pH during the formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine, and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear, and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT-PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues, including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts, and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as a pH regulator. SLC26A4 does not appear to be critical for ameloblast function and is probably compensated by other pH regulators. © 2011 Eur J Oral Sci.

Analysis of common deafness gene mutations in deaf people from unique ethnic groups in Gansu Province, China.

PubMed

Xu, Bai-Cheng; Bian, Pan-Pan; Liu, Xiao-Wen; Zhu, Yi-Ming; Yang, Xiao-Long; Ma, Jian-Li; Chen, Xing-Jian; Wang, Yan-Li; Guo, Yu-Fen

2014-09-01

The GJB2 gene mutation characteristic of Dongxiang was the interaction result of ethnic background and geographical environment, and Yugur exhibited the typical founder effect. The SLC26A4 gene mutation characteristic of Dongxiang was related to caucasian backgrounds and selection of purpose exons, i.e. ethnic background and the penetrance of ethnic specificity caused the low mtDNA1555A>G mutation frequency in Dongxiang. To determine the prevalence of GJB2 and SLC26A4 genes and mtDNA1555A>G mutations and analyze the ethnic specificity in the non-syndromic sensorineural hearing loss (NSHL) of unique ethnic groups in Gansu Province. Peripheral blood samples were obtained from Dongxiang, Yugur, Bonan, and ethnic Han groups with moderately severe to profound NSHL in Gansu Province. Bidirectional sequencing (or enzyme digestion) was applied to identify the sequence variations. The pathogenic allele frequency of the three gene mutations was different. The frequency of the GJB2 gene among the Dongxiang, Yugur, Bonan, and ethnic Han groups was 9.03%, 12.5%, 5.88%, and 12.17%, respectively. No difference was found between the ethnic groups. The frequencies of the SLC26A4 genes were 3.23%, 8.33%, 0%, and 9.81%, respectively. The mutation frequency of mtDNA1555A>G was 0%, 0%, 0%, and 6.03%, respectively. No difference was found between the ethnic groups, except for the Dongxiang and ethnic Han groups, both in SLC26A4 gene and mtDNA1555A>G.

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

PubMed Central

Klotz, Jenna; Porter, Brenda E; Colas, Claire; Schlessinger, Avner; Pajor, Ana M

2016-01-01

Mutations in the SLC13A5 gene that codes for the Na+/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In this study, we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and the treatment strategies. Currently, there are no effective treatments, but some antiepileptic drugs targeting the γ-aminobutyric acid system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical antiseizure medication, decreases seizures in four patients. In contrast to previous reports, the ketogenic diet and fasting resulted in worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improved transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, this study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na+/citrate transporters. PMID:27261973

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient.

PubMed

Wyant, Gregory A; Abu-Remaileh, Monther; Wolfson, Rachel L; Chen, Walter W; Freinkman, Elizaveta; Danai, Laura V; Vander Heiden, Matthew G; Sabatini, David M

2017-10-19

The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, Henk; Rassekh, S Rod; Sandor, George S; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Rogers, Paul C; Rieder, Michael J; Carleton, Bruce C; Hayden, Michael R; Ross, Colin J

2015-01-01

To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

SLC2A9 is a high-capacity urate transporter in humans.

PubMed

Caulfield, Mark J; Munroe, Patricia B; O'Neill, Deb; Witkowska, Kate; Charchar, Fadi J; Doblado, Manuel; Evans, Sarah; Eyheramendy, Susana; Onipinla, Abiodun; Howard, Philip; Shaw-Hawkins, Sue; Dobson, Richard J; Wallace, Chris; Newhouse, Stephen J; Brown, Morris; Connell, John M; Dominiczak, Anna; Farrall, Martin; Lathrop, G Mark; Samani, Nilesh J; Kumari, Meena; Marmot, Michael; Brunner, Eric; Chambers, John; Elliott, Paul; Kooner, Jaspal; Laan, Maris; Org, Elin; Veldre, Gudrun; Viigimaa, Margus; Cappuccio, Francesco P; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Moley, Kelle H; Cheeseman, Chris

2008-10-07

Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82). This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.

SLC2A9 Is a High-Capacity Urate Transporter in Humans

PubMed Central

O'Neill, Deb; Witkowska, Kate; Charchar, Fadi J; Doblado, Manuel; Evans, Sarah; Eyheramendy, Susana; Onipinla, Abiodun; Howard, Philip; Shaw-Hawkins, Sue; Dobson, Richard J; Wallace, Chris; Newhouse, Stephen J; Brown, Morris; Connell, John M; Dominiczak, Anna; Farrall, Martin; Lathrop, G. Mark; Samani, Nilesh J; Kumari, Meena; Marmot, Michael; Brunner, Eric; Chambers, John; Elliott, Paul; Kooner, Jaspal; Laan, Maris; Org, Elin; Veldre, Gudrun; Viigimaa, Margus; Cappuccio, Francesco P; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Moley, Kelle H; Cheeseman, Chris

2008-01-01

Background Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. Methods and Findings We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (K i = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82). Conclusions This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout. PMID:18842065

[Genetic counseling and instruction of marriage for deaf young people: study of 115 cases].

PubMed

Han, Bing; Dai, Pu; Wang, Guo-Jian; Yuan, Yong-Yi; Li, Qi; Zhang, Xin; Kang, Dong-Yang; Han, Dong-Yi

2009-03-17

To invesigate the molecular pathogenesis of deafness among the youth by means of genetic testing so as to provide pre-marriage genetic counseling and instruction for the deaf youth. 217 deaf young people, 126 males and 91 females, aged 18.9 (16 - 26), from Yunnan and Guizhou provinces, underwent history taking, auditory testing, and collection of peripheral blood samples. Genomic DNA and mitochondrial DNA were extracted to undergo sequence analysis of the entire gene GJB2, common point mutation of SLC26A4 gene, and mutation of mtDNA A1555G. Genetic prediction and marriage instruction were provided to each subject based on these results. Twenty-three of the 117 persons (10.5%), 13 males and 10 females, were mtDNA A1555G mutation carriers and they were instructed that they, their maternal relatives, and the offspring of the female carriers, should they be born, should strictly avoid the administration of amino glycoside antibiotics. Twenty eight of the 115 persons (12.9%), were confirmed to carry homozygous or compound GJB2 mutations, 5 individuals (2.3%) carried heterozygous GJB2 mutation, 19 (8.8%) carried homozygous or compound SLC26A4 mutations, and one (0.5%) carried heterozygous SLC26A4 mutation. The suggestion for them was to avoid getting married with deaf partners caused by the same deaf gene or with individuals carrying mutations in the same deaf gene. Meanwhile, suggestions such as avoiding aggressive exercises and head injury were provided to the deaf young people with SLC26A4 mutations. Genetic testing can provide more accurate and useful genetic counseling and instruction to deaf young people for their partner selection and eugenics.

Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases.

PubMed

Zha, Weibin

2018-04-01

The growing use of natural products in cardiovascular (CV) patients has been greatly raising the concerns about potential natural product-CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product-CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product-drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins) have been identified to be substrates and inhibitors of the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients) are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product-CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product-CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product-CV drug interactions and help public and physicians understand these type of interactions. Copyright © 2017. Published by Elsevier B.V.

Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

PubMed

Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

2015-05-01

Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter.

PubMed

Yu, Dongke; Zhang, Han; Lionarons, Daniel A; Boyer, James L; Cai, Shi-Ying

2017-04-01

The Na + -dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na + -dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [ 3 H]TCA uptake assay revealed that skSlc10a1 functioned as a Na + -dependent transporter, but with low affinity for TCA ( K m = 92.4 µM) and scymnol sulfate ( K i = 31 µM), compared with hNTCP (TCA, K m = 5.4 µM; Scymnol sulfate, K i = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na + -dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. Copyright © 2017 the American Physiological Society.

7. Photocopy of photograph (original photograph in possession of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

7. Photocopy of photograph (original photograph in possession of the Ralph M. Parsons Company, Los Angeles, California). Photography by Ralph M. Parsons Co. circa August 1959. AERIAL VIEW OF ORIGINAL CONSTRUCTION OF POINT ARGUELLO LAUNCH COMPLEX 1 (SLC-3) FROM THE SOUTHEAST. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

11. Photocopy of photograph (original photograph in possession of Val ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

11. Photocopy of photograph (original photograph in possession of Val Brose, General Dynamics Space Systems Division, Vandenberg Air Force Base, California). Photographer unknown, circa July 1961. CREW OF FIRST LAUNCH FROM POINT ARGUELLO LAUNCH COMPLEX 1, PAD 2, (SLC-3E) ON LAUNCH PAD. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

The Physiological Effects of Deleting the Mouse Slc30a8 Gene Encoding Zinc Transporter-8 Are Influenced by Gender and Genetic Background

PubMed Central

Pound, Lynley D.; Sarkar, Suparna A.; Ustione, Alessandro; Dadi, Prasanna K.; Shadoan, Melanie K.; Lee, Catherine E.; Walters, Jay A.; Shiota, Masakazu; McGuinness, Owen P.; Jacobson, David A.; Piston, David W.; Hutton, John C.; Powell, David R.; O’Brien, Richard M.

2012-01-01

Objective The SLC30A8 gene encodes the islet-specific transporter ZnT-8, which is hypothesized to provide zinc for insulin-crystal formation. A polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes. Several groups have examined the effect of global Slc30a8 gene deletion but the results have been highly variable, perhaps due to the mixed 129SvEv/C57BL/6J genetic background of the mice studied. We therefore sought to remove the conflicting effect of 129SvEv-specific modifier genes. Methods The impact of Slc30a8 deletion was examined in the context of the pure C57BL/6J genetic background. Results Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin levels and no change in glucose-stimulated insulin secretion (GSIS) from isolated islets in marked contrast to the ∼50% and ∼35% decrease, respectively, in both parameters observed in male mixed genetic background Slc30a8 KO mice. This observation suggests that 129SvEv-specific modifier genes modulate the impact of Slc30a8 deletion. In contrast, female C57BL/6J Slc30a8 KO mice had reduced (∼20%) fasting insulin levels, though this was not associated with a change in fasting blood glucose (FBG), or GSIS from isolated islets. This observation indicates that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation as to why impaired insulin secretion is not accompanied by elevated FBG is unclear. Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance. Conclusions Our data suggest that, despite a marked reduction in islet zinc content, the absence of ZnT-8 does not have a substantial impact on mouse physiology. PMID:22829903

Transport via SLC5A8 (SMCT1) Is Obligatory for 2-Oxothiazolidine-4-Carboxylate to Enhance Glutathione Production in Retinal Pigment Epithelial Cells

PubMed Central

Babu, Ellappan; Ananth, Sudha; Veeranan-Karmegam, Rajalakshmi; Coothankandaswamy, Veena; Smith, Sylvia B.; Boettger, Thomas; Ganapathy, Vadivel

2011-01-01

Purpose. To evaluate the role of SLC5A8 in the transport of 2-oxothiazolidine-4-carboxylate (OTC) and to determine whether OTC augments glutathione production in RPE cells, thereby providing protection against oxidative stress. Methods. SLC5A8-mediated transport of OTC was monitored in Xenopus laevis oocytes by electrophysiological means. Saturation kinetics, Na+-activation kinetics, and inhibition by ibuprofen were analyzed by monitoring OTC-induced currents as a measure of transport activity. Oxidative stress was induced in ARPE-19 cells and primary RPE cells isolated from wild type and Slc5a8-/- mouse retinas using H2O2, and the effects of OTC on cell death and intracellular glutathione concentration were examined. Results. Heterologous expression of human SLC5A8 in X. laevis oocytes induced Na+-dependent inward currents in the presence of OTC under voltage-clamp conditions. The transport of OTC via SLC5A8 was saturable, with a Kt of 104 ± 3 μM. The Na+-activation kinetics was sigmoidal with a Hill coefficient of 1.9 ± 0.1, suggesting involvement of two Na+ in the activation process. Ibuprofen, a blocker of SLC5A8, inhibited SLC5A8-mediated OTC transport; the concentration necessary for half-maximal inhibition was 17 ± 1 μM. OTC increased glutathione levels and protected ARPE-19 and primary RPE cells isolated from wild type mouse retinas from H2O2-induced cell death. These effects were abolished in primary RPE isolated from Slc5a8-/- mouse retinas. Conclusions. OTC is a transportable substrate for SLC5A8. OTC augments glutathione production in RPE cells, thereby protecting them from oxidative damage. Transport via SLC5A8 is obligatory for this process. PMID:21508099

The effects of reduced dietary protein level on amino acid transporters and mTOR signaling pathway in pigs.

PubMed

Wang, Dan; Wan, Xuebin; Peng, Jian; Xiong, Qi; Niu, Hongdan; Li, Huanan; Chai, Jin; Jiang, Siwen

2017-04-01

Amino acid transporter plays an important role in regulating mTOR signaling pathway. This study investigated the effects of reduced dietary protein levels on amino acid transporters and mTOR signaling pathway. A total of 54 weaning pigs were randomly allocated into a 3 × 3 factorial design, followed by slaughtering the pigs separately after 10-, 25- and 45-day feeding, with 18 pigs from each feeding period divided into three subgroups for treatment with three different protein-level diets: 20% crude protein (CP) diet (normal recommended, high protein, HP), 17% CP diet (medium protein, MP) and 14% CP diet (low protein, LP). The results indicated that reduced dietary protein level decreased the weight of longissimus dorsi. Additionally, quantitative PCR chip analysis showed that mRNA expression of amino acid transporters SLC38A2, SLC1A7, SLC7A1, SLC7A5, SLC16A10 and SLC3A2 in the LP group were significantly (P < 0.05) higher than those in the MP or HP group, and the phosphorylation of mTOR and S6K1 decreased in the LP group after 25-day feeding. Furthermore, the vitro experimental results further confirmed that the mRNA levels for SLC7A1, SLC7A5, SLC3A2, SLC38A2 and SLC36A1 were increased and the phosphorylation of mTOR and S6K1 was decreased when the concentration of amino acids in C2C12 myoblasts was reduced. All these results indicated that the LP diet induced a high expression of amino acid transporters and the inhibition of the mTOR activity, which resulting in restriction on protein synthesis and longissimus dorsi growth. Copyright © 2017 Elsevier Inc. All rights reserved.

Unitarity of the Cabibbo-Kobayashi-Maskawa matrix and a nonuniversal gauge interaction model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Kang Young

2007-12-01

Recent measurements of |V{sub us}| from kaon decays strongly support the unitarity of the Cabibbo-Kobayashi-Maskawa matrix. The unitarity provides a stringent constraint on the parameter space of the nonuniversal gauge interaction model based on the separate SU(2){sub L} gauge group acting on the third generation fermions. I show that this constraint is stronger than those from the CERN LEP and SLC data and low-energy experiment data.

SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

PubMed

Brons, A-K; Henthorn, P S; Raj, K; Fitzgerald, C A; Liu, J; Sewell, A C; Giger, U

2013-01-01

Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation.

PubMed

Sun, Chengjun; Pei, Zhou; Zhang, Miaoying; Sun, Bijun; Yang, Lin; Zhao, Zhuhui; Cheng, Ruoqian; Luo, Feihong

2018-01-01

Solute carrier family 19 member 2 (SLC19A2) gene deficiency is one of the causes of permanent neonatal diabetes mellitus (PNDM) and can be effectively managed by thiamine supplementation. Herein we report on a male patient with a novel SLC19A2 mutation and summarize the clinical characteristics of patients with SLC19A2 deficiency. The genetic diagnosis of the patient with PNDM was made by sequencing and quantitative polymerase chain reaction. The clinical characteristics of PNDM were summarized on the basis of a systematic review of the literature. The patient with PNDM had c.848G>A (p.W283X) homozygous mutation in SLC19A2. His father had a wild-type SLC19A2 (c.848G) and his mother was c.848G/A heterozygous. The patient and his father both had a diploid genotype (c.848A/A and c.848G/G). After oral thiamine administration, the patient's fasting C-peptide levels increased gradually, and there was a marked decrease in insulin requirements. A search of the literature revealed that thiamine treatment was effective and improved diabetes in 63% of patients with SLC19A2 deficiency. A novel SLC19A2 mutation (c.848G>A; p.W283X) was identified, which was most likely inherited as segmental uniparental isodisomy. Insulin insufficiency in PNDM caused by SLC19A2 deficiency can be corrected by thiamine supplementation. The differential diagnosis of SLC19A2 deficiency should be considered in children with PNDM accompanied by anemia or hearing defects to allow for early treatment. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH− conductance pathway that is stimulated by rises in intracellular and extracellular pH

PubMed Central

Myers, Evan J.; Marshall, Aniko; Jennings, Michael L.

2016-01-01

The SLC4A11 gene encodes the bicarbonate-transporter-related protein BTR1, which is mutated in syndromes characterized by vision and hearing loss. Signs of these diseases [congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome] are evident in mouse models of Slc4a11 disruption. However, the intrinsic activity of Slc4a11 remains controversial, complicating assignment of its (patho)physiological role. Most studies concur that Slc4a11 transports H+ (or the thermodynamically equivalent species OH−) rather than HCO3−, but disparities have arisen as to whether the transport is coupled to another species such as Na+ or NH3/NH4+. Here for the first time, we examine the action of mouse Slc4a11 in Xenopus oocytes. We simultaneously monitor changes in intracellular pH, membrane potential, and conductance as we alter extracellular pH, revealing the electrical and chemical driving forces that underlie the observed ion fluxes. We find that mSlc4a11 is an ideally selective H+/OH− conductive pathway, the action of which is uncoupled from the cotransport of any other ion. We also find that the activity of mSlc4a11 is independently enhanced by both extracellular and intracellular alkalinization, suggesting OH− as the most likely substrate and providing a novel explanation for the apparent NH3-dependence of Slc4a11-mediated currents reported by others. We suggest that the unique properties of Slc4a11 action underlie its value as a pH regulator in corneal endothelial cells. PMID:27681179

SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters.

PubMed

Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor; Gowda, Vykuntaraju K; Raghavan, Varun S; Varalakshmi, Perumal; Said, Hamid M; Ashokkumar, Balasubramaniem

2016-11-01

Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Functional characterization based on 3 H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2. Copyright © 2016 Elsevier B.V. All rights reserved.

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria*

PubMed Central

Gröger, Nicole; Fröhlich, Henning; Maier, Hannes; Olbrich, Andrea; Kostin, Sawa; Braun, Thomas; Boettger, Thomas

2010-01-01

Maintenance of ion concentration gradients is essential for the function of many organs, including the kidney, the cornea, and the inner ear. Ion concentrations and fluid content in the cornea are regulated by endothelial cells that separate the collagenous avascular corneal stroma from the anterior eye chamber. Failure to maintain correct ion concentrations leads to swelling and destruction of the cornea. In the inner ear, the stria vascularis is responsible for generating proper ion concentrations in the endolymph, which is essential for hearing. Mutations of SLC4A11 in humans lead to syndromes associated with corneal dystrophy and perceptive deafness. The molecular mechanisms underlying these symptoms are poorly understood, impeding therapeutic interventions. The ion transporter SLC4A11 mediates sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions in vitro. Here, we show that SLC4A11 is expressed in the endothelial cells of the cornea where it prevents severe morphological changes of the cornea caused by increased sodium chloride concentrations in the stroma. In the inner ear, SLC4A11 is located in fibrocytes underlying the stria vascularis. Loss of SLC4A11 leads to morphological changes in the fibrocytes and deafness. We demonstrate that SLC4A11 is essential for the generation of the endocochlear potential but not for regulation of potassium concentrations in the endolymph. In the kidney, SLC4A11 is expressed in the thin descending limb of Henle loop. SLC4A11 is essential for urinary concentration, suggesting that SLC4A11 participates in the countercurrent multiplication that concentrates urine in the kidney medulla. PMID:20185830

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

PubMed

Strug, Lisa J; Gonska, Tanja; He, Gengming; Keenan, Katherine; Ip, Wan; Boëlle, Pierre-Yves; Lin, Fan; Panjwani, Naim; Gong, Jiafen; Li, Weili; Soave, David; Xiao, Bowei; Tullis, Elizabeth; Rabin, Harvey; Parkins, Michael D; Price, April; Zuberbuhler, Peter C; Corvol, Harriet; Ratjen, Felix; Sun, Lei; Bear, Christine E; Rommens, Johanna M

2016-10-15

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Identification of Mutations in SLC24A4, Encoding a Potassium-Dependent Sodium/Calcium Exchanger, as a Cause of Amelogenesis Imperfecta

PubMed Central

Parry, David A.; Poulter, James A.; Logan, Clare V.; Brookes, Steven J.; Jafri, Hussain; Ferguson, Christopher H.; Anwari, Babra M.; Rashid, Yasmin; Zhao, Haiqing; Johnson, Colin A.; Inglehearn, Chris F.; Mighell, Alan J.

2013-01-01

A combination of autozygosity mapping and exome sequencing identified a null mutation in SLC24A4 in a family with hypomineralized amelogenesis imperfect a (AI), a condition in which tooth enamel formation fails. SLC24A4 encodes a calcium transporter upregulated in ameloblasts during the maturation stage of amelogenesis. Screening of further AI families identified a missense mutation in the ion-binding site of SLC24A4 expected to severely diminish or abolish the ion transport function of the protein. Furthermore, examination of previously generated Slc24a4 null mice identified a severe defect in tooth enamel that reflects impaired amelogenesis. These findings support a key role for SLC24A4 in calcium transport during enamel formation. PMID:23375655

The Solute Carrier Families Have a Remarkably Long Evolutionary History with the Majority of the Human Families Present before Divergence of Bilaterian Species

PubMed Central

Höglund, Pär J.; Nordström, Karl J.V.; Schiöth, Helgi B.; Fredriksson, Robert

2011-01-01

The Solute Carriers (SLCs) are membrane proteins that regulate transport of many types of substances over the cell membrane. The SLCs are found in at least 46 gene families in the human genome. Here, we performed the first evolutionary analysis of the entire SLC family based on whole genome sequences. We systematically mined and analyzed the genomes of 17 species to identify SLC genes. In all, we identified 4,813 SLC sequences in these genomes, and we delineated the evolutionary history of each of the subgroups. Moreover, we also identified ten new human sequences not previously classified as SLCs, which most likely belong to the SLC family. We found that 43 of the 46 SLC families found in Homo sapiens were also found in Caenorhabditis elegans, whereas 42 of them were also found in insects. Mammals have a higher number of SLC genes in most families, perhaps reflecting important roles for these in central nervous system functions. This study provides a systematic analysis of the evolutionary history of the SLC families in Eukaryotes showing that the SLC superfamily is ancient with multiple branches that were present before early divergence of Bilateria. The results provide foundation for overall classification of SLC genes and are valuable for annotation and prediction of substrates for the many SLCs that have not been tested in experimental transport assays. PMID:21186191

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

PubMed Central

Anagnostopoulou, Pinelopi; Riederer, Brigitte; Duerr, Julia; Michel, Sven; Binia, Aristea; Agrawal, Raman; Liu, Xuemei; Kalitzki, Katrin; Xiao, Fang; Chen, Mingmin; Schatterny, Jolanthe; Hartmann, Dorothee; Thum, Thomas; Kabesch, Michael; Soleimani, Manoocher; Seidler, Ursula; Mall, Marcus A.

2012-01-01

Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl–) secretion plays a role in the disease. However, the molecular mechanism underlying Cl– secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl– channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl– secretion in the airways of wild-type but not Slc26a9-deficient mice. While IL-13–induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3′ UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl– channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl– secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging. PMID:22945630

A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

PubMed Central

Maruyama, Shin-ya; Ito, Momoe; Ikami, Yuusuke; Okitsu, Yu; Ito, Chizuru; Toshimori, Kiyotaka; Fujii, Wataru; Yogo, Keiichiro

2016-01-01

We previously identified solute carrier 22a14 (Slc22a14) as a spermatogenesis-associated transmembrane protein in mice. Although Slc22a14 is a member of the organic anion/cation transporter family, its expression profile and physiological role have not been elucidated. Here, we show that Slc22a14 is crucial for sperm motility and male fertility in mice. Slc22a14 is expressed specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility. Although the overall differentiation of sperm was normal, Slc22a14−/− cauda epididymal spermatozoa showed reduced motility with abnormal flagellar bending. Further, the ability to migrate into the female reproductive tract and fertilise the oocyte were also impaired in Slc22a14−/− spermatozoa. The abnormal flagellar bending was thought to be partly caused by osmotic cell swelling since osmotic challenge or membrane permeabilisation treatment alleviated the tail abnormality. In addition, we found structural abnormalities in Slc22a14−/− sperm cells: the annulus, a ring-like structure at the mid-piece–principal piece junction, was disorganised, and expression and localisation of septin 4, an annulus component protein that is essential for the annulus formation, was also impaired. Taken together, our results demonstrated that Slc22a14 plays a pivotal role in normal flagellar structure, motility and fertility in mouse spermatozoa. PMID:27811987

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer

PubMed Central

Andrew, Angeline S.; Nelson, Heather H.; Li, Zhongze; Punshon, Tracy; Schned, Alan; Marsit, Carmen J.; Morris, J. Steven; Moore, Jason H.; Tyler, Anna L.; Gilbert-Diamond, Diane; Guerinot, Mary-Lou; Kelsey, Karl T.

2012-01-01

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case–control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case–control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure. PMID:21947419

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer.

PubMed

Karagas, Margaret R; Andrew, Angeline S; Nelson, Heather H; Li, Zhongze; Punshon, Tracy; Schned, Alan; Marsit, Carmen J; Morris, J Steven; Moore, Jason H; Tyler, Anna L; Gilbert-Diamond, Diane; Guerinot, Mary-Lou; Kelsey, Karl T

2012-03-01

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.

The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways

PubMed Central

Shimoda, Shinji; Mishima, Kenji; Higashiyama, Hiroyuki; Idaira, Yayoi; Asada, Yoshinobu; Kitamura, Hiroshi; Yamasaki, Satoru; Hojyo, Shintaro; Nakayama, Manabu; Ohara, Osamu; Koseki, Haruhiko; dos Santos, Heloisa G.; Bonafe, Luisa; Ha-Vinh, Russia; Zankl, Andreas; Unger, Sheila; Kraenzlin, Marius E.; Beckmann, Jacques S.; Saito, Ichiro; Rivolta, Carlo; Ikegawa, Shiro; Superti-Furga, Andrea; Hirano, Toshio

2008-01-01

Background Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Methodology/Principal Findings Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-β signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Conclusions/Significance Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-β signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-β signaling and connective tissue dysfunction. PMID:18985159

The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production.

PubMed

Kobayashi, Toshihiko; Shimabukuro-Demoto, Shiho; Yoshida-Sugitani, Reiko; Furuyama-Tanaka, Kaori; Karyu, Hitomi; Sugiura, Yuki; Shimizu, Yukiko; Hosaka, Toshiaki; Goto, Motohito; Kato, Norihiro; Okamura, Tadashi; Suematsu, Makoto; Yokoyama, Shigeyuki; Toyama-Sorimachi, Noriko

2014-09-18

SLC15A4 is a lysosome-resident, proton-coupled amino-acid transporter that moves histidine and oligopeptides from inside the lysosome to the cytosol of eukaryotic cells. SLC15A4 is required for Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) and is involved in the pathogenesis of certain diseases including lupus-like autoimmunity. How SLC15A4 contributes to diseases is largely unknown. Here we have shown that B cell SLC15A4 was crucial for TLR7-triggered IFN-I and autoantibody productions in a mouse lupus model. SLC15A4 loss disturbed the endolysosomal pH regulation and probably the v-ATPase integrity, and these changes were associated with disruption of the mTOR pathway, leading to failure of the IFN regulatory factor 7 (IRF7)-IFN-I regulatory circuit. Importantly, SLC15A4's transporter activity was necessary for the TLR-triggered cytokine production. Our findings revealed that SLC15A4-mediated optimization of the endolysosomal state is integral to a TLR7-triggered, mTOR-dependent IRF7-IFN-I circuit that leads to autoantibody production. Copyright © 2014 Elsevier Inc. All rights reserved.

The ABCs of membrane transporters in health and disease (SLC series): Introduction☆☆☆

PubMed Central

Hediger, Matthias A.; Clémençon, Benjamin; Burrier, Robert E.; Bruford, Elspeth A.

2013-01-01

The field of transport biology has steadily grown over the past decade and is now recognized as playing an important role in manifestation and treatment of disease. The SLC (solute carrier) gene series has grown to now include 52 families and 395 transporter genes in the human genome. A list of these genes can be found at the HUGO Gene Nomenclature Committee (HGNC) website (see www.genenames.org/genefamilies/SLC). This special issue features mini-reviews for each of these SLC families written by the experts in each field. The existing online resource for solute carriers, the Bioparadigms SLC Tables (www.bioparadigms.org), has been updated and significantly extended with additional information and cross-links to other relevant databases, and the nomenclature used in this database has been validated and approved by the HGNC. In addition, the Bioparadigms SLC Tables functionality has been improved to allow easier access by the scientific community. This introduction includes: an overview of all known SLC and “non-SLC” transporter genes; a list of transporters of water soluble vitamins; a summary of recent progress in the structure determination of transporters (including GLUT1/SLC2A1); roles of transporters in human diseases and roles in drug approval and pharmaceutical perspectives. PMID:23506860

Boric acid increases the expression levels of human anion exchanger genes SLC4A2 and SLC4A3.

PubMed

Akbas, F; Aydin, Z

2012-04-03

Boron is an important micronutrient in plants and animals. The role of boron in living systems includes coordinated regulation of gene expression, growth and proliferation of higher plants and animals. There are several well-defined genes associated with boron transportation and tolerance in plants and these genes show close homology with human anion exchanger genes. Mutation of these genes also characterizes some genetic disorders. We investigated the toxic effects of boric acid on HEK293 cells and mRNA expression of anion exchanger (SLC4A1, SLC4A2 and SLC4A3) genes. Cytotoxicity of boric acid at different concentrations was tested by using the methylthiazolyldiphenyl-tetrazolium bromide assay. Gene expression profiles were examined using quantitative real-time PCR. In the HEK293 cells, the nontoxic upper concentration of boric acid was 250 μM; more than 500 μM caused cytotoxicity. The 250 μM boric acid concentration increased gene expression level of SLC4A2 up to 8.6-fold and SLC4A3 up to 2.6-fold, after 36-h incubation. There was no significant effect of boric acid on SLC4A1 mRNA expression levels.

SLC20A2 DEFICIENCY IN MICE LEADS TO ELEVATED PHOSPHATE LEVELS IN CEREBROSPINAL FLUID AND GLYMPHATIC PATHWAY-ASSOCIATED ARTERIOLAR CALCIFICATION, AND RECAPITULATES HUMAN IDIOPATHIC BASAL GANGLIA CALCIFICATION

PubMed Central

Wallingford, MC; Chia, J; Leaf, EM; Borgeia, S; Chavkin, NW; Sawangmake, C; Marro, K; Cox, TC; Speer, MY; Giachelli, CM

2016-01-01

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/− mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification. PMID:26822507

Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2.

PubMed

Carland, Jane E; Thomas, Michael; Mostyn, Shannon N; Subramanian, Nandhitha; O'Mara, Megan L; Ryan, Renae M; Vandenberg, Robert J

2018-03-21

Transporters in the SLC6 family play key roles in regulating neurotransmission and are the targets for a wide range of therapeutics. Important insights into the transport mechanisms and the specificity of drug interactions of SLC6 transporters have been obtained from the crystal structures of a bacterial homologue of the family, LeuT Aa , and more recently the Drosophila dopamine transporter and the human serotonin transporter. However, there is disputed evidence that the bacterial leucine transporter, LeuT Aa , contains two substrate binding sites that work cooperatively in the mechanism of transport, with the binding of a second substrate being required for the release of the substrate from the primary site. An alternate proposal is that there may be low affinity binding sites that serve to direct the flow of substrates to the primary site. We have used a combination of molecular dynamics simulations of substrate interactions with a homology model of GlyT2, together with radiolabeled amino acid uptake assays and electrophysiological analysis of wild-type and mutant transporters, to provide evidence that substrate selectivity of GlyT2 is determined entirely by the primary substrate binding site and, furthermore, if a secondary site exists then it is a low affinity nonselective amino acid binding site.

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer.

PubMed

Koppula, Pranavi; Zhang, Yilei; Zhuang, Li; Gan, Boyi

2018-04-25

Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.

Association of SNPs in dopamine and serotonin pathway genes and their interacting genes with temperament traits in Charolais cows.

PubMed

Garza-Brenner, E; Sifuentes-Rincón, A M; Randel, R D; Paredes-Sánchez, F A; Parra-Bracamonte, G M; Arellano Vera, W; Rodríguez Almeida, F A; Segura Cabrera, A

2017-08-01

Cattle temperament is a complex trait, and molecular studies aimed at defining this trait are scarce. We used an interaction networks approach to identify new genes (interacting genes) and to estimate their effects and those of 19 dopamine- and serotonin-related genes on the temperament traits of Charolais cattle. The genes proopiomelanocortin (POMC), neuropeptide Y (NPY), solute carrier family 18, member 2 (SLC18A2) and FBJ murine osteosarcoma viral oncogene homologue (FOSFBJ) were identified as new candidates. Their potential to be associated with temperament was estimated according to their reported biological activities, which included interactions with neural activity, receptor function, targeting or synthesis of neurotransmitters and association with behaviour. Pen score (PS) and exit velocity (EV) measures were determined from 412 Charolais cows to calculate their temperament score (TS). Based on the TS, calm (n = 55; TS, 1.09 ± 0.33) and temperamental (n = 58; TS, 2.27 ± 0.639) cows were selected and genotyped using a 248 single-nucleotide variation (SNV) panel. Of the 248 variations in the panel, only 151 were confirmed to be polymorphic (single-nucleotide polymorphisms; SNPs) in the tested population. Single-marker association analyses between genotypes and temperament measures (EV, PS and/or TS) indicated significant associations of six SNPs from four candidate genes. The markers rs109576799 and rs43696138, located in the DRD3 and HTR2A genes, respectively, were significantly associated with both EV and TS traits. Four markers, rs110365063 and rs137756569 from the POMC gene and rs110365063 and rs135155082 located in SLC18A2 and DRD2, respectively, were associated with PS. The variant rs110365063 located in bovine SLC18A2 causes a change in the amino acid sequence from Ala to Thr. Further studies are needed to confirm the association of genetic profile with cattle temperament; however, our study represents important progress in understanding the regulation of cattle temperament by different genes with divergent functions.

The SLAC linac as used in the SLC collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seeman, J.T.; Abrams, G.; Adolphsen, C.

The linac of the SLAC Linear Collider (SLC) must accelerate three high intensity bunches on each linac pulse from 1.2 GeV to 50 GeV with minimal increase of the small transverse emittance. The procedures and adjustments used to obtain this goal are outlined. Some of the accelerator parameters and components which interact are the beam energy, transverse position, component alignment, RF manipulation, feedback systems, quadrupole lattice, BNS damping, energy spectra, phase space matching, collimation, instrumentation and modelling. The method to bring these interdependent parameters collectively into specification has evolved over several years. This review is ordered in the sequence whichmore » is used to turn on the linac from a cold start and produce acceptable beams for the final focus and collisions. Approximate time estimates for the various activities are given. 21 refs.« less

Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome.

PubMed

Ganaha, Akira; Kaname, Tadashi; Yanagi, Kumiko; Naritomi, Kenji; Tono, Tetsuya; Usami, Shin-ichi; Suzuki, Mikio

2013-05-24

Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient's clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon-intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2(-ΔΔCT)) method were used to determine the pathogenicity associated with gene substitutions. SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.

Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome

PubMed Central

2013-01-01

Background Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. Methods We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient’s clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon–intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2−ΔΔCT) method were used to determine the pathogenicity associated with gene substitutions. Results SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. Conclusions The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA. PMID:23705809

Solute carrier transporters: potential targets for digestive system neoplasms.

PubMed

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms.

Solute carrier transporters: potential targets for digestive system neoplasms

PubMed Central

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms. PMID:29416375

2. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE NORTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

1. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE SOUTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure.

PubMed

Staud, Frantisek; Cerveny, Lukas; Ceckova, Martina

2012-11-01

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

9. Photocopy of photograph (original photograph in possession of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

9. Photocopy of photograph (original photograph in possession of the Ralph M. Parsons Company, Los Angeles, California). Photography by the Ralph M. Parsons Co. circa 1959. VIEW FROM THE SOUTH OF ORIGINAL CONSTRUCTION OF A-FRAME ATLAS GANTRY AT POINT ARGUELLO LAUNCH COMPLEX 1, PAD 1 (SLC-3W) - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

8. Photocopy of photograph (original photograph in possession of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. Photocopy of photograph (original photograph in possession of the Ralph M. Parsons Company, Los Angeles, California). Photography by United States Navy, July 8, 1959. VIEW OF FORMWORK FOR NORTH WALL OF POINT ARGUELLO LAUNCH COMPLEX 1, PAD 2 (SLC-3 EAST) LAUNCH PAD AND SERVICE BUILDING (BLDG. 751). - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells

PubMed Central

D’Agostino, Sabrina; Lanzillotta, Delia; Varano, Mariaconcetta; Botta, Cirino; Baldrini, Antonio; Bilotta, Anna; Scalise, Stefania; Dattilo, Vincenzo; Amato, Rosario; Gaudio, Eugenio; Paduano, Francesco; Palmieri, Camillo; Iuliano, Rodolfo; Perrotti, Nicola; Indiveri, Cesare; Fusco, Alfredo; Gaspari, Marco; Trapasso, Francesco

2018-01-01

PTPRJ, a receptor protein tyrosine phosphatase strongly downregulated in human cancer, displays tumor suppressor activity by negatively modulating several proteins involved in proliferating signals. Here, through a proteomic-based approach, we identified a list of potential PTPRJ-interacting proteins and among them we focused on CD98hc, a type II glycosylated integral membrane protein encoded by SLC3A2, corresponding to the heavy chain of a heterodimeric transmembrane amino-acid transporter, including LAT1. CD98hc is widely overexpressed in several types of cancers and contributes to the process of tumorigenesis by interfering with cell proliferation, adhesion, and migration. We first validated PTPRJ-CD98hc interaction, then demonstrated that PTPRJ overexpression dramatically reduces CD98hc protein levels in A549 lung cancer cells. In addition, following to the treatment of PTPRJ-transduced cells with MG132, a proteasome inhibitor, CD98hc levels did not decrease compared to controls, indicating that PTPRJ is involved in the regulation of CD98hc proteasomal degradation. Moreover, PTPRJ overexpression combined with CD98hc silencing consistently reduced cell proliferation and triggered apoptosis of lung cancer cells. Interestingly, by interrogating the can Evolve database, we observed an inverse correlation between PTPRJ and SLC3A2 gene expression. Indeed, the non-small cell lung cancers (NSCLCs) of patients showing a short survival rate express the lowest and the highest levels of PTPRJ and SLC3A2, respectively. Therefore, the results reported here contribute to shed lights on PTPRJ signaling in cancer cells: moreover, our findings also support the development of a novel anticancer therapeutic approach by targeting the pathway of PTPRJ that is usually downregulated in highly malignant human neoplasias.

SLC24A5 and ASIP as phenotypic predictors in Brazilian population for forensic purposes.

PubMed

Lima, F A; de Araújo Lima, Felícia; Gonçalves, F T; de Toledo Gonçalves, Fernanda; Fridman, C; Fridman, Cintia

2015-07-01

Pigmentation is a variable and complex trait in humans and it is determined by the interaction of environmental factors, age, disease, hormones, exposure to ultraviolet radiation and genetic factors, including pigmentation genes. Many polymorphisms of these genes have been associated with phenotypic diversity of skin, eyes and hair color in homogeneous populations. Phenotype prediction from biological samples using genetic information has benefited forensic area in some countries, leading some criminal investigations. Herein, we evaluated the association between polymorphisms in the genes SLC24A5 (rs1426654) and ASIP (rs6058017) with skin, eyes and hair colors, in 483 healthy individuals from Brazilian population for attainable use in forensic practice. The volunteers answered a questionnaire where they self-reported their skin, eye and hair colors. The polymorphic homozygous genotype of rs1426654∗A and rs6058017∗A in SLC24A5 and ASIP respectively, showed strongest association with fairer skin (OR 47.8; CI 14.1-161.6 and OR 8.6; CI 2.5-29.8); SLC24A5 alone showed associations with blue eyes (OR 20.7; CI 1.2-346.3) and blond hair (OR 26.6; CI 1.5-460.9). Our data showed that polymorphic genotypes (AA), in both genes, are correlated with characteristics of light pigmentation, while the ancestral genotype (GG) is related to darker traits, corroborating with previous studies in European and African populations. These associations show that specific molecular information of an individual may be useful to access some phenotypic features in an attempt to help forensic investigations, not only on crime scene samples but also in cases of face reconstructions in unknown bodies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Synopsis of the 48 annual meeting of the Lake Cumberland Biological Transport Group and the second biannual meeting of the Pendrin Consortium.

PubMed

Dossena, Silvia; Nofziger, Charity; Morabito, Rossana; Adragna, Norma C; Paulmichl, Markus

2013-01-01

Ion transporters are the molecular basis for ion homeostasis of the cell and the whole organism. The anion exchanger pendrin is only one of a number of examples where a complete or partial loss of function and/or deregulation of expression of ion transporters may lead or contribute to pathological conditions in humans. A complete understanding of the function of ion transporters in health and disease may pave the way for the identification of new and focused therapeutic approaches. Exchange of knowledge and connectivity between the experts in the feld of transport physiology is essential in facing these challenging tasks. The Lake Cumberland Biological Transport Group and the Pendrin Consortium are examples of scientific forums where investigators combine their efforts towards a better understanding of molecular pathophysiology of ion transport. This issue discusses the versatility of ion transporters involved in the regulation of cellular volume and other functions, such as the solute carrier (SLC) 12A gene family members SLC12A4-7, encoding the Na(+)-independent cation-chloride cotransporters commonly known as the K(+)-Cl(-) cotransporters KCC1-4, and the betaine/γ-aminobutyric acid transport system (BGT1, SLC6A12), just to name a few. The issue further addresses the pathophysiology of intestinal and respiratory epithelia and related therapeutic tools and techniques to investigate interactions between proteins and proteins and small compounds. Finally, the current knowledge and new findings on the expression, regulation and function of pendrin (SLC26A4) in the inner ear, kidney, airways and blood platelets are presented. © 2014 S. Karger AG, Basel.

The rise and fall of novel renal magnesium transporters.

PubMed

Schäffers, Olivier J M; Hoenderop, Joost G J; Bindels, René J M; de Baaij, Jeroen H F

2018-06-01

Body Mg 2+ balance is finely regulated in the distal convoluted tubule (DCT), where a tight interplay among transcellular reabsorption, mitochondrial exchange, and basolateral extrusion takes place. In the last decades, several research groups have aimed to identify the molecular players in these processes. A multitude of proteins have been proposed to function as Mg 2+ transporter in eukaryotes based on phylogenetic analysis, differential gene expression, and overexpression studies. However, functional evidence for many of these proteins is lacking. The aim of this review is, therefore, to critically reconsider all putative Mg 2+ transporters and put their presumed function in context of the renal handling of Mg 2+ . Sufficient experimental evidence exists to acknowledge transient receptor potential melastatin (TRPM) 6 and TRPM7, solute carrier family 41 (SLC41) A1 and SLC41A3, and mitochondrial RNA splicing 2 (MRS2) as Mg 2+ transporters. TRPM6/7 facilitate Mg 2+ influx, SLC41A1 mediates Mg 2+ extrusion, and MRS2 and SLC41A3 are implicated in mitochondrial Mg 2+ homeostasis. These proteins are highly expressed in the DCT. The function of cyclin M (CNNM) proteins is still under debate. For the other proposed Mg 2+ transporters including Mg 2+ transporter subtype 1 (MagT1), nonimprinted in Prader-Willi/Angelman syndrome (NIPA), membrane Mg 2+ transport (MMgT), Huntingtin-interacting protein 14 (HIP14), and ATP13A4, functional evidence is limited, or functions alternative to Mg 2+ transport have been suggested. Additional characterization of their Mg 2+ transport proficiency should be provided before further claims about their role as Mg 2+ transporter can be made.

Serotonin Transporter Gene, Depressive Symptoms and Interleukin-6

PubMed Central

Su, Shaoyong; Zhao, Jinying; Bremner, J. Douglas; Miller, Andrew H.; Tang, Weining; Bouzyk, Mark; Snieder, Harold; Novik, Olga; Afzal, Nadeem; Goldberg, Jack; Vaccarino, Viola

2009-01-01

Background We explored the relationship of genetic variants of the serotonin transporter gene SLC6A4, a key regulator of the serotonergic neurotransmission, with both depressive symptoms and plasma Interleukin-6 (IL-6) levels. Methods and Results We genotyped 20 polymorphisms in 360 male twins (mean age: 54) from the Vietnam Era Twin Registry. Current depressive symptoms were measured with the Beck Depression Inventory-II (BDI-II). IL-6 was assessed using a commercially available ELISA kit. Genotype associations were analyzed using generalized estimating equations. To study how SLC6A4 genetic vulnerability influences the relationship between depressive symptoms and IL-6, bivariate models were constructed using structural equation modeling. Of the 20 polymorphisms examined, the effective number of independent tests was 6 and the threshold of significance after Bonferroni correction was 0.008. There were 6 SNPs significantly associated with BDI (P≤0.008), including rs8071667, rs2020936, rs25528, rs6354, rs11080122 and rs8076005, and 1 SNP borderline associated (rs12150214, P=0.017). Of these 7 SNPs, 3 were also significantly associated with IL-6 (P<0.008), including rs25528, rs6354 and rs8076005, and the other 4 were borderline associated (P=0.009~0.025). The subjects with one copy of the minor allele of these 7 SNPs had higher BDI scores and IL-6 levels. Further bivariate modeling revealed that approximately 10% of the correlation between BDI and IL-6 could be explained by the SLC6A4 gene. Conclusions Genetic vulnerability involving the SLC6A4 gene is significantly associated with both increased depressive symptoms and elevated IL-6 plasma levels. Common pathophysiological processes may link depression and inflammation, and implicate the serotonin pathway in neural-immune interactions. PMID:20031642

Influence of Serotonin Transporter SLC6A4 Genotype on the Effect of Psychosocial Stress on Cognitive Performance: An Exploratory Pilot Study.

PubMed

Beversdorf, David Q; Carpenter, Allen L; Alexander, Jessica K; Jenkins, Neil T; Tilley, Michael R; White, Catherine A; Hillier, Ashleigh J; Smith, Ryan M; Gu, Howard H

2018-06-01

Previous research has shown an effect of various psychosocial stressors on unconstrained cognitive flexibility, such as searching through a large set of potential solutions in the lexical-semantic network during verbal problem-solving. Functional magnetic resonance imaging has shown that the presence of the short (S) allele (lacking a 43-base pair repeat) of the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5-HTT) protein is associated with a greater amygdalar response to emotional stimuli and a greater response to stressors. Therefore, we hypothesized that the presence of the S-allele is associated with greater stress-associated impairment in performance on an unconstrained cognitive flexibility task, anagrams. In this exploratory pilot study, 28 healthy young adults were genotyped for long (L)-allele versus S-allele promoter region polymorphism of the 5-HTT gene, SLC6A4. Participants solved anagrams during the Trier Social Stress Test, which included public speaking and mental arithmetic stressors. We compared the participants' cognitive response to stress across genotypes. A Gene×Stress interaction effect was observed in this small sample. Comparisons revealed that participants with at least one S-allele performed worse during the Stress condition. Genetic susceptibility to stress conferred by SLC6A4 appeared to modulate unconstrained cognitive flexibility during psychosocial stress in this exploratory sample. If confirmed, this finding may have implications for conditions associated with increased stress response, including performance anxiety and cocaine withdrawal. Future work is needed both to confirm our findings with a larger sample and to explore the mechanisms of this proposed effect.

Identification and functional characterization of a solute carrier family 15, member 4 gene in Litopenaeus vannamei.

PubMed

Chen, Yong-Gui; Yuan, Kai; Zhang, Ze-Zhi; Yuan, Feng-Hua; Weng, Shao-Ping; Yue, Hai-Tao; He, Jian-Guo; Chen, Yi-Hong

2016-04-01

Innate immunity in shrimp is important in resisting bacterial infection. The NF-κB pathway is pivotal in such an immune response. This study cloned and functionally characterized the solute carrier family (SLC) 15 member A 4 (LvSLC15A4) gene in Litopenaeus vannamei. The open reading frame of LvSLC15A4 is 1, 902 bp long and encodes a putative 633-amino acid protein, which is localized in the plasma membrane and intracellular vesicular compartments. Results of the reporter gene assay showed that LvSLC15A4 upregulated NF-κB target genes, including the immediate-early gene 1 of white spot syndrome virus, as well as several antimicrobial peptide genes, such as pen4, CecA, AttA, and Mtk in S2 cells. Moreover, knocked-down expression of LvSLC15A4 reduced pen4 expression in L. vannamei. LvSLC15A4 down-regulation also increased the cumulative mortality of Vibrio parahemolyticus-infected L. vannamei. Furthermore, LvSLC15A4 expression was induced by unfolded protein response (UPR) in L. vannamei hematocytes. These results suggest that LvSLC15A4 participates in L. vannamei innate immunity via the NF-κB pathway and thus may be related to UPR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1*

PubMed Central

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-01

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H+) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na+-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H+-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. PMID:25371203

SLC26A4 mutation testing for hearing loss associated with enlargement of the vestibular aqueduct

PubMed Central

Ito, Taku; Muskett, Julie; Chattaraj, Parna; Choi, Byung Yoon; Lee, Kyu Yup; Zalewski, Christopher K; King, Kelly A; Li, Xiangming; Wangemann, Philine; Shawker, Thomas; Brewer, Carmen C; Alper, Seth L; Griffith, Andrew J

2014-01-01

Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct (EVA), and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in ¼ of North American or European EVA populations, one mutant allele is detected in another ¼ of patient populations, and no mutations are detected in the other ½. The presence of two mutant alleles of SLC26A4 is associated with abnormal iodide organification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The presence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not have an effect on hearing thresholds. This is consistent with observations of an Slc26a4 mutant mouse model of EVA in which hearing loss is independent of endolymphatic hydrops or inner ear malformations. Segregation analyses of EVA in families suggest that the patients carrying one mutant allele of SLC26A4 have a second, undetected mutant allele of SLC26A4, and the probability of a sibling having EVA is consistent with its segregation as an autosomal recessive trait. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. SLC26A4 mutation testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling. PMID:25960948

Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter.

PubMed

Miyauchi, Seiji; Gopal, Elangovan; Babu, Ellappan; Srinivas, Sonne R; Kubo, Yoshiyuki; Umapathy, Nagavedi S; Thakkar, Santoshanand V; Ganapathy, Vadivel; Prasad, Puttur D

2010-06-01

Pyroglutamate, also known as 5-oxoproline, is a structural analog of proline. This amino acid derivative is a byproduct of glutathione metabolism, and is reabsorbed efficiently in kidney by Na(+)-coupled transport mechanisms. Previous studies have focused on potential participation of amino acid transport systems in renal reabsorption of this compound. Here we show that it is not the amino acid transport systems but instead the Na(+)-coupled monocarboxylate transporter SLC5A8 that plays a predominant role in this reabsorptive process. Expression of cloned human and mouse SLC5A8 in mammalian cells induces Na(+)-dependent transport of pyroglutamate that is inhibitable by various SLC5A8 substrates. SLC5A8-mediated transport of pyroglutamate is saturable with a Michaelis constant of 0.36+/-0.04mM. Na(+)-activation of the transport process exhibits sigmoidal kinetics with a Hill coefficient of 1.8+/-0.4, indicating involvement of more than one Na(+) in the activation process. Expression of SLC5A8 in Xenopuslaevis oocytes induces Na(+)-dependent inward currents in the presence of pyroglutamate under voltage-clamp conditions. The concentration of pyroglutamate necessary for induction of half-maximal current is 0.19+/-0.01mM. The Na(+)-activation kinetics is sigmoidal with a Hill coefficient of 2.3+/-0.2. Ibuprofen, a blocker of SLC5A8, suppressed pyroglutamate-induced currents in SLC5A8-expressing oocytes; the concentration of the blocker necessary for causing half-maximal inhibition is 14+/-1microM. The involvement of SLC5A8 can be demonstrated in rabbit renal brush border membrane vesicles by showing that the Na(+)-dependent uptake of pyroglutamate in these vesicles is inhibitable by known substrates of SLC5A8. The Na(+) gradient-driven pyroglutamate uptake was stimulated by an inside-negative K(+) diffusion potential induced by valinomycin, showing that the uptake process is electrogenic.

Evaluation of scatter limitation correction: a new method of correcting photopenic artifacts caused by patient motion during whole-body PET/CT imaging.

PubMed

Miwa, Kenta; Umeda, Takuro; Murata, Taisuke; Wagatsuma, Kei; Miyaji, Noriaki; Terauchi, Takashi; Koizumi, Mitsuru; Sasaki, Masayuki

2016-02-01

Overcorrection of scatter caused by patient motion during whole-body PET/computed tomography (CT) imaging can induce the appearance of photopenic artifacts in the PET images. The present study aimed to quantify the accuracy of scatter limitation correction (SLC) for eliminating photopenic artifacts. This study analyzed photopenic artifacts in (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT images acquired from 12 patients and from a National Electrical Manufacturers Association phantom with two peripheral plastic bottles that simulated the human body and arms, respectively. The phantom comprised a sphere (diameter, 10 or 37 mm) containing fluorine-18 solutions with target-to-background ratios of 2, 4, and 8. The plastic bottles were moved 10 cm posteriorly between CT and PET acquisitions. All PET data were reconstructed using model-based scatter correction (SC), no scatter correction (NSC), and SLC, and the presence or absence of artifacts on the PET images was visually evaluated. The SC and SLC images were also semiquantitatively evaluated using standardized uptake values (SUVs). Photopenic artifacts were not recognizable in any NSC and SLC image from all 12 patients in the clinical study. The SUVmax of mismatched SLC PET/CT images were almost equal to those of matched SC and SLC PET/CT images. Applying NSC and SLC substantially eliminated the photopenic artifacts on SC PET images in the phantom study. SLC improved the activity concentration of the sphere for all target-to-background ratios. The highest %errors of the 10 and 37-mm spheres were 93.3 and 58.3%, respectively, for mismatched SC, and 73.2 and 22.0%, respectively, for mismatched SLC. Photopenic artifacts caused by SC error induced by CT and PET image misalignment were corrected using SLC, indicating that this method is useful and practical for clinical qualitative and quantitative PET/CT assessment.

A novel sodium bicarbonate cotransporter-like gene in an ancient duplicated region: SLC4A9 at 5q31

PubMed Central

Lipovich, Leonard; Lynch, Eric D; Lee, Ming K; King, Mary-Claire

2001-01-01

Background: Sodium bicarbonate cotransporter (NBC) genes encode proteins that execute coupled Na+ and HCO3- transport across epithelial cell membranes. We report the discovery, characterization, and genomic context of a novel human NBC-like gene, SLC4A9, on chromosome 5q31. Results: SLC4A9 was initially discovered by genomic sequence annotation and further characterized by sequencing of long-insert cDNA library clones. The predicted protein of 990 amino acids has 12 transmembrane domains and high sequence similarity to other NBCs. The 23-exon gene has 14 known mRNA isoforms. In three regions, mRNA sequence variation is generated by the inclusion or exclusion of portions of an exon. Noncoding SLC4A9 cDNAs were recovered multiple times from different libraries. The 3' untranslated region is fragmented into six alternatively spliced exons and contains expressed Alu, LINE and MER repeats. SLC4A9 has two alternative stop codons and six polyadenylation sites. Its expression is largely restricted to the kidney. In silico approaches were used to characterize two additional novel SLC4A genes and to place SLC4A9 within the context of multiple paralogous gene clusters containing members of the epidermal growth factor (EGF), ankyrin (ANK) and fibroblast growth factor (FGF) families. Seven human EGF-SLC4A-ANK-FGF clusters were found. Conclusion: The novel sodium bicarbonate cotransporter-like gene SLC4A9 demonstrates abundant alternative mRNA processing. It belongs to a growing class of functionally diverse genes characterized by inefficient highly variable splicing. The evolutionary history of the EGF-SLC4A-ANK-FGF gene clusters involves multiple rounds of duplication, apparently followed by large insertions and deletions at paralogous loci and genome-wide gene shuffling. PMID:11305939

Short communication: High incubation temperature in bovine mammary epithelial cells reduced the activity of the mTOR signaling pathway.

PubMed

Kaufman, J D; Kassube, K R; Almeida, R A; Ríus, A G

2018-05-02

Hyperthermia alters utilization of AA in protein synthesis and cell-signaling activity in bovine mammary cells. Essential AA and insulin regulate translation of proteins by controlling the activity of mammalian target of rapamycin (mTOR) signaling pathway. The objectives of this study were to evaluate (1) the effects of incubation temperature on the mTOR signaling pathway and transcription of AA transporters in a bovine mammary alveolar cell line (MAC-T) and (2) the combined effects of incubation temperature and insulin on the mTOR signaling pathway in this cell line. Cells were cultured in medium with 10% fetal bovine serum at 37°C and 5% CO 2 . In experiment 1, cells were subjected to 37°C (control) or 41.5°C (high incubation temperature; HT) for 12 h. In experiment 2, cells were assigned to 1 of 4 treatments as a 2 × 2 factorial arrangement, including 2 cell culture temperatures (control and HT) and absence or presence of 1.0 μg/mL of insulin. Proteins were harvested and separated by gel electrophoresis. In experiment 1, gene expression of AA transporters (SLC1A1, SLC1A5, SLC3A2, SLC7A1, SLC7A5, and SLC36A1) were evaluated, and changes of ≥2 fold were deemed significantly different. In experiments 1 and 2, immunoblotting was used to identify total and site-specific phosphorylated forms of protein kinase B (Akt1; Ser473), p70 S6 kinase (S6K1; Thr389), ribosomal protein S6 (rpS6; Ser235/236), and eukaryotic elongation factor 2 (eEF2; Thr56). Phosphorylated and total forms of Akt1, S6K1, rpS6, and eEF2 were quantified and expressed as the ratio of phosphorylated to total protein. In experiment 1, HT resulted in a ≥2-fold increase expression of SLC1A1 and SLC3A2. High incubation temperature reduced the phosphorylated to total ratio of Akt1 and rpS6 and increased the phosphorylated to total ratio of eEF2. In experiment 2, we found no temperature by insulin interactions on phosphorylation state of the protein factors of interest. High incubation temperature reduced the phosphorylated to total ratio of Akt1. The addition of insulin increased the phosphorylated to total ratio of Akt1, S6K1, and rpS6. In summary, HT reduced the activity of the mTOR signaling pathway and increased the expression of AA transporters. High incubation temperature possibly reduced protein translation by reducing the mTOR signaling pathway activity in an effort to adapt to thermal stress. These results may help explain the direct effect of elevated temperature on AA metabolism and protein translation in heat-stressed animals. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

PubMed Central

Kurosawa, Yuko; DeGrauw, Ton J.; Lindquist, Diana M.; Blanco, Victor M.; Pyne-Geithman, Gail J.; Daikoku, Takiko; Chambers, James B.; Benoit, Stephen C.; Clark, Joseph F.

2012-01-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8–/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8–/y mouse was comparable to that of human patients. We successfully treated the Slc6a8–/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8–/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8–/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency. PMID:22751104

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

PubMed

Kurosawa, Yuko; Degrauw, Ton J; Lindquist, Diana M; Blanco, Victor M; Pyne-Geithman, Gail J; Daikoku, Takiko; Chambers, James B; Benoit, Stephen C; Clark, Joseph F

2012-08-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Uncertainty of the 20th century sea-level rise due to vertical land motion errors

NASA Astrophysics Data System (ADS)

Santamaría-Gómez, Alvaro; Gravelle, Médéric; Dangendorf, Sönke; Marcos, Marta; Spada, Giorgio; Wöppelmann, Guy

2017-09-01

Assessing the vertical land motion (VLM) at tide gauges (TG) is crucial to understanding global and regional mean sea-level changes (SLC) over the last century. However, estimating VLM with accuracy better than a few tenths of a millimeter per year is not a trivial undertaking and many factors, including the reference frame uncertainty, must be considered. Using a novel reconstruction approach and updated geodetic VLM corrections, we found the terrestrial reference frame and the estimated VLM uncertainty may contribute to the global SLC rate error by ± 0.2 mmyr-1. In addition, a spurious global SLC acceleration may be introduced up to ± 4.8 ×10-3 mmyr-2. Regional SLC rate and acceleration errors may be inflated by a factor 3 compared to the global. The difference of VLM from two independent Glacio-Isostatic Adjustment models introduces global SLC rate and acceleration biases at the level of ± 0.1 mmyr-1 and 2.8 ×10-3 mmyr-2, increasing up to 0.5 mm yr-1 and 9 ×10-3 mmyr-2 for the regional SLC. Errors in VLM corrections need to be budgeted when considering past and future SLC scenarios.

The human gene SLC25A29, of solute carrier family 25, encodes a mitochondrial transporter of basic amino acids.

PubMed

Porcelli, Vito; Fiermonte, Giuseppe; Longo, Antonella; Palmieri, Ferdinando

2014-05-09

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport carboxylates, amino acids, nucleotides, and cofactors across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. In this work, a member of this family, SLC25A29, previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier, has been thoroughly characterized biochemically. The SLC25A29 gene was overexpressed in Escherichia coli, and the gene product was purified and reconstituted in phospholipid vesicles. Its transport properties and kinetic parameters demonstrate that SLC25A29 transports arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine. Carnitine and acylcarnitines were not transported by SLC25A29. This carrier catalyzed substantial uniport besides a counter-exchange transport, exhibited a high transport affinity for arginine and lysine, and was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. The main physiological role of SLC25A29 is to import basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation.

28. VIEW SOUTH FROM SLC3W MST STATION 63. FOREGROUND LEFT: ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

28. VIEW SOUTH FROM SLC-3W MST STATION 63. FOREGROUND LEFT: THEODOLITE SHELTER (BLDG. 786) CENTER LEFT TO RIGHT: GLOBAL POSITIONING SYSTEM AZIMUTH STATION (BLDG. 775), PYROTECHNIC SHED (BLDG. 757), PORTABLE GUARD SHED, METEOROLOGICAL SHED (BLDG. 756), METEOROLOGICAL TOWER. BACKGROUND CENTER TO RIGHT: STORAGE SHED (BLDG. 776), LIQUID OXYGEN APRON, SLC-3E MST, TOP OF SLC-3E FUEL STORAGE TANK. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Identification of the putative goldfish (Carassius auratus) magnesium transporter SLC41a1 and functional regulation in the gill, kidney, and intestine in response to dietary and environmental manipulations.

PubMed

Kodzhahinchev, Vladimir; Kovacevic, Drago; Bucking, Carol

2017-04-01

While magnesium requirements for teleost fish highlight the physiological importance of this cation for homeostasis, little is known regarding the molecular identity of transporters responsible for magnesium absorption or secretion. The recent characterization of the vertebrate magnesium transporter solute carrier 41a1 (SLC41a1) in the kidney of a euryhaline fish has provided a glimpse of possible moieties involved in piscine magnesium regulation. The present study obtained a novel SLC41a1 coding sequence for Carassius auratus and demonstrated ubiquitous expression in all tissues examined. Transcriptional regulation of SLC41a1 in response to dietary and environmental magnesium concentrations was observed across tissues. Specifically, decreased environmental magnesium correlated with decreased expression of SLC41a1 in the intestine, whereas the gill and kidney were unaffected. Dietary magnesium restriction correlated with decreased expression of SLC41a1 in the intestine and gill, while again no effects were detected in the kidney. Finally, elevated dietary magnesium correlated with increased expression of SLC41a1 in the kidney, while expression in the intestine and gill remained stable. Plasma magnesium was maintained in all treatments, and dietary assimilation efficiency increased with decreased dietary magnesium. Consumption of a single meal failed to impact SLC41a1 expression, and transcript abundance remained stable over the course of digestion in all treatments. Transcriptional regulation occurred between 7 and 14days following dietary and environmental manipulations and short-term regulation (e.g. <24h) was not observed. Overall the data supports transcriptional regulation of SLC41a1 reflecting a possible role in magnesium loss or secretion across tissues in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy.

PubMed

Srour, Myriam; Shimokawa, Noriaki; Hamdan, Fadi F; Nassif, Christina; Poulin, Chantal; Al Gazali, Lihadh; Rosenfeld, Jill A; Koibuchi, Noriyuki; Rouleau, Guy A; Al Shamsi, Aisha; Michaud, Jacques L

2017-05-04

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

PubMed

Dello Strologo, Luca; Pras, Elon; Pontesilli, Claudia; Beccia, Ercole; Ricci-Barbini, Vittorino; de Sanctis, Luisa; Ponzone, Alberto; Gallucci, Michele; Bisceglia, Luigi; Zelante, Leopoldo; Jimenez-Vidal, Maite; Font, Mariona; Zorzano, Antonio; Rousaud, Ferran; Nunes, Virginia; Gasparini, Paolo; Palacín, Manuel; Rizzoni, Gianfranco

2002-10-01

Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients.

Associations Between Neurotransmitter Genes and Fatigue and Energy Levels in Women Following Breast Cancer Surgery

PubMed Central

Eshragh, Jasmine; Dhruva, Anand; Paul, Steven M.; Cooper, Bruce A.; Mastick, Judy; Hamolsky, Deborah; Levine, Jon D.; Miaskowski, Christine; Kober, Kord M.

2016-01-01

Context Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy. Objectives In patients with breast cancer, variations in neurotransmitter genes between Lower and Higher Fatigue latent classes and between the Higher and Lower Energy latent classes were evaluated. Methods Patients completed assessments prior to and monthly for 6 months following surgery. Growth mixture modeling was used to identify distinct latent classes for fatigue severity and energy levels. Thirty candidate genes involved in various aspects of neurotransmission were evaluated. Results Eleven single nucleotide polymorphisms (SNPs) or haplotypes (i.e., ADRB2 rs1042718, BDNF rs6265, COMT rs9332377, CYP3A4 rs4646437, GALR1 rs949060, GCH1 rs3783642, NOS1 rs9658498, NOS1 rs2293052, NPY1R Haplotype A04, SLC6A2 rs17841327 and 5HTTLPR + rs25531 in SLC6A4) were associated with latent class membership for fatigue. Seven SNPs or haplotypes (i.e., NOS1 rs471871, SLC6A1 rs2675163, SLC6A1 Haplotype D01, SLC6A2 rs36027, SLC6A3 rs37022, SLC6A4 rs2020942, and TAC1 rs2072100) were associated with latent class membership for energy. Three of thirteen genes (i.e., NOS1, SLC6A2, SLC6A4) were associated with latent class membership for both fatigue and energy. Conclusions Molecular findings support the hypothesis that fatigue and energy are distinct, yet related symptoms. Results suggest that a large number of neurotransmitters play a role in the development and maintenance of fatigue and energy levels in breast cancer patients. PMID:27720787

Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1*

PubMed Central

Okamura, Ayako; Koyanagi, Satoru; Dilxiat, Adila; Kusunose, Naoki; Chen, Jia Jun; Matsunaga, Naoya; Shibata, Shigenobu; Ohdo, Shigehiro

2014-01-01

Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter. PMID:25016014

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab.

PubMed

Ma, Huanrong; Wu, Zhenzhen; Peng, Jianjun; Li, Yang; Huang, Hongxiang; Liao, Yi; Zhou, Minyu; Sun, Li; Huang, Na; Shi, Min; Bin, Jianping; Liao, Yulin; Rao, Jinjun; Wang, Lin; Liao, Wangjun

2018-06-15

Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC. © 2018 UICC.

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

PubMed

Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

2013-10-14

MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Functional characterization of 5-oxoproline transport via SLC16A1/MCT1.

PubMed

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-23

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H (+)) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na(+)-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H(+)-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Testing of SLC26A4 Variants—Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria

PubMed Central

Bernardinelli, Emanuele; Nofziger, Charity; Patsch, Wolfgang; Rasp, Gerd; Paulmichl, Markus; Dossena, Silvia

2018-01-01

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype. PMID:29320412

Is mini-laparoscopic cholecystectomy any better than the gold standard?: A comparative study.

PubMed

Shaikh, Haris R; Abbas, Asad; Aleem, Salik; Lakhani, Miqdad R

2017-01-01

Mini-laparoscopic cholecystectomy (MLC) has widened the horizons of modern laparoscopic surgery. Standard four port laparoscopic cholecystectomy (SLC), which has long been established as the "Gold Standard" for gall bladder diseases, is under reconsideration following the advent of further minimally-invasive procedures including MLC. Our study aims to provide a comparison between MLC and SLC and assesses whether MLC has any added benefits. Patients with symptomatic gall bladder disease undergoing MLC or SLC during the 2.5-month period were included in the study. Thirty-two patients underwent MLC while SLC was performed on 40 patients by the same surgeon. Data was collected prospectively and analysed retrospectively using a predesigned questionnaire. In our study, both the groups had similar age, body mass index (BMI) and gender distribution. No cases of MLC required insertion of additional ports. The mean operative time for MLC was 38.2 min (33-61 min), which is longer than SLC; but it was not statistically significant. There was no significant difference in mean operative blood loss, postoperative pain, analgesia requirement and mobilization. Patients who underwent MLC were able to return to normal activity earlier than patients undergoing SLC (P < 0.01). Our experience suggests that MLC can safely be used as an alternative to SLC. Compared to SLC, it has the added benefit of an early return to work along with excellent cosmetic results. Further large scale trials are required to prove any additional benefit of MLC.

Is mini-laparoscopic cholecystectomy any better than the gold standard?: A comparative study

PubMed Central

Shaikh, Haris R.; Abbas, Asad; Aleem, Salik; Lakhani, Miqdad R.

2017-01-01

BACKGROUND: Mini-laparoscopic cholecystectomy (MLC) has widened the horizons of modern laparoscopic surgery. Standard four port laparoscopic cholecystectomy (SLC), which has long been established as the “Gold Standard” for gall bladder diseases, is under reconsideration following the advent of further minimally-invasive procedures including MLC. Our study aims to provide a comparison between MLC and SLC and assesses whether MLC has any added benefits. MATERIALS AND METHODS: Patients with symptomatic gall bladder disease undergoing MLC or SLC during the 2.5-month period were included in the study. Thirty-two patients underwent MLC while SLC was performed on 40 patients by the same surgeon. Data was collected prospectively and analysed retrospectively using a predesigned questionnaire. RESULTS: In our study, both the groups had similar age, body mass index (BMI) and gender distribution. No cases of MLC required insertion of additional ports. The mean operative time for MLC was 38.2 min (33-61 min), which is longer than SLC; but it was not statistically significant. There was no significant difference in mean operative blood loss, postoperative pain, analgesia requirement and mobilization. Patients who underwent MLC were able to return to normal activity earlier than patients undergoing SLC (P < 0.01). CONCLUSION: Our experience suggests that MLC can safely be used as an alternative to SLC. Compared to SLC, it has the added benefit of an early return to work along with excellent cosmetic results. Further large scale trials are required to prove any additional benefit of MLC. PMID:27251827

Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain.

PubMed

Hardt, Stefanie; Heidler, Juliana; Albuquerque, Boris; Valek, Lucie; Altmann, Christine; Wilken-Schmitz, Annett; Schäfer, Michael K E; Wittig, Ilka; Tegeder, Irmgard

2017-11-01

Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naïve progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease. Copyright © 2017. Published by Elsevier B.V.

Prenatal ethanol exposure alters adult hippocampal VGLUT2 expression with concomitant changes in promoter DNA methylation, H3K4 trimethylation and miR-467b-5p levels.

PubMed

Zhang, Christine R; Ho, Mei-Fong; Vega, Michelle C Sanchez; Burne, Thomas H J; Chong, Suyinn

2015-01-01

Maternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders. We and others have proposed that epigenetic modifications, such as DNA methylation and post-translational histone modifications, mediate the effects of prenatal alcohol exposure on gene expression and, ultimately, phenotype. Here we use an inbred C57BL/6J mouse model of early gestational ethanol exposure equivalent, developmentally, to the first 3-4 weeks of pregnancy in humans to examine the long-term effects on gene expression and epigenetic state in the hippocampus. Gene expression analysis in the hippocampus revealed sex- and age-specific up-regulation of solute carrier family 17 member 6 (Slc17a6), which encodes vesicular glutamate transporter 2 (VGLUT2). Transcriptional up-regulation correlated with decreased DNA methylation and enrichment of histone H3 lysine 4 trimethylation, an active chromatin mark, at the Slc17a6 promoter. In contrast to Slc17a6 mRNA levels, hippocampal VGLUT2 protein levels were significantly decreased in adult ethanol-exposed offspring, suggesting an additional level of post-transcriptional control. MicroRNA expression profiling in the hippocampus identified four ethanol-sensitive microRNAs, of which miR-467b-5p was predicted to target Slc17a6. In vitro reporter assays showed that miR-467b-5p specifically interacted with the 3'UTR of Slc17a6, suggesting that it contributes to the reduction of hippocampal VGLUT2 in vivo. A significant correlation between microRNA expression in the hippocampus and serum of ethanol-exposed offspring was also observed. Prenatal ethanol exposure has complex transcriptional and post-transcriptional effects on Slc17a6 (VGLUT2) expression in the mouse hippocampus. These effects are observed following a relatively moderate exposure that is restricted to early pregnancy, modelling human consumption of alcohol before pregnancy is confirmed, and are only apparent in male offspring in adulthood. Our findings are consistent with the idea that altered epigenetic and/or microRNA-mediated regulation of glutamate neurotransmission in the hippocampus contributes to the cognitive and behavioural phenotypes observed in foetal alcohol spectrum disorders. Although further work is needed in both mice and humans, the results also suggest that circulating microRNAs could be used as biomarkers of early gestational ethanol exposure and hippocampal dysfunction.

10. PAYLOAD CONTROL CONSOLE NEAR SOUTH WALL OF SLC3W CONTROL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. PAYLOAD CONTROL CONSOLE NEAR SOUTH WALL OF SLC-3W CONTROL ROOM. DECALS ON CONSOLE IN FOREGROUND INDICATE PAYLOAD PROGRAMS LAUNCHED FROM SLC-3W. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Pasting characteristics of starch-lipid composites

USDA-ARS?s Scientific Manuscript database

Starch-lipid composites (SLC) have been used as fat replacers and stabilizers in beef patties, dairy products, and baked goods. The SLC are produced by mixing aqueous starch slurry with a lipid source, and steam jet-cooking. The SLC may be dried using a drum drier and then milled in a Retch mill. ...

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tachibana, Keisuke, E-mail: nya@phs.osaka-u.ac.jp; Takeuchi, Kentaro; Inada, Hirohiko

2009-11-20

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial {beta}-oxidation. The peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is a ligand-activated transcription factor that plays an important role in the regulation of {beta}-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPAR{alpha} and found that PPAR{alpha} induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPAR{alpha} regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health

PubMed Central

Vaiman, Anne; Beauvallet, Christian; Floriot, Sandrine; Rodriguez, Sabrina; Vilotte, Marthe; Boulanger, Laurent; Albaric, Olivier; Guillaume, François; Boukadiri, Abdelhak; Richard, Laurence; Bertaud, Maud; Timsit, Edouard; Guatteo, Raphaël; Jaffrézic, Florence; Calvel, Pierre; Helary, Louise; Mahla, Rachid; Esquerré, Diane; Péchoux, Christine; Liuu, Sophie; Boichard, Didier; Slama, Abdelhamid; Vilotte, Jean-Luc

2017-01-01

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the “Turning calves syndrome”, a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics. PMID:28376083

Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.

PubMed

Haack, Tobias B; Makowski, Christine; Yao, Yoshiaki; Graf, Elisabeth; Hempel, Maja; Wieland, Thomas; Tauer, Ulrike; Ahting, Uwe; Mayr, Johannes A; Freisinger, Peter; Yoshimatsu, Hiroki; Inui, Ken; Strom, Tim M; Meitinger, Thomas; Yonezawa, Atsushi; Prokisch, Holger

2012-11-01

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment.

The Human Gene SLC25A29, of Solute Carrier Family 25, Encodes a Mitochondrial Transporter of Basic Amino Acids*

PubMed Central

Porcelli, Vito; Fiermonte, Giuseppe; Longo, Antonella; Palmieri, Ferdinando

2014-01-01

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport carboxylates, amino acids, nucleotides, and cofactors across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. In this work, a member of this family, SLC25A29, previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier, has been thoroughly characterized biochemically. The SLC25A29 gene was overexpressed in Escherichia coli, and the gene product was purified and reconstituted in phospholipid vesicles. Its transport properties and kinetic parameters demonstrate that SLC25A29 transports arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine. Carnitine and acylcarnitines were not transported by SLC25A29. This carrier catalyzed substantial uniport besides a counter-exchange transport, exhibited a high transport affinity for arginine and lysine, and was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. The main physiological role of SLC25A29 is to import basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation. PMID:24652292

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

PubMed Central

Boulet, Aren; Vest, Katherine E.; Maynard, Margaret K.; Gammon, Micah G.; Russell, Antoinette C.; Mathews, Alexander T.; Cole, Shelbie E.; Zhu, Xinyu; Phillips, Casey B.; Kwong, Jennifer Q.; Dodani, Sheel C.; Leary, Scot C.; Cobine, Paul A.

2018-01-01

Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo. PMID:29237729

MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma

PubMed Central

Lau, Diana T.; Flemming, Claudia L.; Gherardi, Samuele; Perini, Giovanni; Oberthuer, André; Fischer, Matthias; Juraeva, Dilafruz; Brors, Benedikt; Xue, Chengyuan; Norris, Murray D.; Marshall, Glenn M.; Haber, Michelle

2015-01-01

MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression. PMID:25860940

Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells.

PubMed

Uchida, Yasuo; Ito, Katsuaki; Ohtsuki, Sumio; Kubo, Yoshiyuki; Suzuki, Takashi; Terasaki, Tetsuya

2015-07-01

The purpose of this study was to clarify the expression of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) and its contribution to the supply of biotin and pantothenic acid to the human brain via the blood-brain barrier. DNA microarray and immunohistochemical analyses confirmed that SLC5A6 is expressed in microvessels of human brain. The absolute expression levels of SLC5A6 protein in isolated human and monkey brain microvessels were 1.19 and 0.597 fmol/μg protein, respectively, as determined by a quantitative targeted absolute proteomics technique. Using an antibody-free method established by Kubo et al. (2015), we found that SLC5A6 was preferentially localized at the luminal membrane of brain capillary endothelium. Knock-down analysis using SLC5A6 siRNA showed that SLC5A6 accounts for 88.7% and 98.6% of total [(3) H]biotin and [(3) H]pantothenic acid uptakes, respectively, by human cerebral microvascular endothelial cell line hCMEC/D3. SLC5A6-mediated transport in hCMEC/D3 was markedly inhibited not only by biotin and pantothenic acid, but also by prostaglandin E2, lipoic acid, docosahexaenoic acid, indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen. This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier. In humans, it was unclear (not concluded) about what transport system at the blood-brain barrier (BBB) is responsible for the brain uptakes of two vitamins, biotin and pantothenic acid, which are necessary for brain proper function. This study clarified for the first time that the solute carrier 5A6/Na(+) -dependent multivitamin transporter SLC5A6/SMVT is responsible for the supplies of biotin and pantothenic acid into brain across the BBB in humans. DHA, docosahexaenoic acid; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2. © 2015 International Society for Neurochemistry.

Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer’s Disease or Depressive Disorder

PubMed Central

Kitzlerová, Eva; Lelková, Petra; Jirák, Roman; Zvěřová, Martina; Hroudová, Jana; Manukyan, Ada; Martásek, Pavel; Raboch, Jiří

2018-01-01

Background Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer’s disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. Material/Methods A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. Results Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ɛ4 allele of APOE. Conclusions Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ɛ4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ɛ4 allele. PMID:29703883

SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome

PubMed Central

Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A.; Landau, Daniel

2017-01-01

Abstract A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9’s highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling. PMID:28334855

Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia.

PubMed

Huang, Xiao; Anderle, Pascale; Hostettler, Lu; Baumann, Marc U; Surbek, Daniel V; Ontsouka, Edgar C; Albrecht, Christiane

2018-03-02

Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE.

[Serotonergic genes in the development of anxiety/depression-like state and pathology of aggressive behavior in male mice: RNA-seq data].

PubMed

Kudryavtseva, N N; Smagin, D A; Kovalenko, I L; Galyamina, A G; Vishnivetskaya, G B; Babenko, V N; Orlov, Yu L

2017-01-01

In course of daily agonistic interactions, mice tend to stratify into those with chronic social defeats and those that repeatedly display aggression, which lead to the development of mixed anxiety/depression-like state and the pathology of aggressive behavior, respectively. Using the data of whole transcriptome analysis (RNA-seq), the changes in the expression of serotonergic genes involved in the synthesis, inactivation, and reception of serotonin, as well as of the Creb1 (transcription factor) gene and the Bdnf (brain-derived neurotrophic factor) gene were detected in the striatum (STR), ventral tegmental area (VTA), midbrain raphe nuclei (MRN), hypothalamus (HYP), and hippocampus (HIP) of defeated and aggressive male mice. In mice of both groups, the Tph2, Ddc, Slc6a4, Htr2a, Htr3a, Htr5b, Slc18a2, and Bdnf genes were downregulated in the MRN and the Tph2, Ddc, and Slc6a4 genes were upregulated in the VTA. These changes were more significant in defeated mice. The Htr5b gene has first been shown to be involved in mechanisms of depression and pathology of aggressive behavior. In the defeated mice, the expression levels of the Htr4 and Aldh1b1 genes were increased in the MRN, and expression levels of the Maob, Htr4, Htr1a, and Slc18a2 genes were increased in the VTA, while the expression level of the Htr3a gene was decreased. In the HYP of aggressive mice the Maoa, Htr2a, Htr2c, and Creb1 genes were downregulated and the Htr6 gene was upregulated. In the defeated mice, the Maoa and Creb1 genes were downregulated and the Htr6 and Aldh1b1 genes were upregulated in the HYP. In the STR, the Htr1a gene was downregulated and the Htr7 and Bdnf genes were upregulated. The Htr1b gene was upregulated in the HIP. The coexpression of dopaminergic and serotonergic genes in the MRN and VTA in the control of pathological behaviors is discussed. Thus, the complex pattern of differential expression of serotonergic genes in brain regions developing under repeated agonistic interactions in mice in dependence on behavioral pathology have been observed.

Human SLC4A11 Is a Novel NH3/H+ Co-transporter*

PubMed Central

Zhang, Wenlin; Ogando, Diego G.; Bonanno, Joseph A.; Obukhov, Alexander G.

2015-01-01

SLC4A11 has been proposed to be an electrogenic membrane transporter, permeable to Na+, H+ (OH−), bicarbonate, borate, and NH4+. Recent studies indicate, however, that neither bicarbonate or borate is a substrate. Here, we examined potential NH4+, Na+, and H+ contributions to electrogenic ion transport through SLC4A11 stably expressed in Na+/H+ exchanger-deficient PS120 fibroblasts. Inward currents observed during exposure to NH4Cl were determined by the [NH3]o, not [NH4+]o, and current amplitudes varied with the [H+] gradient. These currents were relatively unaffected by removal of Na+, K+, or Cl− from the bath but could be reduced by inclusion of NH4Cl in the pipette solution. Bath pH changes alone did not generate significant currents through SLC4A11, except immediately following exposure to NH4Cl. Reversal potential shifts in response to changing [NH3]o and pHo suggested an NH3/H+-coupled transport mode for SLC4A11. Proton flux through SLC4A11 in the absence of ammonia was relatively small, suggesting that ammonia transport is of more physiological relevance. Methylammonia produced currents similar to NH3 but with reduced amplitude. Estimated stoichiometry of SLC4A11 transport was 1:2 (NH3/H+). NH3-dependent currents were insensitive to 10 μm ethyl-isopropyl amiloride or 100 μm 4,4′- diisothiocyanatostilbene-2,2′-disulfonic acid. We propose that SLC4A11 is an NH3/2H+ co-transporter exhibiting unique characteristics. PMID:26018076

Genes and proteins of urea transporters.

PubMed

Sands, Jeff M; Blount, Mitsi A

2014-01-01

A urea transporter protein in the kidney was first proposed in 1987. The first urea transporter cDNA was cloned in 1993. The SLC14a urea transporter family contains two major subgroups: SLC14a1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14a2, the UT-A group originally isolated from kidney inner medulla. Slc14a1, the human UT-B gene, arises from a single locus located on chromosome 18q12.1-q21.1, which is located close to Slc14a2. Slc14a1 includes 11 exons, with the coding region extending from exon 4 to exon 11, and is approximately 30 kb in length. The Slc14a2 gene is a very large gene with 24 exons, is approximately 300 kb in length, and encodes 6 different isoforms. Slc14a2 contains two promoter elements: promoter I is located in the typical position, upstream of exon 1, and drives the transcription of UT-A1, UT-A1b, UT-A3, UT-A3b, and UT-A4; while promoter II is located within intron 12 and drives the transcription of UT-A2 and UT-A2b. UT-A1 and UT-A3 are located in the inner medullary collecting duct, UT-A2 in the thin descending limb and liver, UT-A5 in testis, UT-A6 in colon, UT-B1 primarily in descending vasa recta and erythrocytes, and UT-B2 in rumen.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.

PubMed

Johnson, Janel O; Gibbs, J Raphael; Megarbane, Andre; Urtizberea, J Andoni; Hernandez, Dena G; Foley, A Reghan; Arepalli, Sampath; Pandraud, Amelie; Simón-Sánchez, Javier; Clayton, Peter; Reilly, Mary M; Muntoni, Francesco; Abramzon, Yevgeniya; Houlden, Henry; Singleton, Andrew B

2012-09-01

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease

PubMed Central

Johnson, Janel O.; Gibbs, J. Raphael; Megarbane, Andre; Urtizberea, J. Andoni; Hernandez, Dena G.; Foley, A. Reghan; Arepalli, Sampath; Pandraud, Amelie; Simón-Sánchez, Javier; Clayton, Peter; Reilly, Mary M.; Muntoni, Francesco; Abramzon, Yevgeniya; Houlden, Henry

2012-01-01

Brown–Vialetto–Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown–Vialetto–Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown–Vialetto–Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown–Vialetto–Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results. PMID:22740598

Sodium bicarbonate cotransporter NBCe2 gene variants increase sodium and bicarbonate transport in human renal proximal tubule cells.

PubMed

Gildea, John J; Xu, Peng; Kemp, Brandon A; Carlson, Julia M; Tran, Hanh T; Bigler Wang, Dora; Langouët-Astrié, Christophe J; McGrath, Helen E; Carey, Robert M; Jose, Pedro A; Felder, Robin A

2018-01-01

Salt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension. However, little is known about how NBCe2 contributes to salt sensitivity, although NBCe2 regulates renal tubular sodium bicarbonate transport. We hypothesized that SLC4A5 rs10177833 and rs7571842 increase NBCe2 expression and human renal proximal tubule cell (hRPTC) sodium transport and may be a cause of salt sensitivity of blood pressure. To characterize the hRPTC ion transport of wild-type (WT) and homozygous variants (HV) of SLC4A5. The expressions of NBCe2 mRNA and protein were not different between hRPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, luminal to basolateral sodium transport, NHE3 protein, and Cl-/HCO3- exchanger activity in hRPTCs were higher in HV than WT SLC4A5. Increasing intracellular sodium enhanced the apical location of NBCe2 in HV hRPTCs (4.24±0.35% to 11.06±1.72% (P<0.05, N = 3, 2-way ANOVA, Holm-Sidak test)) as determined by Total Internal Reflection Fluorescence Microscopy (TIRFM). In hRPTCs isolated from kidney tissue, increasing intracellular sodium enhanced bicarbonate-dependent pH recovery rate and increased NBCe2 mRNA and protein expressions to a greater extent in HV than WT SLC4A5 (+38.00±6.23% vs HV normal salt (P<0.01, N = 4, 2-way ANOVA, Holm-Sidak test)). In hRPTCs isolated from freshly voided urine, bicarbonate-dependent pH recovery was also faster in those from salt-sensitive and carriers of HV SLC4A5 than from salt-resistant and carriers of WT SLC4A5. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was normalized by SLC4A5- but not SLC4A4-shRNA. The binding of purified hepatocyte nuclear factor type 4A (HNF4A) to DNA was increased in hRPTCs carrying HV SLC4A5 rs7571842 but not rs10177833. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was abolished by HNF4A antagonists. NBCe2 activity is stimulated by an increase in intracellular sodium and is hyper-responsive in hRPTCs carrying HV SLC4A5 rs7571842 through an aberrant HNF4A-mediated mechanism.

Solution of monotone complementarity and general convex programming problems using a modified potential reduction interior point method

DOE PAGES

Huang, Kuo -Ling; Mehrotra, Sanjay

2016-11-08

We present a homogeneous algorithm equipped with a modified potential function for the monotone complementarity problem. We show that this potential function is reduced by at least a constant amount if a scaled Lipschitz condition (SLC) is satisfied. A practical algorithm based on this potential function is implemented in a software package named iOptimize. The implementation in iOptimize maintains global linear and polynomial time convergence properties, while achieving practical performance. It either successfully solves the problem, or concludes that the SLC is not satisfied. When compared with the mature software package MOSEK (barrier solver version 6.0.0.106), iOptimize solves convex quadraticmore » programming problems, convex quadratically constrained quadratic programming problems, and general convex programming problems in fewer iterations. Moreover, several problems for which MOSEK fails are solved to optimality. In addition, we also find that iOptimize detects infeasibility more reliably than the general nonlinear solvers Ipopt (version 3.9.2) and Knitro (version 8.0).« less

Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease.

PubMed

Neves, Joana; Leitz, Dominik; Kraut, Simone; Brandenberger, Christina; Agrawal, Raman; Weissmann, Norbert; Mühlfeld, Christian; Mall, Marcus A; Altamura, Sandro; Muckenthaler, Martina U

2017-06-01

Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1 C326S ), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1 C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

SLC: The End Game

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raimondi, Pantaleo

The design of the Stanford Linear Collider (SLC) called for a beam intensity far beyond what was practically achievable. This was due to intrinsic limitations in many subsystems and to a lack of understanding of the new physics of linear colliders. Real progress in improving the SLC performance came from precision, non-invasive diagnostics to measure and monitor the beams and from new techniques to control the emittance dilution and optimize the beams. A major contribution to the success of the last 1997-98 SLC run came from several innovative ideas for improving the performance of the Final Focus (FF). This papermore » describes some of the problems encountered and techniques used to overcome them. Building on the SLC experience, we will also present a new approach to the FF design for future high energy linear colliders.« less

Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

PubMed

Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

2014-04-01

Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

Fructose Synthesis and Transport at the Uterine-Placental Interface of Pigs: Cell-Specific Localization of SLC2A5, SLC2A8, and Components of the Polyol Pathway.

PubMed

Steinhauser, Chelsie B; Landers, McKinsey; Myatt, Louise; Burghardt, Robert C; Vallet, Jeffrey L; Bazer, Fuller W; Johnson, Greg A

2016-11-01

The fetal fluids and uterine flushings of pigs contain higher concentrations of fructose than glucose, but fructose is not detected in maternal blood. Fructose can be synthesized from glucose via enzymes of the polyol pathway, aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD), transported across cell membranes by solute carriers SLC2A5 and SLC2A8, and converted to fructose-1-phosphate by ketohexokinase (KHK). SLC2A8, SLC2A5, AKR1B1, SORD, and KHK mRNAs and proteins were analyzed using quantitative PCR and immunohistochemistry or in situ hybridization in endometria and placentae of cyclic and pregnant gilts, cyclic gilts injected with estrogen, and ovariectomized gilts injected with progesterone. Progesterone up-regulated SLC2A8 protein in uterine luminal (LE) and glandular epithelia during the peri-implantation period, and expression became exclusively placental, chorion and blood vessels, after Day 30. P4 up-regulated SLC2A5 mRNA in uterine LE and glandular epithelia after implantation, and the chorion expressed SLC2A5 between Days 30 and 85. AKR1B1 and SORD proteins localized to uterine LE during the peri-implantation period, but expression switched to chorion by Day 20 and was maintained through Day 85. Uterine expression of AKR1B1 mRNA was down-regulated by estrogen. KHK protein localized to trophectoderm/chorion throughout gestation. These results provide evidence that components for the conversion of glucose to fructose and for fructose transport are present at the uterine-placental interface of pigs. The shift in expression from LE to chorion during pregnancy suggests free-floating conceptuses are supported by fructose synthesized by the uterus, but after implantation, the chorion becomes self-sufficient for fructose synthesis and transport. © 2016 by the Society for the Study of Reproduction, Inc.

SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures.

PubMed

Palmer, Samantha; Towne, Meghan C; Pearl, Phillip L; Pelletier, Renee C; Genetti, Casie A; Shi, Jiahai; Beggs, Alan H; Agrawal, Pankaj B; Brownstein, Catherine A

2016-11-01

Epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy or Doose syndrome, has been recently linked to variants in the SLC6A1 gene. Epilepsy with myoclonic-atonic seizures is often refractory to antiepileptic drugs, and the ketogenic diet is known for treating medically intractable seizures, although the mechanism of action is largely unknown. We report a novel SLC6A1 variant in a patient with epilepsy with myoclonic-atonic seizures, analyze its effects, and suggest a mechanism of action for the ketogenic diet. We describe a ten-year-old girl with epilepsy with myoclonic-atonic seizures and a de novo SLC6A1 mutation who responded well to the ketogenic diet. She carried a c.491G>A mutation predicted to cause p.Cys164Tyr amino acid change, which was identified using whole exome sequencing and confirmed by Sanger sequencing. High-resolution structural modeling was used to analyze the likely effects of the mutation. The SLC6A1 gene encodes a transporter that removes gamma-aminobutyric acid from the synaptic cleft. Mutations in SLC6A1 are known to disrupt the gamma-aminobutyric acid transporter protein 1, affecting gamma-aminobutyric acid levels and causing seizures. The p.Cys164Tyr variant found in our study has not been previously reported, expanding on the variants linked to epilepsy with myoclonic-atonic seizures. A 10-year-old girl with a novel SLC6A1 mutation and epilepsy with myoclonic-atonic seizures had an excellent clinical response to the ketogenic diet. An effect of the diet on gamma-aminobutyric acid reuptake mediated by gamma-aminobutyric acid transporter protein 1 is suggested. A personalized approach to epilepsy with myoclonic-atonic seizures patients carrying SLC6A1 mutation and a relationship between epilepsy with myoclonic-atonic seizures due to SLC6A1 mutations, GABAergic drugs, and the ketogenic diet warrants further exploration. Copyright © 2016 Elsevier Inc. All rights reserved.

Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.

PubMed

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9.

Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

PubMed Central

Snaith, Michael; Lindmark, Helena; Lundberg, Johanna; Östlund-Lindqvist, Ann-Margret; Angelin, Bo; Rudling, Mats

2012-01-01

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes. PMID:22662222

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis.

PubMed

Zou, Minjing; Alzahrani, Ali S; Al-Odaib, Ali; Alqahtani, Mohammad A; Babiker, Omer; Al-Rijjal, Roua A; BinEssa, Huda A; Kattan, Walaa E; Al-Enezi, Anwar F; Al Qarni, Ali; Al-Faham, Manar S A; Baitei, Essa Y; Alsagheir, Afaf; Meyer, Brian F; Shi, Yufei

2018-05-01

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. To identify the mutation spectrum of CH-causing genes. Fifty-five patients from 47 families were studied by next-generation exome sequencing. Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

Sulfate transporters involved in sulfate secretion in the kidney are localized in the renal proximal tubule II of the elephant fish (Callorhinchus milii)

PubMed Central

Kato, Akira; Watanabe, Taro; Takagi, Wataru; Romero, Michael F.; Bell, Justin D.; Toop, Tes; Donald, John A.; Hyodo, Susumu

2016-01-01

Most vertebrates, including cartilaginous fishes, maintain their plasma SO42− concentration ([SO42−]) within a narrow range of 0.2–1 mM. As seawater has a [SO42−] about 40 times higher than that of the plasma, SO42− excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO42− via the kidney. However, little is known about the underlying mechanisms for SO42− transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish (Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO42− transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO42− transporter, while cmSlc26a6 is an apically located, electrogenic Cl−/SO42− exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO42− was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO42− by the kidney of elephant fish. Possible mechanisms for SO42− secretion in the PII segment are discussed. PMID:27122370

Colloid centrifugation of fresh stallion semen before cryopreservation decreased microorganism load of frozen-thawed semen without affecting seminal kinetics.

PubMed

Guimarães, T; Lopes, G; Pinto, M; Silva, E; Miranda, C; Correia, M J; Damásio, L; Thompson, G; Rocha, A

2015-01-15

Freezability of equine semen may be influenced by microorganism population of semen. The objective of this study was to verify the effect of single-layer density gradient centrifugation (SLC) of fresh semen before cryopreservation on semen's microbial load (ML) and sperm cells kinetics after freezing-thawing. For that, one ejaculate was collected from 20 healthy stallions and split into control (C) samples (cryopreserved without previous SLC) and SLC samples (subjected to SLC). Semen cryopreservation was performed according to the same protocol in both groups. Microbial load of each microorganism species and total microbial load (TML) expressed in colony-forming units (CFU/mL) as well as frozen-thawed sperm kinetics were assessed in both groups. Additional analysis of the TML was performed, subdividing the frozen-thawed samples in "suitable" (total motility ≥ 30%) and "unsuitable" (total motility < 30%) semen for freezing programs, and comparing the C and SLC groups within these subpopulations. After thawing, SLC samples had less (P < 0.05) TML (88.65 × 10(2) ± 83.8 × 10(2) CFU/mL) than C samples (155.69 × 10(2) ± 48.85 × 10(2) CFU/mL), mainly due to a reduction of Enterococcus spp. and Bacillus spp. A relationship between post-thaw motility and SLC effect on ML was noted, as only in samples with more than 30% total motility was ML reduced (P < 0.05) by SLC (from 51.33 × 10(2) ± 33.26 × 10(2) CFU/mL to 26.68 × 10(2) ± 12.39 × 10(2) CFU/mL in "suitable" frozen-thawed semen vs. 240.90 × 10(2) ± 498.20 × 10(2) to 139.30 × 10(2) ± 290.30 × 10(2) CFU/mL in "unsuitable" frozen-thawed semen). The effect of SLC on kinetics of frozen-thawed sperm cells was negligible. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+ breast cancer stem cells.

PubMed

Lv, Yonggang; Wang, Ting; Fan, Jing; Zhang, Zhenzhen; Zhang, Juliang; Xu, Cheng; Li, Yongping; Zhao, Ge; He, Chenyang; Meng, Huimin; Yang, Hua; Wang, Zhen; Liu, Jiayun; Chen, Jianghao; Wang, Ling

2017-04-01

The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147 + cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147 + cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147 + BCSCs was enhanced compared with that in differentiated adherent progeny of CD147 + BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147 + BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147 + BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147 + BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147 + BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.

PubMed

Boulet, Aren; Vest, Katherine E; Maynard, Margaret K; Gammon, Micah G; Russell, Antoinette C; Mathews, Alexander T; Cole, Shelbie E; Zhu, Xinyu; Phillips, Casey B; Kwong, Jennifer Q; Dodani, Sheel C; Leary, Scot C; Cobine, Paul A

2018-02-09

Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2 Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo . © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

PubMed Central

Boyd, Nathaniel H.; Walker, Kiera; Fried, Joshua; Hackney, James R.; McDonald, Paul C.; Benavides, Gloria A.; Spina, Raffaella; Audia, Alessandra; Scott, Sarah E.; Libby, Catherine J.; Tran, Anh Nhat; Bevensee, Mark O.; Griguer, Corinne; Nozell, Susan; Gillespie, G. Yancey; Nabors, Burt; Bhat, Krishna P.; Bar, Eli E.; Darley-Usmar, Victor; Xu, Bo; Gordon, Emily; Dedhar, Shoukat; Hjelmeland, Anita B.

2017-01-01

Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care. PMID:29263302

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

PubMed Central

Fu, Li; Qin, Yan-Ru; Ming, Xiao-Yan; Zuo, Xian-Bo; Diao, Yu-Wen; Zhang, Li-Yi; Ai, Jiaoyu; Liu, Bei-Lei; Huang, Tu-Xiong; Cao, Ting-Ting; Tan, Bin-Bin; Xiang, Di; Zeng, Chui-Mian; Gong, Jing; Zhang, Qiangfeng; Dong, Sui-Sui; Chen, Juan; Liu, Haibo; Wu, Jian-Lin; Qi, Robert Z.; Xie, Dan; Wang, Li-Dong

2017-01-01

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals. PMID:28533408

Study and Fabrication of Super Low-Cost Solar Cell (SLC-SC) Based on Counter Electrode from Animal’s Bone

NASA Astrophysics Data System (ADS)

Fadlilah, D. R.; Fajar, M. N.; Aini, A. N.; Haqqiqi, R. I.; Wirawan, P. R.; Endarko

2018-04-01

The synthesized carbon from bones of chicken, cow, and fish with the calcination temperature at 450 and 600°C have been successfully fabricated for counter electrode in the Super Low-Cost Solar Cell (SLC-LC) based the structure of Dye-Sensitized Solar Cells (DSSC). The main proposed study was to fabricate SLC-SC and investigate the influence of the synthesized carbon from animal’s bone for counter electrode towards to photovoltaic performance of SLC-SC. X-Ray Diffraction and UV-Vis was used to characterize the phase and the optical properties of TiO2 as photoanode in SLC-SC. Meanwhile, the morphology and particle size distribution of the synthesized carbon in counter electrodes were investigated by Scanning Electron Microscopy (SEM) and Particle Size Analyzer (PSA). The results showed that the TiO2 has anatase phase with the absorption wavelength of 300 to 550 nm. The calcination temperature for synthesizing of carbon could affect morphology and particle size distribution. The increasing temperature gave the effect more dense in morphology and increased the particle size of carbon in the counter electrode. Changes in morphology and particle size of carbon give effect to the performance of the SLC-SC where the increased morphology’s compact and particle size make decreased in the performance of the SLC-SC.

Interactions between Serotonin Transporter Gene Haplotypes and Quality of Mothers' Parenting Predict the Development of Children's Noncompliance

ERIC Educational Resources Information Center

Sulik, Michael J.; Eisenberg, Nancy; Lemery-Chalfant, Kathryn; Spinrad, Tracy L.; Silva, Kassondra M.; Eggum, Natalie D.; Betkowski, Jennifer A.; Kupfer, Anne; Smith, Cynthia L.; Gaertner, Bridget; Stover, Daryn A.; Verrelli, Brian C.

2012-01-01

The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children's (N = 138) noncompliance and aggression from age 18-54 months. Quality of mothers' parenting behavior was observed when…

1. AERIAL VIEW OF SLC3 FROM THE NORTHEAST SHOWING THE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. AERIAL VIEW OF SLC-3 FROM THE NORTHEAST SHOWING THE EAST (LEFT) AND WEST (RIGHT) LAUNCH PADS, AND CABLE TRAYS FROM SLC-3W. SEWAGE TREATMENT PLANT (BLDG. 769) AND STORAGE SHED (BLDG. 773) IN LEFT FOREGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Genetic Architecture of Skin and Eye Color in an African-European Admixed Population

PubMed Central

Beleza, Sandra; Johnson, Nicholas A.; Candille, Sophie I.; Absher, Devin M.; Coram, Marc A.; Lopes, Jailson; Campos, Joana; Araújo, Isabel Inês; Anderson, Tovi M.; Vilhjálmsson, Bjarni J.; Nordborg, Magnus; Correia e Silva, António; Shriver, Mark D.; Rocha, Jorge

2013-01-01

Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10−62, SLC24A5 P = 9.6×10−9) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10−27, TYR P = 1.1×10−9, APBA2[OCA2] P = 1.5×10−8, SLC45A2 P = 6×10−9) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (∼44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ∼70% of the estimated heritability. PMID:23555287

Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects

PubMed Central

2013-01-01

Introduction There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets. Methods A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata. Results A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039). Conclusions Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data. PMID:24360580

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

PubMed Central

2013-01-01

Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs. PMID:24304581

Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma.

PubMed

Park, Yun-Yong; Sohn, Bo Hwa; Johnson, Randy L; Kang, Myoung-Hee; Kim, Sang Bae; Shim, Jae-Jun; Mangala, Lingegowda S; Kim, Ji Hoon; Yoo, Jeong Eun; Rodriguez-Aguayo, Cristian; Pradeep, Sunila; Hwang, Jun Eul; Jang, Hee-Jin; Lee, Hyun-Sung; Rupaimoole, Rajesha; Lopez-Berestein, Gabriel; Jeong, Woojin; Park, Inn Sun; Park, Young Nyun; Sood, Anil K; Mills, Gordon B; Lee, Ju-Seog

2016-01-01

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma. YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. © 2015 by the American Association for the Study of Liver Diseases.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.

PubMed

Pan, Wei; Song, Im-Sook; Shin, Ho-Jung; Kim, Min-Hye; Choi, Yeong-Lim; Lim, Su-Jeong; Kim, Woo-Young; Lee, Sang-Seop; Shin, Jae-Gook

2011-06-01

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.

PubMed

Frodl, Thomas; Szyf, Moshe; Carballedo, Angela; Ly, Victoria; Dymov, Sergiy; Vaisheva, Farida; Morris, Derek; Fahey, Ciara; Meaney, James; Gill, Michael; Booij, Linda

2015-09-01

The aim of the present study was to investigate the association of fMRI blood oxygen-level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing. Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Involvement of riboflavin transporter RFVT2/Slc52a2 in hepatic homeostasis of riboflavin in mice.

PubMed

Yao, Yoshiaki; Yonezawa, Atsushi; Yoshimatsu, Hiroki; Omura, Tomohiro; Masuda, Satohiro; Matsubara, Kazuo

2013-08-15

Riboflavin (vitamin B2) acts as an intermediary during various biochemical oxidation-reduction reactions in the liver. Hepatic riboflavin homeostasis is suggested to be maintained through its transporter(s). Riboflavin transporters, RFVT2/Slc52a2 and RFVT3/Slc52a3, have been identified in rodents. However, the role of each RFVT in the hepatic homeostasis of riboflavin has not yet been fully clarified. In this study, we assessed the contribution of each RFVT to riboflavin uptake into the liver using in vitro and in vivo studies. The uptake of riboflavin by mouse primary hepatocytes increased in a time-dependent and a concentration-dependent manner. Riboflavin transport was independent of extracellular Na(+). However, the uptake decreased slightly along with the extracellular pH increases. Real-time PCR analysis revealed that the mRNA level of Slc52a2, or coding for mouse (m)RFVT2, in the mouse liver was 10 times higher than that of Slc52a3 (coding for mRFVT3). The uptake of riboflavin at pH 7.4 by primary hepatocytes was significantly decreased by the transfection of Slc52a2-small interfering RNA (siRNA), but not Slc52a3-siRNA. Furthermore, we also confirmed the contribution of riboflavin transporters in vivo. The riboflavin concentrations in plasma, but not in the liver, were significantly decreased in mice fed on a riboflavin-deficient diet for 8 weeks. The expression of Slc52a2 mRNA was significantly upregulated by riboflavin deprivation. These results strongly suggest that mRFVT2 was involved in hepatic riboflavin homeostasis. © 2013 Elsevier B.V. All rights reserved.

MiR-133 is Involved in Estrogen Deficiency-Induced Osteoporosis through Modulating Osteogenic Differentiation of Mesenchymal Stem Cells.

PubMed

Lv, Hao; Sun, Yujie; Zhang, Yuchen

2015-05-27

MiR-133 expression is dysregulated in postmenopausal osteoporosis. However, its role in postmenopausal osteoporosis is still not well understood. In the current study, we explore how estrogen deficiency affects miR-133 expression and how miR-133 is involved in osteogenic differentiation of mesenchymal stem cells (MSCs). qRT-PCR analysis was performed to assess miR-133 expression in MSCs isolated from bone marrow of an ovariectomized (OVX) animal model and postmenopausal osteoporosis patients (PMOP) and their corresponding controls. The binding between miR-133 and predicted target SLC39A1 was verified using dual luciferase assay and Western blot analysis. The effect of miR-133 and SLC39A1 on osteogenic differentiation of MSCs was assessed through measuring alkaline phosphatase (ALP), mineralization nodules, and osteoblast-specific genes Runx2 and Osterix expression. miR-133 expression is significantly enhanced as a result of estrogen deficiency. Its overexpression is negatively correlated to osteogenic differentiation of hMSCs. SLC39A1 showed an inverse expression trend to miR-133 during the differentiation. miR-133 can directly target 3'UTR of SLC39A1 and thereby modulate its expression in hMSCs. The miR-133-SLC39A1 axis might play an important role in osteogenic differentiation of hMSCs. SLC39A1 can promote ALP activity and formation of mineralization nodules. In addition, SLC39A1 expression level is also positively correlated with RUNX2 and Osterix. Estrogen deficiency is associated with miR-133 overexpression. MiR-133 can induce postmenopausal osteoporosis by weakening osteogenic differentiation of hMSCs, at least partly through repressing SLC39A1 expression.

MiR-133 is Involved in Estrogen Deficiency-Induced Osteoporosis through Modulating Osteogenic Differentiation of Mesenchymal Stem Cells

PubMed Central

Lv, Hao; Sun, Yujie; Zhang, Yuchen

2015-01-01

Background MiR-133 expression is dysregulated in postmenopausal osteoporosis. However, its role in postmenopausal osteoporosis is still not well understood. In the current study, we explore how estrogen deficiency affects miR-133 expression and how miR-133 is involved in osteogenic differentiation of mesenchymal stem cells (MSCs). Material/Methods qRT-PCR analysis was performed to assess miR-133 expression in MSCs isolated from bone marrow of an ovariectomized (OVX) animal model and postmenopausal osteoporosis patients (PMOP) and their corresponding controls. The binding between miR-133 and predicted target SLC39A1 was verified using dual luciferase assay and Western blot analysis. The effect of miR-133 and SLC39A1 on osteogenic differentiation of MSCs was assessed through measuring alkaline phosphatase (ALP), mineralization nodules, and osteoblast-specific genes Runx2 and Osterix expression. Results miR-133 expression is significantly enhanced as a result of estrogen deficiency. Its overexpression is negatively correlated to osteogenic differentiation of hMSCs. SLC39A1 showed an inverse expression trend to miR-133 during the differentiation. miR-133 can directly target 3′UTR of SLC39A1 and thereby modulate its expression in hMSCs. The miR-133-SLC39A1 axis might play an important role in osteogenic differentiation of hMSCs. SLC39A1 can promote ALP activity and formation of mineralization nodules. In addition, SLC39A1 expression level is also positively correlated with RUNX2 and Osterix. Conclusions Estrogen deficiency is associated with miR-133 overexpression. MiR-133 can induce postmenopausal osteoporosis by weakening osteogenic differentiation of hMSCs, at least partly through repressing SLC39A1 expression. PMID:26013661

Ion and solute transport by prestin in Drosophila and Anopheles

PubMed Central

Hirata, Taku; Czapar, Anna; Brin, Lauren R.; Haritonova, Alyona; Bondeson, Daniel P.; Linser, Paul J.; Cabrero, Pablo; Dow, Julian A. T.; Romero, Michael F.

2012-01-01

The gut and Malpighian tubules of insects are the primary sites of active solute and water transport for controlling hemolymph and urine composition, pH, and osmolarity. These processes depend on ATPase (pumps), channels and solute carriers (Slc proteins). Maturation of genomic databases enables us to identify the putative molecular players for these processes. Anion transporters of the Slc4 family, AE1 and NDAE1, have been reported as HCO3− transporters, but are only part of the story. Here we report Dipteran (Drosophila melanogaster (d) and Anopheles gambiae (Ag)) anion exchangers, belonging to the Slc26 family, which are multi-functional anion exchangers. One Drosophila and two Ag homologues of mammalian Slc26a5 (prestin) and Slc26a6 (aka, PAT1, CFEX) were identified and designated dPrestin, AgPrestinA and AgPrestinB. dPrestin and AgPrestinB show electrogenic anion exchange (Cl−/nHCO3−, Cl−/SO42− and Cl−/oxalate2−) in an oocyte expression system. Since these transporters are the only Dipteran Slc26 proteins whose transport is similar to mammalian Slc26a6, we submit that Dipteran Prestin are functional and even molecular orthologues of mammalian Slc26a6. OSR1 kinase increases dPrestin ion transport, implying another set of physiological processes controlled by WNK/SPAK signaling in epithelia. All of these mRNAs are highly expressed in the gut and Malpighian tubules. Dipteran Prestin proteins appear suited for central roles in bicarbonate, sulfate and oxalate metabolism including generating the high pH conditions measured in the Dipteran midgut lumen. Finally, we present and discuss Drosophila genetic models that integrate these processes. PMID:22321763

A Novel SLC27A4 Splice Acceptor Site Mutation in Great Danes with Ichthyosis.

PubMed

Metzger, Julia; Wöhlke, Anne; Mischke, Reinhard; Hoffmann, Annalena; Hewicker-Trautwein, Marion; Küch, Eva-Maria; Naim, Hassan Y; Distl, Ottmar

2015-01-01

Ichthyoses are a group of various different types of hereditary disorders affecting skin cornification. They are characterized by hyperkeratoses of different severity levels and are associated with a dry and scaling skin. Genome-wide association analysis of nine affected and 13 unaffected Great Danes revealed a genome-wide significant peak on chromosome 9 at 57-58 Mb in the region of SLC27A4. Sequence analysis of genomic DNA of SLC27A4 revealed the non-synonymous SNV SLC27A4:g.8684G>A in perfect association with ichthyosis-affection in Great Danes. The mutant transcript of SLC27A4 showed an in-frame loss of 54 base pairs in exon 8 probably induced by a new splice acceptor site motif created by the mutated A- allele of the SNV. Genotyping 413 controls from 35 different breeds of dogs and seven wolves revealed that this mutation could not be found in other populations except in Great Danes. Affected dogs revealed high amounts of mutant transcript but only low levels of the wild type transcript. Targeted analyses of SLC27A4 protein from skin tissues of three affected and two unaffected Great Danes indicated a markedly reduced or not detectable wild type and truncated protein levels in affected dogs but a high expression of wild type SLC27A4 protein in unaffected controls. Our data provide evidence of a new splice acceptor site creating SNV that results in a reduction or loss of intact SLC27A4 protein and probably explains the severe skin phenotype in Great Danes. Genetic testing will allow selective breeding to prevent ichthyosis-affected puppies in the future.

The association between the SLC6A3 VNTR 9-repeat allele and alcoholism-a meta-analysis.

PubMed

Du, Yanlei; Nie, Yuqiang; Li, Yuyuan; Wan, Yu-Jui Y

2011-09-01

Dopamine transporter gene (SLC6A3) represents a promising candidate involved in the development of alcoholism. This study aimed to explore the association between the 9-repeat allele (A9) of a 40-bp variable number tandem repeat (VNTR) polymorphism in the 3' un-translated region (3' UTR) of the SLC6A3 gene and alcoholism. The SLC6A3 VNTR was genotyped by PCR in unrelated Mexican Americans including 337 controls and 365 alcoholics. Pearson's chi-square test or Fisher's exact test was used to compare the genotype and allele distribution. Meta-analyses were performed for population-based case-control association studies of the SLC6A3 VNTR polymorphism with alcoholism. Data were analyzed under random effect models with the Comprehensive Meta-analysis (v.2) statistical software package. In Mexican Americans, no significant difference was found in allele and genotype distribution between controls and alcoholics or between controls and alcoholics with alcohol withdrawal seizure (AWS) or delirium tremens (DT) (unadjusted p > 0.05). A total of 13 research articles were included in the meta-analyses. No significant difference of the SLC6A3 VNTR A9 was noted between controls and alcoholics at the genotypic and allelic level when all ethnic populations, only Caucasian populations, or only Asian populations were considered (p > 0.05). Significant associations were observed between SLC6A3 VNTR A9 and alcoholics with AWS or DT at the genotypic as well as allelic level when all ethnic populations or only Caucasian populations were considered (p < 0.05, OR 1.5-2.1). Meta-analyses suggest a possible association between the SLC6A3 VNTR A9 and alcoholic subgroup with AWS or DT. 2011 by the Research Society on Alcoholism.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

PubMed

Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E; Zhao, Ningning; Dadswell, Chris; Abdul-Sada, Alaa; Hung, Christina Y; Simpson, Michael A; Chong, W K; Jacques, Thomas S; Woltjer, Randy L; Eaton, Simon; Gregory, Allison; Sanford, Lynn; Kara, Eleanna; Houlden, Henry; Cuno, Stephan M; Prokisch, Holger; Valletta, Lorella; Tiranti, Valeria; Younis, Rasha; Maher, Eamonn R; Spencer, John; Straatman-Iwanowska, Ania; Gissen, Paul; Selim, Laila A M; Pintos-Morell, Guillem; Coroleu-Lletget, Wifredo; Mohammad, Shekeeb S; Yoganathan, Sangeetha; Dale, Russell C; Thomas, Maya; Rihel, Jason; Bodamer, Olaf A; Enns, Caroline A; Hayflick, Susan J; Clayton, Peter T; Mills, Philippa B; Kurian, Manju A; Wilson, Stephen W

2016-05-27

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia

PubMed Central

Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E.; Zhao, Ningning; Dadswell, Chris; Abdul-Sada, Alaa; Hung, Christina Y.; Simpson, Michael A.; Chong, W. K.; Jacques, Thomas S.; Woltjer, Randy L.; Eaton, Simon; Gregory, Allison; Sanford, Lynn; Kara, Eleanna; Houlden, Henry; Cuno, Stephan M.; Prokisch, Holger; Valletta, Lorella; Tiranti, Valeria; Younis, Rasha; Maher, Eamonn R.; Spencer, John; Straatman-Iwanowska, Ania; Gissen, Paul; Selim, Laila A. M.; Pintos-Morell, Guillem; Coroleu-Lletget, Wifredo; Mohammad, Shekeeb S.; Yoganathan, Sangeetha; Dale, Russell C.; Thomas, Maya; Rihel, Jason; Bodamer, Olaf A.; Enns, Caroline A.; Hayflick, Susan J.; Clayton, Peter T.; Mills, Philippa B.; Kurian, Manju A.; Wilson, Stephen W.

2016-01-01

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates. PMID:27231142

N-ethylmaleimide-sensitive factor interacts with the serotonin transporter and modulates its trafficking: implications for pathophysiology in autism

PubMed Central

2014-01-01

Background Changes in serotonin transporter (SERT) function have been implicated in autism. SERT function is influenced by the number of transporter molecules present at the cell surface, which is regulated by various cellular mechanisms including interactions with other proteins. Thus, we searched for novel SERT-binding proteins and investigated whether the expression of one such protein was affected in subjects with autism. Methods Novel SERT-binding proteins were examined by a pull-down system. Alterations of SERT function and membrane expression upon knockdown of the novel SERT-binding protein were studied in HEK293-hSERT cells. Endogenous interaction of SERT with the protein was evaluated in mouse brains. Alterations in the mRNA expression of SERT (SLC6A4) and the SERT-binding protein in the post-mortem brains and the lymphocytes of autism patients were compared to nonclinical controls. Results N-ethylmaleimide-sensitive factor (NSF) was identified as a novel SERT-binding protein. NSF was co-localized with SERT at the plasma membrane, and NSF knockdown resulted in decreased SERT expression at the cell membranes and decreased SERT uptake function. NSF was endogenously co-localized with SERT and interacted with SERT. While SLC6A4 expression was not significantly changed, NSF expression tended to be reduced in post-mortem brains, and was significantly reduced in lymphocytes of autistic subjects, which correlated with the severity of the clinical symptoms. Conclusions These data clearly show that NSF interacts with SERT under physiological conditions and is required for SERT membrane trafficking and uptake function. A possible role for NSF in the pathophysiology of autism through modulation of SERT trafficking, is suggested. PMID:24834316

78. GENERAL VIEW OF SLC3W FUEL APRON FROM NORTH. HELIUM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

78. GENERAL VIEW OF SLC-3W FUEL APRON FROM NORTH. HELIUM AND NITROGEN STORAGE TANKS AND CONTROL SKIDS IN LEFT CENTER. FUEL STORAGE TANK AND CONTROL SKID IN RIGHT BACKGROUND. SLC-3E MST IN DISTANT RIGHT BACKGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss.

PubMed

Ma, Zhaoxin; Xia, Wenjun; Liu, Fei; Ma, Jing; Sun, Shaoyang; Zhang, Jin; Jiang, Nan; Wang, Xu; Hu, Jiongjiong; Ma, Duan

2017-01-15

Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss. Whole-exome sequencing revealed SLC44A4, which encodes the choline transport protein, as the pathogenic gene in this family. In the zebrafish model, downregulation of slc44a4 using morpholinos led to significant abnormalities in the zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4. We concluded that mutation of SLC44A4 may cause defects in the Choline- acetylcholine system, which is crucial to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury, leading to hearing loss. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells.

PubMed

Ikeda, Kayo; Kinoshita, Makoto; Kayama, Hisako; Nagamori, Shushi; Kongpracha, Pornparn; Umemoto, Eiji; Okumura, Ryu; Kurakawa, Takashi; Murakami, Mari; Mikami, Norihisa; Shintani, Yasunori; Ueno, Satoko; Andou, Ayatoshi; Ito, Morihiro; Tsumura, Hideki; Yasutomo, Koji; Ozono, Keiichi; Takashima, Seiji; Sakaguchi, Shimon; Kanai, Yoshikatsu; Takeda, Kiyoshi

2017-11-14

Foxp3 + regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3 + Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3 + Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

PubMed

Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A; Landau, Daniel; Birk, Ohad S

2017-04-01

A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

SLC11A1 polymorphisms and host susceptibility to cutaneous leishmaniasis in Pakistan.

PubMed

Sophie, Mariam; Hameed, Abdul; Muneer, Akhtar; Samdani, Azam J; Saleem, Saima; Azhar, Abid

2017-01-07

The vector-borne cutaneous leishmaniasis (CL) is endemic in several regions of Pakistan mainly affecting poor populations. Host genetic factors, particularly SLC11A1 (solute carrier transmembrane protein) within macrophages, play a crucial role in disease pathology and susceptibility. Association of SLC11A1 with cutaneous leishmaniasis, a neglected tropical disease, is not well established. Inconsistencies have been observed within different populations worldwide with respect to genetic susceptibility. This study was designed to investigate genetic variation(s) in SLC11A1 and to assess possible association with cutaneous leishmaniasis in Pakistan. Eight polymorphisms (rs2276631, rs3731864, rs2290708, rs2695342, rs201565523, rs17215556, rs17235409, rs17235416) were genotyped across SLC11A1 in 274 patients and 119 healthy controls. Six polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Two single nucleotide polymorphisms were analyzed with newly designed semi-nested PCR assays. Case-control analysis showed no association between selected polymorphisms in SLC11A1 and cutaneous leishmaniasis. No significant difference was observed in the distribution of alleles between leishmaniasis patients and healthy individuals. Strong pairwise linkage disequilibrium was observed between rs2276631 and rs2290708 (r 2  = 64); and rs17235409 and rs17235416 (r 2  = 78). This study shows that genetic variations in the candidate gene SLC11A1 do not affect susceptibility to cutaneous leishmaniasis in the sample population from Pakistan.

Evaluation of non-coding variation in GLUT1 deficiency.

PubMed

Liu, Yu-Chi; Lee, Jia Wei Audrey; Bellows, Susannah T; Damiano, John A; Mullen, Saul A; Berkovic, Samuel F; Bahlo, Melanie; Scheffer, Ingrid E; Hildebrand, Michael S

2016-12-01

Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants. We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant. The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript. Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes. © 2016 Mac Keith Press.

Illustrating the (in)visible: Understanding the impact of loss in adults living with secondary lymphedema after cancer

PubMed Central

Thomas, Roanne; Hamilton, Ryan

2014-01-01

Life with a disability is often riddled with paradoxes, one of which is being visibly marked, while personal experiences, losses, and challenges remain hidden. Our article draws attention to this paradox among people who live with secondary lymphedema after cancer (SLC). SLC is a relatively unfamiliar chronic condition within medical and lay discourses of cancer, which proves challenging for the many cancer survivors who are in search of information and understanding. Thirteen men and women with SLC were recruited from two research sites (Fredericton, NB, and Ottawa, ON, Canada) to participate in semi-structured interviews about the physical and psychosocial aspects of SLC. Using a methodology of interpretive description, our analysis of participant interviews reveals the complex ways in which men and women felt both visible and invisible within various contexts. We discuss three majors themes: (in)visibility and appearance related to material losses; (in)visibility and action connected to visible losses in function, as well as invisible struggles to care for oneself; and the loss of present and future well-being, as SLC renders some limitations visible while potentially obscuring a hopeful future indefinitely. Our research indicates that timely diagnosis of SLC would be an immediate first step in recognizing the physical and emotional dimensions of the condition. To accomplish this, increased awareness is needed. To enhance quality of life for those living with SLC, the development of new resources and psychosocial supports is also required. PMID:25148936

Application of Adaptive Starling-Like Controller to Total Artificial Heart Using Dual Rotary Blood Pumps.

PubMed

Ng, Boon C; Smith, Peter A; Nestler, Frank; Timms, Daniel; Cohn, William E; Lim, Einly

2017-03-01

The successful clinical applicability of rotary left ventricular assist devices (LVADs) has led to research interest in devising a total artificial heart (TAH) using two rotary blood pumps (RBPs). The major challenge when using two separately controlled LVADs for TAH support is the difficulty in maintaining the balance between pulmonary and systemic blood flows. In this study, a starling-like controller (SLC) hybridized with an adaptive mechanism was developed for a dual rotary LVAD TAH. The incorporation of the adaptive mechanism was intended not only to minimize the risk of pulmonary congestion and atrial suction but also to match cardiac demand. A comparative assessment was performed between the proposed adaptive starling-like controller (A-SLC) and a conventional SLC as well as a constant speed controller. The performance of all controllers was evaluated by subjecting them to three simulated scenarios [rest, exercise, head up tilt (HUT)] using a mock circulation loop. The overall results showed that A-SLC was superior in matching pump flow to cardiac demand without causing hemodynamic instabilities. In contrast, improper flow regulation by the SLC resulted in pulmonary congestion during exercise. From resting supine to HUT, overpumping of the RBPs at fixed speed (FS) caused atrial suction, whereas implementation of SLC resulted in insufficient flow. The comparative study signified the potential of the proposed A-SLC for future TAH implementation particularly among outpatients, who are susceptible to variety of clinical scenarios.

Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder.

PubMed

Kim, Yong-Ku; Hwang, Jung-A; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Ko, Young-Hoon; Lee, Bun-Hee; Jung, Han-Yong; Hahn, Sang-Woo; Na, Kyoung-Sae

2014-04-01

Although several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. Three single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. In the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446-rs28386840-rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. Modest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. Our results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk. Copyright © 2014 Elsevier B.V. All rights reserved.

Identification of DLG5 and SLC22A5 gene polymorphisms in Malaysian patients with Crohn's disease.

PubMed

Chua, Kek Heng; Lian, Lay Hoong; Kee, Boon Pin; Thum, Chooi Mei; Lee, Way Seah; Hilmi, Ida; Goh, Khean Lee

2011-12-01

The aim of this study was to investigate the association of DLG5 and SLC22A5 gene polymorphisms with the onset of Crohn's disease (CD) in a Malaysian cohort. Genomic DNA of 80 CD patients and 100 healthy unrelated control individuals was extracted and analyzed via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on DLG5 (4136 C/A), DLG5_e26 and SLC22A5 (-207 G/C) genetic polymorphisms. Data obtained from the study were then subjected to statistical analysis to test for risk association. Significant associations of both DLG5 polymorphisms with the development of CD in the Malaysian patients were observed in this study. The homozygous C genotype of the DLG5 polymorphism was significantly related to CD patients (P = 0.0023, OR = 2.5320), while the homozygous A was significant in control individuals (P = 0.0224, OR = 0.4480). In DLG5_e26 polymorphisms, we found a significant distribution of the homozygous insA genotype in CD patients (P = 0.0006, OR = 2.8916), whereas the heterozygous insA/delA genotype was significant in controls (P = 0.0007, OR = 0.3487). We hypothesized that there might be a complex interaction of both alleles, which confered a protective effect against the onset of CD. However, we did not observe any significant correlation of SLC22A5 polymorphisms with this disease. In our study, both polymorphisms in the DLG5 gene were found to be associated with CD patients in Malaysia. Therefore, these loci can be potentially used as susceptibility markers in the Malaysian population. © 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

105. VIEW NORTH FROM SLC3W CABLE TUNNEL INTO CABLE VAULT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

105. VIEW NORTH FROM SLC-3W CABLE TUNNEL INTO CABLE VAULT AND SLC-3E CABLE TUNNEL. NOTE WOODEN PLANKING ON FLOOR OF TUNNEL AND CABLE TRAYS LINING TUNNEL WALLS. STAIRS ON EAST WALL OF CABLE VAULT LEAD INTO LANDLINE INSTRUMENTATION ROOM. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Complex Analysis of Urate Transporters SLC2A9, SLC22A12 and Functional Characterization of Non-Synonymous Allelic Variants of GLUT9 in the Czech Population: No Evidence of Effect on Hyperuricemia and Gout

PubMed Central

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Objective Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. Methods The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. Results We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Conclusion Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9. PMID:25268603

RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

PubMed Central

Hosonaga, Mari; Koya, Ikuko

2017-01-01

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients. PMID:28210624

Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11).

PubMed

Wang, Li; Sweet, Douglas H

2012-10-15

Phenolic acids exert beneficial health effects such as anti-oxidant, anti-carcinogenic, and anti-inflammatory activities and show systemic exposure after consumption of common fruits, vegetables, and beverages. However, knowledge regarding which components convey therapeutic benefits and the mechanism(s) by which they cross cell membranes is extremely limited. Therefore, we determined the inhibitory effects of nine food-derived phenolic acids, p-coumaric acid, ferulic acid, gallic acid, gentisic acid, 4-hydroxybenzoic acid, protocatechuic acid, sinapinic acid, syringic acid, and vanillic acid, on human organic anion transporter 1 (hOAT1), hOAT3, and hOAT4. In the present study, inhibition of OAT-mediated transport of prototypical substrates (1 μM) by phenolic acids (100 μM) was examined in stably expressing cell lines. All compounds significantly inhibited hOAT3 transport, while just ferulic, gallic, protocatechuic, sinapinic, and vanillic acid significantly blocked hOAT1 activity. Only sinapinic acid inhibited hOAT4 (~35%). For compounds exhibiting inhibition > ~60%, known clinical plasma concentration levels and plasma protein binding in humans were examined to select compounds to evaluate further with dose-response curves (IC(50) values) and drug-drug interaction (DDI) index determinations. IC(50) values ranged from 1.24 to 18.08 μM for hOAT1 and from 7.35 to 87.36 μM for hOAT3. Maximum DDI indices for gallic and gentisic acid (≫0.1) indicated a very strong potential for DDIs on hOAT1 and/or hOAT3. This study indicates that gallic acid from foods or supplements, or gentisic acid from salicylate-based drug metabolism, may significantly alter the pharmacokinetics (efficacy and toxicity) of concomitant therapeutics that are hOAT1 and/or hOAT3 substrates. Copyright © 2012 Elsevier Inc. All rights reserved.

Oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6.

PubMed

Jin, Hai; Wen, Guorong; Deng, Shili; Wan, Shuo; Xu, Jingyu; Liu, Xuemei; Xie, Rui; Dong, Hui; Tuo, Biguang

2016-11-01

What is the central question of this study? Duodenal ulcer is a common disease. A sex-based difference in the incidence of duodenal ulcer has long been observed clinically, but the cause is unclear. What is the main finding and its importance? Duodenal mucosal bicarbonate secretion is the most important protective factor in duodenal mucosa against acid-induced damage. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion. We demonstrate that endogenous oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6, which contributes to the sex difference in the prevalence of duodenal ulcer. The incidence of duodenal ulcer is markedly lower in women than men, but the cause of the sex difference is not clear. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion, which is an important protective factor against acid-induced duodenal injury. The aim of this study was to investigate the effect of oestrogen on the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa. We found that the expression levels of duodenal CFTR and SLC26A6 were markedly higher in young (20- to 30-year-old) women than in young men and old (60- to 70-year-old) women and men. The expression levels of CFTR and SLC26A6 in young women were markedly higher in preovulatory phases than in premenstrual phases, which was consistent with the changes of serum estradiol concentrations. Further results showed that duodenal CFTR and SLC26A6 expression levels in female mice were markedly decreased after ovariectomy, and supplementation with estradiol reversed the changes in CFTR and SLC26A6. 17β-Estradiol increased CFTR and SLC26A6 expression levels of human duodenocytes in experiments in vitro. Functional experiments showed that basal and forskolin- and prostaglandin E 2 -stimulated duodenal bicarbonate secretion in ovariectomized mice was markedly decreased and, likewise, supplementation with 17β-estradiol reversed the changes. In conclusion, endogenous oestrogen upregulates the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa, which could contribute to protection of the duodenum and explain the sex difference in the prevalence of duodenal ulcer. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry.

PubMed

Mercimek-Mahmutoglu, Saadet; Muehl, Adolf; Salomons, Gajja S; Neophytou, Birgit; Moeslinger, Dorothea; Struys, Eduard; Bodamer, Olaf A; Jakobs, Cornelis; Stockler-Ipsiroglu, Sylvia

2009-04-01

High urinary creatine to creatinine ratio (U-CrCrtR) is a potential diagnostic marker of X-linked creatine transporter (SLC6A8) deficiency. We developed a tandem mass-spectrometry method to simultaneously determine urinary creatine and creatinine in 975 individuals (0-18 years). U-CrCrtR increased up to 8 years and decreased thereafter. U-CrCrtR was 2.29 and 2.12 (99th percentile: 1.87) in two males with subsequently confirmed SLC6A8 mutations. The frequency of SLC6A8 deficiency was 2.3% in 157 males at risk.

The cyanobacterial bicarbonate transporter BicA: its physiological role and the implications of structural similarities with human SLC26 transporters.

PubMed

Price, G Dean; Howitt, Susan M

2011-04-01

The cyanobacterial Na+-dependent HCO3- transporter BicA is a member of the ubiquitous and important SulP/SLC26 family of anion transporters found in eukaryotes and prokaryotes. BicA is an important component of the cyanobacterial CO2 concentrating mechanism, an adaptation that contributes to cyanobacteria being able to achieve an estimated 25% of global primary productivity, largely in the oceans. The human SLC26 members are involved in a range of key cellular functions involving a diverse range of anion transport activities including Cl-/HCO3-, I-/HCO3-, and SO42-/HCO3- exchange; mutations in SLC26 members are known to be associated with debilitating diseases such as Pendred syndrome, chondrodysplasias, and congenital chloride diarrhoea. We have recently experimentally determined the membrane topology of BicA using the phoA-lacZ reporter system and here consider some of the extrapolated implications for topology of the human SLC26 family and the Sultr plant sulphate transporters.

Influence of SLC6A3 and COMT Variation on Neural Activation During Response Inhibition

PubMed Central

Congdon, Eliza; Constable, R. Todd; Lesch, Klaus Peter; Canli, Turhan

2009-01-01

There is evidence concerning the neural and genetic correlates of inhibitory control, but there have been limited attempts to combine this information. This study tested the hypothesis that two dopaminergic polymorphisms, SLC6A3 and COMT, influence neural activation during response inhibition. Healthy adults were genotyped for these polymorphisms and performed a measure of response inhibition while undergoing functional magnetic resonance imaging (fMRI). Results support the role of key frontostriatal regions underlying response inhibition. Furthermore, results support a significant influence of SLC6A3 and COMT variants on neural activity during inhibition, with greater activation during inhibition in carriers of the SLC6A3 9-allele or the COMT met-allele as compared to carriers of the SLC6A3 10/10 genotype or the COMT val/val genotype. These results add to a growing literature suggesting that inhibitory control is sensitive to variation in dopamine function, and suggest that this variation may be detectable at the level of individuals’ genotypes. PMID:19482231

Nutrient transport in the mammary gland: calcium, trace minerals and water soluble vitamins.

PubMed

Montalbetti, Nicolas; Dalghi, Marianela G; Albrecht, Christiane; Hediger, Matthias A

2014-03-01

Milk nutrients are secreted by epithelial cells in the alveoli of the mammary gland by several complex and highly coordinated systems. Many of these nutrients are transported from the blood to the milk via transcellular pathways that involve the concerted activity of transport proteins on the apical and basolateral membranes of mammary epithelial cells. In this review, we focus on transport mechanisms that contribute to the secretion of calcium, trace minerals and water soluble vitamins into milk with particular focus on the role of transporters of the SLC series as well as calcium transport proteins (ion channels and pumps). Numerous members of the SLC family are involved in the regulation of essential nutrients in the milk, such as the divalent metal transporter-1 (SLC11A2), ferroportin-1 (SLC40A1) and the copper transporter CTR1 (SLC31A1). A deeper understanding of the physiology and pathophysiology of these transporters will be of great value for drug discovery and treatment of breast diseases.

The renal urate transporter SLC17A1 locus: confirmation of association with gout.

PubMed

Hollis-Moffatt, Jade E; Phipps-Green, Amanda J; Chapman, Brett; Jones, Gregory T; van Rij, Andre; Gow, Peter J; Harrison, Andrew A; Highton, John; Jones, Peter B; Montgomery, Grant W; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R

2012-04-27

Two major gout-causing genes have been identified, the urate transport genes SLC2A9 and ABCG2. Variation within the SLC17A1 locus, which encodes sodium-dependent phosphate transporter 1, a renal transporter of uric acid, has also been associated with serum urate concentration. However, evidence for association with gout is equivocal. We investigated the association of the SLC17A1 locus with gout in New Zealand sample sets. Five variants (rs1165196, rs1183201, rs9358890, rs3799344, rs12664474) were genotyped across a New Zealand sample set totaling 971 cases and 1,742 controls. Cases were ascertained according to American Rheumatism Association criteria. Two population groups were studied: Caucasian and Polynesian. At rs1183201 (SLC17A1), evidence for association with gout was observed in both the Caucasian (odds ratio (OR) = 0.67, P = 3.0 × 10-6) and Polynesian (OR = 0.74, P = 3.0 × 10-3) groups. Meta-analysis confirmed association of rs1183201 with gout at a genome-wide level of significance (OR = 0.70, P = 3.0 × 10-8). Haplotype analysis suggested the presence of a common protective haplotype. We confirm the SLC17A1 locus as the third associated with gout at a genome-wide level of significance.

A multi-scale segmentation approach to filling gaps in Landsat ETM+ SLC-off images

USGS Publications Warehouse

Maxwell, S.K.; Schmidt, Gail L.; Storey, James C.

2007-01-01

On 31 May 2003, the Landsat Enhanced Thematic Plus (ETM+) Scan Line Corrector (SLC) failed, causing the scanning pattern to exhibit wedge-shaped scan-to-scan gaps. We developed a method that uses coincident spectral data to fill the image gaps. This method uses a multi-scale segment model, derived from a previous Landsat SLC-on image (image acquired prior to the SLC failure), to guide the spectral interpolation across the gaps in SLC-off images (images acquired after the SLC failure). This paper describes the process used to generate the segment model, provides details of the gap-fill algorithm used in deriving the segment-based gap-fill product, and presents the results of the gap-fill process applied to grassland, cropland, and forest landscapes. Our results indicate this product will be useful for a wide variety of applications, including regional-scale studies, general land cover mapping (e.g. forest, urban, and grass), crop-specific mapping and monitoring, and visual assessments. Applications that need to be cautious when using pixels in the gap areas include any applications that require per-pixel accuracy, such as urban characterization or impervious surface mapping, applications that use texture to characterize landscape features, and applications that require accurate measurements of small or narrow landscape features such as roads, farmsteads, and riparian areas.

Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori)

PubMed Central

Tang, Xin; Liu, Huawei; Chen, Quanmei; Wang, Xin; Xiong, Ying; Zhao, Ping

2016-01-01

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family. PMID:27706106

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

PubMed

O'Shea, Joseph P; Nagarsekar, Kalpa; Wieber, Alena; Witt, Vanessa; Herbert, Elisabeth; O'Driscoll, Caitriona M; Saal, Christoph; Lubda, Dieter; Griffin, Brendan T; Dressman, Jennifer B

2017-10-01

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. © 2017 Royal Pharmaceutical Society.

Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori).

PubMed

Tang, Xin; Liu, Huawei; Chen, Quanmei; Wang, Xin; Xiong, Ying; Zhao, Ping

2016-10-03

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family.

Involvement of the anion exchanger SLC26A6 in prostaglandin E2- but not forskolin-stimulated duodenal HCO3- secretion.

PubMed

Tuo, Biguang; Riederer, Brigitte; Wang, Zhaohui; Colledge, William H; Soleimani, Manoocher; Seidler, Ursula

2006-02-01

SLC26A6 is a recently identified apical Cl(-)/HCO(3)(-) exchanger with strong expression in murine duodenum. The present study was designed to examine the role of SLC26A6 in prostaglandin E(2) (PGE(2))-, forskolin-, and carbachol-induced duodenal HCO(3)(-) secretion. Murine duodenal mucosal HCO(3)(-) secretion was examined in vitro in Ussing chambers and mucosal SLC26A6 expression levels were analyzed by semiquantitative reverse-transcription polymerase chain reaction. Basal HCO(3)(-) secretion was diminished by 20%, PGE(2)-stimulated HCO(3)(-) secretory response by 59%, and carbachol-stimulated response was reduced by 35% in SLC26A6-/- compared with +/+ duodenal mucosa, whereas the forskolin-stimulated HCO(3)(-) secretory response was not different. In Cl(-)-free solutions, PGE(2)- and carbachol-stimulated HCO(3)(-) secretion was reduced by 81% and 44%, respectively, whereas forskolin-stimulated HCO(3)(-) secretion was not altered significantly. PGE(2) and carbachol, but not forskolin, were able to elicit a Cl(-)-dependent HCO(3)(-) secretory response in the absence of short-circuit current changes in cystic fibrosis transmembrane conductance regulator knockout mice. In murine duodenum, PGE(2)-mediated HCO(3)(-) secretion is strongly SLC26A6 dependent and cystic fibrosis transmembrane conductance regulator independent, whereas forskolin-stimulated HCO(3)(-) secretion is completely SLC26A6 independent and cystic fibrosis transmembrane conductance regulator dependent. Carbachol-induced secretion is less pronounced, but occurs via both transport pathways. This suggests that PGE(2) and forskolin activate distinct HCO(3)(-) transport pathways in the murine duodenum.

SLC52A3, A Brown–Vialetto–van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation

PubMed Central

Intoh, Atsushi; Suzuki, Naoki; Koszka, Kathryn; Eggan, Kevin

2016-01-01

Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown–Vialetto–Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 −/− embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development. PMID:26976849

B0AT2 (SLC6A15) Is Localized to Neurons and Astrocytes, and Is Involved in Mediating the Effect of Leucine in the Brain

PubMed Central

Hägglund, Maria G. A.; Roshanbin, Sahar; Löfqvist, Erik; Hellsten, Sofie V.; Nilsson, Victor C. O.; Todkar, Aniruddha; Zhu, Yinan; Stephansson, Olga; Drgonova, Jana; Uhl, George R.; Schiöth, Helgi B.; Fredriksson, Robert

2013-01-01

The B0AT2 protein is a product of the SLC6A15 gene belonging to the SLC6 subfamily and has been shown to be a transporter of essential branched-chain amino acids. We aimed to further characterize the B0AT2 transporter in CNS, and to use Slc6a15 knock out (KO) mice to investigate whether B0AT2 is important for mediating the anorexigenic effect of leucine. We used the Slc6a15 KO mice to investigate the role of B0AT2 in brain in response to leucine and in particular the effect on food intake. Slc6a15 KO mice show lower reduction of food intake as well as lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to leucine injections compared to wild type mice. We also used RT-PCR on rat tissues, in situ hybridization and immunohistochemistry on mouse CNS tissues to document in detail the distribution of SLC6A15 on gene and protein levels. We showed that B0AT2 immunoreactivity is mainly neuronal, including localization in many GABAergic neurons and spinal cord motor neurons. B0AT2 immunoreactivity was also found in astrocytes close to ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in epithelial cells of the choroid plexus. The data suggest that B0AT2 play a role in leucine homeostasis in the brain. PMID:23505546

Adaptation to different salinities exposes functional specialization in the intestine of the sea bream (Sparus aurata L.).

PubMed

Gregório, Sílvia F; Carvalho, Edison S M; Encarnação, Sandra; Wilson, Jonathan M; Power, Deborah M; Canário, Adelino V M; Fuentes, Juan

2013-02-01

The processing of intestinal fluid, in addition to a high drinking rate, is essential for osmoregulation in marine fish. This study analyzed the long-term response of the sea bream (Sparus aurata L.) to relevant changes of external salinity (12, 35 and 55 p.p.t.), focusing on the anterior intestine and in the less-often studied rectum. Intestinal water absorption, epithelial HCO(3)(-) secretion and gene expression of the main molecular mechanisms (SLC26a6, SLC26a3, SLC4a4, atp6v1b, CFTR, NKCC1 and NKCC2) involved in Cl(-) and HCO(3)(-) movements were examined. The anion transporters SLC26a6 and SLC26a3 are expressed severalfold higher in the anterior intestine, while the expression of Atp6v1b (V-type H(+)-ATPase β-subunit) is severalfold higher in the rectum. Prolonged exposure to altered external salinity was without effect on water absorption but was associated with concomitant changes in intestinal fluid content, epithelial HCO(3)(-) secretion and salinity-dependent expression of SLC26a6, SLC26a3 and SLC4a4 in the anterior intestine. However, the most striking response to external salinity was obtained in the rectum, where a 4- to 5-fold increase in water absorption was paralleled by a 2- to 3-fold increase in HCO(3)(-) secretion in response to a salinity of 55 p.p.t. In addition, the rectum of high salinity-acclimated fish shows a sustained (and enhanced) secretory current (I(sc)), identified in vitro in Ussing chambers and confirmed by the higher expression of CFTR and NKCC1 and by immunohistochemical protein localization. Taken together, the present results suggest a functional anterior-posterior specialization with regard to intestinal fluid processing and subsequently to salinity adaptation of the sea bream. The rectum becomes more active at higher salinities and functions as the final controller of intestinal function in osmoregulation.

Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function

PubMed Central

Kippler, Maria; Alhamdow, Ayman; Rahman, Syed Moshfiqur; Smith, Donald R.; Vahter, Marie; Lucchini, Roberto G.; Broberg, Karin

2016-01-01

Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (−24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (−18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. PMID:26628504

Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat

PubMed Central

Raj, Karthik; Osborne, Carl; Giger, Urs

2016-01-01

Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats. PMID:27404572

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

PubMed Central

2014-01-01

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9×10−13; odds ratio (OR)=1.29). The association was stronger in younger, leaner people with T2D, and replicated in independent samples (P=1.1×10−4; OR=1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ≈50% frequency in Native American samples and ≈10% in East Asian, but rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism. PMID:24390345

Single-layer centrifugation through PureSperm® 80 selects improved quality spermatozoa from frozen-thawed dog semen.

PubMed

Dorado, J; Alcaraz, L; Gálvez, M J; Acha, D; Ortiz, I; Urbano, M; Hidalgo, M

2013-08-01

The aim of this study was to investigate whether single-layer centrifugation (SLC) with PureSperm® 80 could select good quality spermatozoa, including those with specific motility patterns, from doses of frozen dog semen. Semen from 5 dogs was collected and cryopreserved following a standard protocol. After thawing, semen samples were divided into two aliquots: one of them was used as control and the other one processed by SLC. Assessment of sperm motility (assessed by computer-assisted semen analysis), morphology (Diff-Quick staining) and viability (triple fluorescent stain of propidium iodine/isothiocyanate-labeled peanut (Arachis hypogaea) agglutinin/Rhodamine 123), were performed on aliquots of fresh semen, frozen-thawed control and frozen-thawed SLC treated samples. A multivariate clustering procedure separated 26,051 motile spermatozoa into three subpopulations (sP): sP1 consisting of highly active but non-progressive spermatozoa (40.3%), sP2 consisting of spermatozoa with high velocity and progressive motility (30.0%), and sP3 consisting of poorly active and non-progressive spermatozoa (29.7%). SLC with PureSperm® 80 yielded sperm suspensions with improved motility, morphology, viability and acrosome integrity (P<0.001). The frozen-thawed SLC treated samples were enriched in sP2, reaching a proportion of 44.1% of the present spermatozoa. From these results, we concluded that SLC with PureSperm® 80 may be an alternative and successful method for improving the quality of frozen-thawed dog spermatozoa. Moreover, sP2 (high-speed and progressive spermatozoa) was more frequently observed after SLC. Finally, this study also demonstrated that the general motile sperm structure present in dogs remained constant despite the effect caused by either cryopreservation or separation by SLC through PureSperm® 80. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of fasting and refeeding on gene expression of slc15a1a, a gene encoding an oligopeptide transporter (PepT1), in the intestine of Mozambique tilapia.

PubMed

Orozco, Zenith Gaye A; Soma, Satoshi; Kaneko, Toyoji; Watanabe, Soichi

2017-01-01

The tissue distribution of slc15a1a, a gene that encodes an oligopeptide transporter, PepT1, and its response to fasting and refeeding were investigated in the intestinal epithelium of Mozambique tilapia for a better understanding of its role on nutrient absorption. The slc15a1a was predominantly expressed in the absorptive epithelia of the anterior part of the intestine, suggesting that digested oligopeptides are primarily absorbed in the anterior intestine. The response of slc15a1a to fasting was evaluated at 1, 2, 4, 7 and 14days after the last feeding. Fasting revealed a biphasic effect, where short-term fasting significantly upregulated slc15a1a expression and long-term fasting resulted in downregulation. The expression level continued to decrease and fell below the pre-fasted level from day 4 to 14. Proximal (the hepatic loop, HL) and distal parts (the proximal major coil, PMC) of the anterior intestine showed different magnitudes of responses to fasting; slc15a1a expression in the PMC showed greater upregulation and downregulation than that in the HL. Refeeding significantly stimulated slc15a1a expression at day 3, although the expression did not exceed the pre-fasted level. Observed responses of slc15a1a to fasting and refeeding suggest that the expression level of this gene can serve as a sensitive indicator of the changes that may occur in altering nutritional conditions. These findings contribute to a better understanding of the role of PepT1 in nutrition and of the complex mechanisms underlying the absorption of oligopeptides and amino acids in the intestine, and may lead to development of possible means to manipulate the absorption processes for the improvement of growth and other metabolic and physiological conditions in fish. Copyright © 2016. Published by Elsevier Inc.

Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression.

PubMed

Zheng, Yuxuan; Ritzenthaler, Jeffrey D; Burke, Tom J; Otero, Javier; Roman, Jesse; Watson, Walter H

2018-04-01

Aging is associated with progressive oxidation of the extracellular environment. The redox state of human plasma, defined by the concentrations of cysteine (Cys) and cystine (CySS), becomes more oxidized as we age. Recently, we showed that fibroblasts isolated from the lungs of young and old mice retain this differential phenotype; old cells produce and maintain a more oxidizing extracellular redox potential (E h (Cys/CySS)) than young cells. Microarray analysis identified down-regulation of Slc7a11, the light subunit of the CySS/glutamate transporter, as a potential mediator of age-related oxidation in these cells. The purpose of the present study was to investigate the mechanistic link between Slc7a11 expression and extracellular E h (Cys/CySS). Sulforaphane treatment or overexpression of Slc7a11 was used to increase Slc7a11 in lung fibroblasts from old mice, and sulfasalazine treatment or siRNA-mediated knock down was used to decrease Slc7a11 in young fibroblasts. Slc7a11 mRNA levels were measured by real-time PCR, Slc7a11 activity was determined by measuring the rate of glutamate release, Cys, CySS, glutathione (GSH) and its disulfide (GSSG) were measured by HPLC, and E h (Cys/CySS) was calculated from the Nernst equation. The results showed that both E h (Cys/CySS) and E h (GSH/GSSG) were more oxidized in the conditioned media of old cells than in young cells. Up-regulation of Slc7a11 via overexpression or sulforaphane treatment restored extracellular E h (Cys/CySS) in cultures of old cells, whereas down-regulation reproduced the oxidizing E h (Cys/CySS) in young cells. Only sulforaphane treatment was able to increase total GSH and restore E h (GSH/GSSG), whereas overexpression, knock down and sulfasalazine had no effect on these parameters. In addition, inhibition of GSH synthesis with buthionine sulfoximine had no effect on the ability of cells to restore their extracellular redox potential in response to an oxidative challenge. In conclusion, our study reveals Slc7a11 is the key regulator of age-dependent changes in extracellular E h (Cys/CySS) in primary mouse lung fibroblasts, and its effects are not dependent on GSH synthesis. Copyright © 2018 Elsevier Inc. All rights reserved.

Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects.

PubMed

Nonose, Renata Watanabe; Lezirovitz, Karina; de Mello Auricchio, Maria Teresa Balester; Batissoco, Ana Carla; Yamamoto, Guilherme Lopes; Mingroni-Netto, Regina Célia

2018-05-08

Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T > G (p. F335 V), c.1553G > A (p.W518X), c.2235 + 2 T > C (IVS19 + 2 T > C), and one already described, c.84C > A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7 + 2 T > C) and the previously described c.1246A > C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. Biallelic pathogenic mutations in SLC26A4 explained ~ 3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~ 13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.

A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study.

PubMed

McAdams-DeMarco, Mara A; Maynard, Janet W; Baer, Alan N; Kao, Linda W; Kottgen, Anna; Coresh, Josef

2013-05-01

To test for a urate gene-by-diuretic interaction on incident gout. The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987-1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median. Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney. Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use.

A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study

PubMed Central

McAdams-DeMarco, Mara A; Maynard, Janet W; Baer, Alan N; Kao, Linda W; Kottgen, Anna; Coresh, Josef

2015-01-01

Objective To test for a urate gene-by-diuretic interaction on incident gout. Methods The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987–1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median. Results Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney. Conclusions Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use. PMID:22753387

Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes.

PubMed

Ndika, Joseph D T; Lusink, Vera; Beaubrun, Claudine; Kanhai, Warsha; Martinez-Munoz, Cristina; Jakobs, Cornelis; Salomons, Gajja S

2014-01-10

Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first experimental evidence of a pseudogene with stronger promoter activity than its parental gene. © 2013.

NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features

PubMed Central

Tavares, Catarina; Coelho, Maria João; Eloy, Catarina; Melo, Miguel; da Rocha, Adriana Gaspar; Pestana, Ana; Batista, Rui; Ferreira, Luciana Bueno; Rios, Elisabete; Selmi-Ruby, Samia; Cavadas, Bruno; Pereira, Luísa; Sobrinho Simões, Manuel

2018-01-01

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, SLC5A5 expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring BRAFV600E mutation. Analysis of SLC5A5 expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring RAS, BRAF and/or TERT promoter (TERTp) mutations presented significantly less SLC5A5 expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for BRAF, NRAS and TERTp mutations. SLC5A5 mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving BRAF, RAS and TERTp. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. SLC5A5 mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features. PMID:29298843

Generation of a Slc39a8 hypomorph mouse: Markedly decreased ZIP8 Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} transporter expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Bin; He, Lei; Dong, Hongbin

2011-07-01

Highlights: {yields} The mouse Slc39a8 gene encodes the ZIP8 transporter. {yields} ZIP8 functions endogenously as a electroneutral Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} symporter. {yields} A Slc39a8(neo/neo) hypomorph mouse, due to retention of the neo mini-gene, has been created. {yields} ZIP8 expression in utero is {approx}90% decreased in all tissues examined. {yields} This mouse model will be useful for studying developmental and in utero physiological functions of ZIP8. -- Abstract: Previously this laboratory has identified the mouse Slc39a8 gene encoding the ZIP8 transporter, important in cadmium uptake. ZIP8 functions endogenously as a electroneutral Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} symporter, moving bothmore » ions into the cell. The overall physiological importance of ZIP8 remains unclear. Herein we describe generation of a mouse line carrying the Slc39a8(neo) allele, containing the Frt-flanked neomycin-resistance (neo) mini-cassette in intron 3 and loxP sites in introns 3 and 6. Cre recombinase functions correctly in Escherichia coli and in adeno-Cre-infected mouse fetal fibroblasts, but does not function in the intact mouse for reasons not clear. Slc39a8(neo) is a hypomorphic allele, because Slc39a8(neo/neo) homozygotes exhibit dramatically decreased ZIP8 expression in embryo, fetus, and visceral yolk sac - in comparison to their littermate wild-type controls. This ZIP8 hypomorph will be instrumental in studying developmental and in utero physiological functions of the ZIP8 transporter.« less

SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells.

PubMed

Tian, Wenjing; Fu, Hualing; Xu, Tuan; Xu, Sherry Li; Guo, Zhiling; Tian, Jijing; Tao, Wuqun; Xie, Heidi Qunhui; Zhao, Bin

2018-06-01

The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver. Copyright © 2018 Elsevier Ltd. All rights reserved.

Supplementation of soybean lecithin-based semen extender by antioxidants: complementary flowcytometric study on post-thawed ram spermatozoa.

PubMed

Sharafi, Mohsen; Zhandi, Mahdi; Akbari Sharif, Abbas

2015-06-01

The purpose of the current study was to evaluate the effects of cysteine (C) and glutathione (G) on the post-thawed ram sperm quality. Collected semen samples from four mature rams were diluted with five soybean lecithin (SL)-based extenders containing: no antioxidant (SL-0), 5 mM cysteine (SL-C5), 10 mM cysteine (SL-C10), 5 mM glutathione (SL-G5) and 10 mM glutathione (SL-G10). After freeze-thawing process, motion and velocity parameters, plasma membrane integrity and functionality, morphological abnormality, lipid peroxidation, acrosomal status, mitochondria activity, and apoptosis status of post-thawed ram spermatozoa were assessed. The results showed that SL-C10 increased the total motility and plasma membrane integrity (p < 0.05) of post-thawed ram spermatozoa (55.86 ± 1.37 and 60.57 ± 1.34 %) compared to other extenders. Progressive motility was significantly higher in SL-C10 (24.71 ± 1.13 %) compared to SL-0 (20 ± 1.13 %) and SL-G10 (15 ± 1.13 %). Mitochondrial activity was significantly higher in SL-C10 (56.83 ± 2.29 %) compared to SL-G10 (38.75 ± 2.29 %). Capacitation and acrosomal status, lipid peroxidation, and the percentage of dead spermatozoa were not affected by different extenders. The percentage of live spermatozoa was higher in SL-C10 (56.33 ± 1.35 %) compared to other extenders. Also, SL-C10 resulted in a lower percentage of apoptotic spermatozoa (14.17 ± 0.53 %) compared to other extenders. The results of this study showed that supplementation of SL-based ram semen extender with 10 mM cysteine resulted in an improved quality of post-thawed ram spermatozoa.

Commercial Slit-Lamp Anterior Segment Photography versus Digital Compact Camera Mounted on a Standard Slit-Lamp with an Adapter.

PubMed

Oliphant, Huw; Kennedy, Alasdair; Comyn, Oliver; Spalton, David J; Nanavaty, Mayank A

2018-06-16

To compare slit lamp mounted cameras (SLC) versus digital compact camera (DCC) with slit-lamp adaptor when used by an inexperienced technician. In this cross sectional study, where posterior capsule opacification (PCO) was used as a comparator, patients were consented for one photograph with SLC and two with DCC (DCC1 and DCC2), with a slit-lamp adaptor. An inexperienced clinic technician, who took all the photographs and masked the images, recruited one eye of each patient. Images were graded for PCO using ECPO2000 software by two independent masked graders. Repeatability between DCC1 & DCC2 and limits-of-agreement between SLC and DCC1 mounted on slit-lamp with an adaptor were assessed. Coefficient-of-repeatability and Bland-Altmann plots were analyzed. Seventy-two patients (eyes) were recruited in the study. First 9 patients (eyes) were excluded due to unsatisfactory image quality from both the systems. Mean EPCO score for SLC was 2.28 (95% CI: 2.09 -2.45), for DCC1 was 2.28 (95% CI: 2.11-2.45), and for the DCC2 was 2.11 (95% CI: 2.11-2.45). There was no significant difference in EPCO scores between SLC Vs. DCC1 (p = 0.98) and between DCC1 and DCC 2 (p = 0.97). Coefficient of repeatability between DCC images was 0.42, and the coefficient of repeatability between DCC and SLC was 0.58. DCC on slit-lamp with an adaptor is comparable to a SLC. There is an initial learning curve, which is similar for both for an inexperienced person. This opens up the possibility for low cost anterior segment imaging in the clinical, research and teaching settings.

Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load.

PubMed

Dalbeth, Nicola; House, Meaghan E; Gamble, Gregory D; Horne, Anne; Pool, Bregina; Purvis, Lauren; Stewart, Angela; Merriman, Marilyn; Cadzow, Murray; Phipps-Green, Amanda; Merriman, Tony R

2013-11-01

SLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is associated with development of hyperuricaemia and gout. To determine whether genetic variation in SLC2A9 influences the acute serum urate response to a fructose load. Following an overnight fast, 76 healthy volunteers (25 Māori, 26 Pacific, 25 European Caucasian) drank a solution containing 64 g fructose. Serum and urine were obtained immediately before and then 30, 60, 120 and 180 min after ingestion. The SLC2A9 single nucleotide polymorphism (SNP) rs11942223 was genotyped and data were analysed based on the presence or absence of the gout protective minor allele (C). The rs11942223 C allele was present in 17 participants (22%). In the entire group, fructose intake led to an increase in serum urate, which peaked 60 min following fructose ingestion (analysis of variance p=0.006). The presence of the C allele was associated with an attenuated hyperuricaemic response (p(SNP)<0.0001) and increased fractional excretion of uric acid (FEUA) (p(SNP)<0.0001) following the fructose load. The effects of rs11942223 variants on serum urate and FEUA in response to fructose were present only in Caucasian ancestral subgroups but not in the Māori and Pacific ancestral subgroup. Variation in SLC2A9 influences acute serum urate and FEUA responses to a fructose load. SLC2A9 genotype may influence the development of gout on exposure to fructose-containing beverages, particularly in European Caucasian populations.

SLC25A13 Gene Analysis in Citrin Deficiency: Sixteen Novel Mutations in East Asian Patients, and the Mutation Distribution in a Large Pediatric Cohort in China

PubMed Central

Song, Yuan-Zong; Zhang, Zhan-Hui; Lin, Wei-Xia; Zhao, Xin-Jing; Deng, Mei; Ma, Yan-Li; Guo, Li; Chen, Feng-Ping; Long, Xiao-Ling; He, Xiang-Ling; Sunada, Yoshihide; Soneda, Shun; Nakatomi, Akiko; Dateki, Sumito; Ngu, Lock-Hock; Kobayashi, Keiko; Saheki, Takeyori

2013-01-01

Background The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet. Methods and Results By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ2 = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China. Conclusions This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients. PMID:24069319

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.

PubMed

Di Giacopo, Andrea; Rubio-Aliaga, Isabel; Cantone, Alessandra; Artunc, Ferruh; Rexhepaj, Rexhep; Frey-Wagner, Isabelle; Font-Llitjós, Mariona; Gehring, Nicole; Stange, Gerti; Jaenecke, Isabel; Mohebbi, Nilufar; Closs, Ellen I; Palacín, Manuel; Nunes, Virginia; Daniel, Hannelore; Lang, Florian; Capasso, Giovambattista; Wagner, Carsten A

2013-12-15

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise.

PubMed

Writzl, Karin; Maver, Ales; Kovačič, Lidija; Martinez-Valero, Paula; Contreras, Laura; Satrustegui, Jorgina; Castori, Marco; Faivre, Laurence; Lapunzina, Pablo; van Kuilenburg, André B P; Radović, Slobodanka; Thauvin-Robinet, Christel; Peterlin, Borut; Del Arco, Araceli; Hennekam, Raoul C

2017-11-02

A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Examining the Role of Components of Slc11a1 (Nramp1) in the Susceptibility of New Zealand Sea Lions (Phocarctos hookeri) to Disease

PubMed Central

Osborne, Amy J.; Pearson, John; Chilvers, B. Louise; Kennedy, Martin A.; Gemmell, Neil J.

2015-01-01

The New Zealand sea lion (NZSL, Phocarctos hookeri) is a Threatened marine mammal with a restricted distribution and a small, declining, population size. The species is susceptible to bacterial pathogens, having suffered three mass mortality events since 1998. Understanding the genetic factors linked to this susceptibility is important in mitigating population decline. The gene solute carrier family 11 member a1 (Slc11a1) plays an important role in mammalian resistance or susceptibility to a wide range of bacterial pathogens. At present, Slc11a1 has not been characterised in many taxa, and despite its known roles in mediating the effects of infectious disease agents, has not been examined as a candidate gene in susceptibility or resistance in any wild population of conservation concern. Here we examine components of Slc11a1 in NZSLs and identify: i) a polymorphic nucleotide in the promoter region; ii) putative shared transcription factor binding motifs between canids and NZSLs; and iii) a conserved polymorphic microsatellite in the first intron of Slc11a1, which together suggest conservation of Slc11a1 gene structure in otariids. At the promoter polymorphism, we demonstrate a shift away from normal allele frequency distributions and an increased likelihood of death from infectious causes with one allelic variant. While this increased likelihood is not statistically significant, lack of significance is potentially due to the complexity of genetic susceptibility to disease in wild populations. Our preliminary data highlight the potential significance of this gene in disease resistance in wild populations; further exploration of Slc11a1 will aid the understanding of susceptibility to infection in mammalian species of conservation significance. PMID:25874773

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

PubMed

Font, M A; Feliubadaló, L; Estivill, X; Nunes, V; Golomb, E; Kreiss, Y; Pras, E; Bisceglia, L; d'Adamo, A P; Zelante, L; Gasparini, P; Bassi, M T; George , A L; Manzoni, M; Riboni, M; Ballabio, A; Borsani, G; Reig, N; Fernández, E; Zorzano, A; Bertran, J; Palacín, M

2001-02-15

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

PubMed

Ehmke, Nadja; Graul-Neumann, Luitgard; Smorag, Lukasz; Koenig, Rainer; Segebrecht, Lara; Magoulas, Pilar; Scaglia, Fernando; Kilic, Esra; Hennig, Anna F; Adolphs, Nicolai; Saha, Namrata; Fauler, Beatrix; Kalscheuer, Vera M; Hennig, Friederike; Altmüller, Janine; Netzer, Christian; Thiele, Holger; Nürnberg, Peter; Yigit, Gökhan; Jäger, Marten; Hecht, Jochen; Krüger, Ulrike; Mielke, Thorsten; Krawitz, Peter M; Horn, Denise; Schuelke, Markus; Mundlos, Stefan; Bacino, Carlos A; Bonnen, Penelope E; Wollnik, Bernd; Fischer-Zirnsak, Björn; Kornak, Uwe

2017-11-02

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P i carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H 2 O 2 ). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H 2 O 2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P i transport to the development of skeletal and connective tissue. Copyright © 2017 American Society of Human Genetics. All rights reserved.

Survey of beam instrumentation used in SLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ecklund, S.D.

A survey of beam instruments used at SLAC in the SLC machine is presented. The basic utility and operation of each device is briefly described. The various beam instruments used at the Stanford Linear Collider (SLC), can be classified by the function they perform. Beam intensity, position and size are typical of the parameters of beam which are measured. Each type of parameter is important for adjusting or tuning the machine in order to achieve optimum performance. 39 refs.

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

PubMed Central

Taslimifar, Mehdi; Oparija, Lalita; Verrey, Francois; Kurtcuoglu, Vartan; Olgac, Ufuk; Makrides, Victoria

2017-01-01

Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity. PMID:28091567

Haplotypes in SLC24A5 Gene as Ancestry Informative Markers in Different Populations

PubMed Central

Giardina, Emiliano; Pietrangeli, Ilenia; Martínez-Labarga, Cristina; Martone, Claudia; de Angelis, Flavio; Spinella, Aldo; De Stefano, Gianfranco; Rickards, Olga; Novelli, Giuseppe

2008-01-01

Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator’s ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population. PMID:19440451

Could Hypoxia increase the prevalence of thrombotic complications in Polycythemia Vera?

PubMed Central

Zangari, Maurizio; Tolomelli, Giulia; Lee, Jasmine CH; Stein, Brady L.; Hickman, Kimberly; Swierczek, Sabina; Kelley, Todd W.; Berno, Tamara; Moliterno, Alison R.; Spivak, Jerry L.; Gordeuk, Victor R.; Prchal, Josef

2013-01-01

Background Thromboses represent a major cause of morbidity and mortality in Polycythemia Vera (PV) but the contributing mechanisms are not fully described. Patients and methods To evaluate whether environmental conditions such as altitude/hypoxia could impact thromboses history, we retrospectively analyzed thrombosis history in 71 PV patients living at an elevation of 5,000 feet or more in the SLC area (SLC) and 166 PV patients living near sea level in the Baltimore area (BLM). The SLC cohort was older with a longer disease duration. No significant differences in type of anticoagulation therapy or prothrombotic factors were present between the two cohorts. After adjusting for age, sex and disease duration, SLC patients experienced an estimated 3.9-fold increase in the odds of a history of thromboses compared to BLM patients (95% confidence interval 1.8-7.6; p = 0.0004). A history of cardiovascular event was present in 58% of the SLC patients compared to 27% of the BLM patients (p<0.0001). Before diagnosis thromboses occurred in 18% and 4% of the SLC and BLM groups respectively (p =0.003). No correlation between JAK2V617F allele burden and thrombosis was observed in this study. Conclusion This retrospective study suggests that even moderate hypoxia associated with 5,000 feet elevation should be considered as independent prothrombotic risk factor. This observation needs to be confirmed by prospective studies. PMID:23392352

Human SLC26A1 gene variants: a pilot study.

PubMed

Dawson, Paul A; Sim, Pearl; Mudge, David W; Cowley, David

2013-01-01

Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.

PubMed

Zaidi, Syed H E; Meyer, Sascha; Peltekova, Vanya D; Lindinger, Angelika; Teebi, Ahmad S; Faiyaz-Ul-Haque, Muhammad

2009-07-01

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient's DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.

Involvement of the Neutral Amino Acid Transporter SLC6A15 and Leucine in Obesity-Related Phenotypes

PubMed Central

Drgonova, Jana; Jacobsson, Josefin A.; Han, Joan C.; Yanovski, Jack A.; Fredriksson, Robert; Marcus, Claude; Schiöth, Helgi B.; Uhl, George R.

2013-01-01

Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes. PMID:24023709

Lessons learned from the SLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phinney, N.

The SLAC Linear Collider (SLC) is the first example of an entirely new type of lepton collider. Many years of effort were required to develop the understanding and techniques needed to approach design luminosity. This paper discusses some of the key issues and problems encountered in producing a working linear collider. These include the polarized source, techniques for emittance preservation, extensive feedback systems, and refinements in beam optimization in the final focus. The SLC experience has been invaluable for testing concepts and developing designs for a future linear collider.

Relations between three dopaminergic system genes, school attachment, and adolescent delinquency.

PubMed

Fine, Adam; Mahler, Alissa; Simmons, Cortney; Chen, Chuansheng; Moyzis, Robert; Cauffman, Elizabeth

2016-11-01

Both environmental factors and genetic variation, particularly in genes responsible for the dopaminergic system such as DRD4, DRD2, and DAT1 (SLC6A3), affect adolescent delinquency. The school context, despite its developmental importance, has been overlooked in gene-environment research. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (NICHD ECCYD), this study examined key interactions between school attachment and (a) each of the DRD4, DRD2, and DAT1 (SLC6A3) genotypes; and (b) a polygenic score. Results indicate that there is a main effect of school attachment, unlike genetic variation, on delinquency. Interestingly, there are important interactive effects of school attachment and dopaminergic genotypes on delinquency. Carriers of the DRD2-A1 allele were differentially affected by both positive and negative school environments, whereas DAT1-10R carriers fared the same as 9R homozygotes in poorer and moderate school environments, but fared disproportionately better in more positive environments. Contrary to expectations, youth without the DRD4-7R allele were particularly affected by the school environment. These findings contribute to the literature considering the roles of both context and genes in delinquency research, and inform our understanding of the individual-level traits that influence sensitivity to particular contexts. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

The AIA Solar Learning Center: Taking Inquiry-based EPO Online

NASA Astrophysics Data System (ADS)

Wills-Davey, Meredith; Attrill, G. D. R.; Engell, A.

2009-05-01

The observations of the Atmospheric Imaging Assembly aboard the Solar Dynamics Observatory (SDO-AIA) are expected to be groundbreaking within the field of heliophysics. To properly promote and explain the data produced by AIA, it is important that an innovative EPO effort be put forth. This has led to the development of "The AIA Solar Learning Center” (SLC), an inquiry-based educational website geared towards teaching about AIA and the Sun in general. The goal of the SLC is to provide K-12 students, teachers, parents, and homeschoolers with information and education about the Sun, primarily through hands-on activity modules that explain different aspects of our nearest star and the methods of observing it. While each module ultimately aims to impart information about the Sun or some related physical process, the activities also range across a host of different disciplines, including geology, chemistry, history, music, and art. In order to make the content applicable and accessible, activities are tailored to multiple difficulty levels, catering to different age groups. There is also a strong push towards facilitating teachers; activities are designed to fulfill specific teaching standards, and a host of additional teaching material is provided, including lesson plans and powerpoint presentations. Ultimately, the SLC aims to make science and the Sun inviting and accessible. The "Meet the Scientists” page will provide pictures and personal bios of participating scientists. Students will have the opportunity to interactively ask solar-related questions. There is even a host of lighter fare, such as a solar music playlist and links to relevant Facebook pages.

Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.

PubMed

Mammen, Cherry; Rupps, Rosemarie; Trnka, Peter; Boerkoel, Cornelius F

2012-02-01

We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

The pre-B cell receptor: turning autoreactivity into self-defense.

PubMed

Vettermann, Christian; Jäck, Hans-Martin

2010-05-01

The first step in establishing the antibody repertoire in humans and mice is the rearrangement of immunoglobulin heavy chain (HC) genes in early B lineage cells. These cells then assemble microHCs with surrogate light chains (SLC) into a pre-B cell receptor (pre-BCR). We propose that the pre-BCR has evolved from an ancient autoreactive BCR, since the SLC is an autoreactive entity that binds to the pre-BCR itself and to other self-antigens. Abrogation of autoreactivity in the SLC diminishes pre-BCR signaling and impairs the clonal expansion of pre-B cells producing functional microHCs. Since SLC expression is restricted to pre-B cells, the autoreactivity encoded by the pre-BCR can be utilized to pre-select the antibody repertoire, while simultaneously avoiding the formation of autoreactive B lymphocytes. Copyright 2010 Elsevier Ltd. All rights reserved.

An evaluation of gap-filled Landsat SLC-off imagery for wildland fire burn severity mapping

USGS Publications Warehouse

Howard, Stephen M.; Lacasse, James M.

2004-01-01

n May 31, 2003 unusual artifacts appeared within image data collected by the Enhanced Thematic Mapper plus (ETM+) instrument on-board the Landsat 7 spacecraft. The U.S. Geological Survey (USGS), with the support of NASA, has been working to find a means of compensating for the data gaps that result from a failure of the instrument’s scan line corrector (SLC). The SLC is an electromechanical device that compensates for the forward motion of the spacecraft by modifying the instrument’s optical path. The problem is likely due to a mechanical failure of the device for which there is no redundancy and that cannot be repaired or coaxed back into service. Further information regarding Landsat 7 and the SLC failure can be found at the Landsat Project home page (http://landsat7.usgs.gov).

SLC6A4 expression and anti-proliferative responses to serotonin transporter ligands chlomipramine and fluoxetine in primary B-cell malignancies.

PubMed

Chamba, Anita; Holder, Michelle J; Jarrett, Ruth F; Shield, Lesley; Toellner, Kai M; Drayson, Mark T; Barnes, Nicholas M; Gordon, John

2010-08-01

B-cell lines of diverse neoplastic origin express the serotonin transporter (SERT/SLC6A4) and growth arrest in response to SERT-ligands, including the antidepressants chlomipramine and fluoxetine. Here we detail SLC6A4 transcript (Q-PCR) and protein (FACS) expression in primary cells from patients with: chronic lymphocytic leukaemia; mantle cell lymphoma; follicular lymphoma; Burkitt's lymphoma; and diffuse large B-cell lymphoma. The ability of the SERT-binding antidepressants to impact the growth of these cells when sustained on CD154-transfected fibroblasts was also determined. The results reveal a broad spectrum of primary B-cell malignancies expressing SLC6A4 with a proportion additionally displaying growth arrest on SERT-ligand exposure. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations.

PubMed

Zhang, X Y; Geng, T T; Liu, L J; Yuan, D Y; Feng, T; Kang, L L; Jin, T B; Chen, C

2015-08-19

Current evidence suggests that heredity and metabolic syndrome contribute to gout progression. SLC2A9 and ZNF518B may play a role in gout progression in different populations, but no studies have focused on the Tibetan Chinese population. In this study, we determined whether variations in these 2 genes were correlated with gout-related indices in Chinese-Tibetan gout patients. We detected 6 single nucleotide polymorphisms in SLC2A9 and ZNF518B in 319 Chinese Tibetan gout patients. One-way analysis of variance was used to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators. Polymorphisms in SLC2A9 and ZNF518B affected multiple risk factors related to gout development. Significant differences in serum triglyceride levels and high-density lipoprotein-cholesterol level were detected between different genotypic groups with SLC2A9 polymorphisms rs13129697 (P = 0.022), rs4447863 (P = 0.018), and rs1014290 (P = 0.045). Similarly in ZNF518B, rs3217 (P = 0.016) and rs10016022 (P = 0.046) were associated with high creatinine and glucose levels, respectively. This study is the first to investigate and identify positive correlations between SLC2A9 and ZNF518B gene polymorphisms and metabolic indices in Tibetan gout patients. We found significant evidence indicating that genetic polymorphisms affect gout-related factors in Chinese Tibetan populations.

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes

PubMed Central

Su, Linlin; Zhang, Yufei; Cheng, Yan C.; Lee, Will M.; Ye, Keping; Hu, Dahai

2015-01-01

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive. PMID:26537751

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes.

PubMed

Su, Linlin; Zhang, Yufei; Cheng, Yan C; Lee, Will M; Ye, Keping; Hu, Dahai

2015-11-05

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive.

Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

PubMed Central

Iqbal, Zafar; Willemsen, Marjolein H.; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M.; Vulto-van Silfhout, Anneke T.; Vissers, Lisenka E.L.M.; de Brouwer, Arjan P.M.; Marouillat, Sylviane; Wienker, Thomas F.; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-01-01

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. PMID:25704603

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency.

PubMed

Simm, Franziska; Griesbeck, Anne; Choukair, Daniela; Weiß, Birgit; Paramasivam, Nagarajan; Klammt, Jürgen; Schlesner, Matthias; Wiemann, Stefan; Martinez, Cristina; Hoffmann, Georg F; Pfäffle, Roland W; Bettendorf, Markus; Rappold, Gudrun A

2017-10-26

PurposeCombined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.MethodsTo identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed.ResultsWe discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.ConclusionThese data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.Genetics in Medicine advance online publication, 26 October 2017; doi:10.1038/gim.2017.165.

The SLC3 and SLC7 families of amino acid transporters.

PubMed

Fotiadis, Dimitrios; Kanai, Yoshikatsu; Palacín, Manuel

2013-01-01

Amino acids are necessary for all living cells and organisms. Specialized transporters mediate the transfer of amino acids across plasma membranes. Malfunction of these proteins can affect whole-body homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of amino acid transporters. The SLC7 family is divided into two subfamilies, the cationic amino acid transporters (CATs), and the L-type amino acid transporters (LATs). The latter are the light or catalytic subunits of the heteromeric amino acid transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic amino acids. In certain cells, CATs play an important role in the delivery of L-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited aminoacidurias, cystinuria and lysinuric protein intolerance. Copyright © 2012 Elsevier Ltd. All rights reserved.

Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

PubMed Central

Tuschl, Karin; Clayton, Peter T.; Gospe, Sidney M.; Gulab, Shamshad; Ibrahim, Shahnaz; Singhi, Pratibha; Aulakh, Roosy; Ribeiro, Reinaldo T.; Barsottini, Orlando G.; Zaki, Maha S.; Del Rosario, Maria Luz; Dyack, Sarah; Price, Victoria; Rideout, Andrea; Gordon, Kevin; Wevers, Ron A.; “Kling” Chong, W.K.; Mills, Philippa B.

2012-01-01

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs∗17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes. PMID:22341972

Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome

PubMed Central

Mohammadi, Mojgan; Tahmasebi Abdar, Hossein; Mollaei, Hamid Reza; Hajghani, Hossein; Baneshi, Mohammad Reza; Hayatbakhsh, Mohammad Mahdi

2017-01-01

BACKGROUND Irritable bowel syndrome (IBS) is a digestive system disorder with an unknown etiology. Serotonin has a key role in the secretion and motility of the intestine. Polymorphism in serotonin re-uptake transporter (SERT or SLC6A4) gene may have a functional role in the gut of patients with IBS. The aims of the present study were to investigate the association between SLC6A4 gene polymorphism and IBS and to detect the correlation between rectal serotonin levels and IBS sub-types. METHODS SLC6A4 gene polymorphism in 131 patients with IBS and 211 healthy controls were analysed using the quantitative polymerase chain reaction high-resolution melting (qPCR-HRM) curve technique. Serotonin was measured in rectal biopsies of patients with IBS using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS The patients were categorized into three groups: IBS with diarrhoea (IBS-D): 70 patients, IBS with constipation (IBS-C): 18 patients, and IBS with mixed symptoms (IBS-M): 43 patients. The frequency of SLC6A4 s/s and l/s genotypes was significantly higher in IBS-C than IBS-D, IBS-M, and controls (p=0.036). Serotonin levels were similar in IBS sub-types. CONCLUSION SLC6A4 polymorphism is a possible candidate gene associated with the pathogenesis of IBS-C. Although serotonin levels did not differ in rectal biopsies of IBS sub-types, further investigation is recommended. PMID:28316763

Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis.

PubMed

Lu, Ya-Jie; Yao, Jun; Wei, Qin-Jun; Xing, Guang-Qian; Cao, Xin

2015-12-01

Many SLC26A4 mutations have been identified in patients with nonsyndromic enlarged vestibular aqueduct (EVA). However, the roles of SLC26A4 genotypes and phenotypes in hereditary deafness remain unexplained. This study aims to perform a meta-analysis based on the PRISMA statement to evaluate the diagnostic value of SLC26A4 mutant alleles and their correlations with multiethnic hearing phenotypes in EVA patients. The systematic literature search of the PubMed, Wiley Online Library, EMBASE, Web of Science, and Science Direct databases was conducted in English for articles published before July 15, 2015. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (ORs) with 95% confidence interval (CI). Twenty-five eligible studies involved 2294 cases with EVA data. A total of 272 SLC26A4 variations were found in deafness with EVA and 26 mutations of SCL26A4 had higher frequency. The overall OR was 646.71 (95% CI: 383.30-1091.15, P = 0.000). A total of 22 mutants were considered statistically significant in all ethnicities (ORs >1, P < 0.05). In particular, 8 mutants were specificity of EVA phenotypes in mutations of SLC26A4 for Asia deafness populations (ORs >1, P < 0.05), 4 mutants for Europe and North America (ORs >1, P < 0.05), and the IVS7-2A>G mutations in SLC26A4 were found to have the highest frequency in deafness individuals with EVA phenotype (62.42%). Moreover, subgroups for studies limited to cases with EVA phenotype, 11 mutants relevant risks (RRs) were P < 0.05, especially for IVS7-2A>G bi-allelic mutants assayed in a deafness population (RR = 0.880, P = 0.000). Diagnostic accuracy of SLC26A4 mutation results also identified the significant association of IVS7-2A>G (AUC = 0.99, 95% CI: 0.97-0.99) and p.H723R (AUC = 0.99, 95% CI: 0.98-1.00) detecting deafness with EVA. To conclude, the IVS7-2A>G and H723R in SLC26A4 present a significant predicting value and discriminatory ability for clinical use on diagnosis of EVA within a deafness population.

Mutations in SLC2A2 Gene Reveal hGLUT2 Function in Pancreatic β Cell Development*

PubMed Central

Michau, Aurélien; Guillemain, Ghislaine; Grosfeld, Alexandra; Vuillaumier-Barrot, Sandrine; Grand, Teddy; Keck, Mathilde; L'Hoste, Sébastien; Chateau, Danielle; Serradas, Patricia; Teulon, Jacques; De Lonlay, Pascale; Scharfmann, Raphaël; Brot-Laroche, Edith; Leturque, Armelle; Le Gall, Maude

2013-01-01

The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and β cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single-nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced β cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic β cell development and insulin secretion. PMID:23986439

Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family.

PubMed

Myles-Worsley, Marina; Tiobech, Josepha; Browning, Sharon R; Korn, Jeremy; Goodman, Sarah; Gentile, Karen; Melhem, Nadine; Byerley, William; Faraone, Stephen V; Middleton, Frank A

2013-03-01

Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+)/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. Copyright © 2013 Wiley Periodicals, Inc.

Isoflavone genistein inhibits estrogen-induced chloride and bicarbonate secretory mechanisms in the uterus in rats.

PubMed

Chinigarzadeh, Asma; Karim, Kamarulzaman; Muniandy, Sekaran; Salleh, Naguib

2017-04-01

We hypothesized that genistein could affect the chloride (Cl - ) and bicarbonate (HCO 3 - ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl - and HCO 3 - concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl - /HCO 3 - exchanger (SLC26a6), Na + /HCO 3 - cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl - and HCO 3 - concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility. © 2016 Wiley Periodicals, Inc.

L-Theanine Administration Modulates the Absorption of Dietary Nutrients and Expression of Transporters and Receptors in the Intestinal Mucosa of Rats.

PubMed

Yan, Qiongxian; Tong, Haiou; Tang, Shaoxun; Tan, Zhiliang; Han, Xuefeng; Zhou, Chuanshe

2017-01-01

L-theanine has various advantageous functions for human health; whether or not it could mediate the nutrients absorption is unknown yet. The effects of L-theanine on intestinal nutrients absorption were investigated using rats ingesting L-theanine solution (0, 50, 200, and 400 mg/kg body weight) per day for two weeks. The decline of insulin secretion and glucose concentration in the serum was observed by L-theanine. Urea and high-density lipoprotein were also reduced by 50 mg/kg L-theanine. Jejunal and ileac basic amino acids transporters SLC7a1 and SLC7a9 , neutral SLC1a5 and SLC16a10 , and acidic SLC1a1 expression were upregulated. The expression of intestinal SGLT3 and GLUT5 responsible for carbohydrates uptake and GPR120 and FABP2 associated with fatty acids transport were inhibited. These results indicated that L-theanine could inhibit the glucose uptake by downregulating the related gene expression in the small intestine of rats. Intestinal gene expression of transporters responding to amino acids absorption was stimulated by L-theanine administration.

Interactions Between Serotonin Transporter Gene Haplotypes and Quality of Mothers’ Parenting Predict the Development of Children’s Noncompliance

PubMed Central

Sulik, Michael J.; Eisenberg, Nancy; Lemery-Chalfant, Kathryn; Spinrad, Tracy L.; Silva, Kassondra M.; Eggum, Natalie D.; Betkowski, Jennifer A.; Kupfer, Anne; Smith, Cynthia L.; Gaertner, Bridget; Stover, Daryn A.; Verrelli, Brian C.

2012-01-01

The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children’s (N = 138) noncompliance and aggression from age 18 –54 months. Quality of mothers’ parenting behavior was observed when children were 18 months old, and nonparental caregivers’ reports of noncompliance and aggression were collected annually from 18 to 54 months of age. Quality of early parenting was negatively related to the slope of noncompliance only for children with the LPR-S/STin2-10 haplotype and to 18-month noncompliance only for children with haplotypes that did not include LPR-S. The findings support the notion that SLC6A4 haplotypes index differential susceptibility to variability in parenting quality, with certain haplotypes showing greater reactivity to both supportive and unsupportive environments. These different genetic backgrounds likely reflect an evolutionary response to variation in the parenting environment. PMID:22059451

New central drift chamber for the MARK II at SLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bartelt, J.E.

A new central drift chamber has been constructed for the Mark II detector for use at the new SLAC Linear Collider (SLC). The design of the chamber is based on a multi-sense-wire cell of the jet chamber type. In addition to drift-time measurements, pulse-height measurements from the sense wires provide electron-hadron separation by dE/dx. The chamber has been tested in operation at PEP before its move to the SLC. The design and construction are described, and measurements from the new chamber are presented.

Regulation of Facilitative Glucose Transporters and AKT/MAPK/PRKAA Signaling via Estradiol and Progesterone in the Mouse Uterine Epithelium1

PubMed Central

Kim, Sung Tae; Moley, Kelle H.

2009-01-01

Adequate uterine glucose metabolism is an essential part of embryo implantation and the development of an adequate utero-fetal environment. However, expression of facilitative glucose transporters (GLUTs [solute transporter family SLC2A]) and AKT/MAPK/PRKAA (PRKAA) signaling has not been described in the mouse uterine cells, to our knowledge. The objective of this study was to determine the hormonal regulation of SLC2A protein expression and AKT/MAPK/PRKAA signaling in the mouse uterine epithelial cells during estrous cycles and peri-implantation periods. SLC2As 1, 4, 8, and 9B were highly expressed in the luminal and glandular epithelia of estrous stage. In metestrous and diestrous stages, expression of SLC2As 1, 4, 8, and 9B was lower than that in proestrous stage. Levels of activated phospho-AKT (p-AKT), p-MAPK3, and p-MAPK1 also varied during the estrous cycle. Estrogen and progesterone injection in an ovariectomized mouse (delayed implantation model) resulted in a decrease and an increase, respectively, in expression of GLUTs in the luminal epithelial cells of the uterus. The expression of SLC2A1, SLC2A8, SLC2A9B, p-AKT, p-MAPK3/1, and p-PRKAA was increased in the decidual region of the implantation sites and was significantly increased in the uterus of activated implantation. Using an artificial decidualization mouse model, it was also demonstrated that expression of the same GLUTs, p-MAPK3/1, and p-PRKAA was dramatically higher in the decidualized uteri than that in the control uteri. These results suggest that steroid hormones regulate expression of uterine epithelial GLUTs possibly through AKT/MAPK/PRKAA signaling pathways and that glucose utilization may have an important role in decidualization and possibly in the maintenance of pregnancy. PMID:19208550

Evaluation of Landsat-7 SLC-off image products for forest change detection

USGS Publications Warehouse

Wulder, Michael A.; Ortlepp, Stephanie M.; White, Joanne C.; Maxwell, Susan

2008-01-01

Since July 2003, Landsat-7 ETM+ has been operating without the scan line corrector (SLC), which compensates for the forward motion of the satellite in the imagery acquired. Data collected in SLC-off mode have gaps in a systematic wedge-shaped pattern outside of the central 22 km swath of the imagery; however, the spatial and spectral quality of the remaining portions of the imagery are not diminished. To explore the continued use of Landsat-7 ETM+ SLC-off imagery to characterize change in forested environments, we compare the change detection results generated from a reference image pair (a 1999 Landsat-7 ETM+ image and a 2003 Landsat-5 TM image) with change detection results generated from the same 1999 Landsat-7 ETM+ image coupled with three different 2003 Landsat-7 SLC-off products: unremediated SLC-off (i.e., with gaps); histogram-based gap-filled; and segment-based gap-filled. The results are compared on both a pixel and polygon basis; on a pixel basis, the unremediated SLC-off product missed 35% of the change identified by the reference data, and the histogram- and segment-based gap-filled products missed 23% and 21% of the change, respectively. When using forest inventory polygons as a context for change (to reduce commission error), the amount of change missed was 31%, 14%, and 12% for the each of the unremediated, histogram-based gap-filled, and segment-based gap-filled products, respectively. Our results indicate that over the time period considered, and given the types and spatial distribution of change events within our study area, the gap-filled products can provide a useful data source for change detection in forested environments. The selection of which product to use is, however, very dependent on the nature of the application and the spatial configuration of change events. ?? 2008 Government of Canada.

Deletions at SLC18A1 increased the risk of CRC and lower SLC18A1 expression associated with poor CRC outcome.

PubMed

Zhang, Dandan; Li, Zhenli; Xu, Xiaohong; Zhou, Dan; Tang, Shunli; Yin, Xiaoyang; Xu, Fangying; Li, Hui; Zhou, Yuan; Zhu, Tao; Deng, Hong; Zhang, Shuai; Huang, Qiong; Wang, Jing; Yin, Wei; Zhu, Yimin; Lai, Maode

2017-10-26

Copy number variations (CNVs) contribute to the development of colorectal cancer (CRC). We conducted a two-stage association study to identify CNV risk loci for CRC. We performed a gene-based rare CNV study on 694 sporadic CRC and 1641 controls using Illumina Human-OmniExpress-12v1.0 BeadChips, and further replicated in 934 CRC cases and 2680 controls for risk CNVs by using TaqMan Copy Number Assay. Tumor buddings, cancer cells in the center of primary tumor and normal intestinal epithelial cells were captured using laser capture microdissection (LCM) and were assayed using AffymetrixGeneChip® Human Genome U133 Plus 2.0 Array. In addition, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data were assessed for the effects of risk CNVs. We found that germline deletions affecting the last six exons of SLC18A1 significantly associated with CRC with a combined P value of 6.4 × 10-5 by a two-stage analysis. Both in TCGA CRC RNA seq dataset and GDS4382, SLC18A1 was significantly down regulated in CRC tissues than in paired normal tissues (N = 32 and 17 pairs, P = 0.004 and 0.009, respectively). In LCM samples, similar observations were obtained that the expression levels of SLC18A1 in the tumor buddings, cancer cells in the center of primary tumor, and stroma of both tumor budding and cancer cells were lower than normal intestinal epithelial and stromal cells (fold change = 0.17-0.62, 0.12-0.57 and 0.37-0.68, respectively). In summary, the germline deletions at SLC18A1 contributed to the development of CRC. The role of SLC18A1 required further exploration. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder.

PubMed

Merker, Sören; Reif, Andreas; Ziegler, Georg C; Weber, Heike; Mayer, Ute; Ehlis, Ann-Christine; Conzelmann, Annette; Johansson, Stefan; Müller-Reible, Clemens; Nanda, Indrajit; Haaf, Thomas; Ullmann, Reinhard; Romanos, Marcel; Fallgatter, Andreas J; Pauli, Paul; Strekalova, Tatyana; Jansch, Charline; Vasquez, Alejandro Arias; Haavik, Jan; Ribasés, Marta; Ramos-Quiroga, Josep Antoni; Buitelaar, Jan K; Franke, Barbara; Lesch, Klaus-Peter

2017-07-01

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome-wide screening approach for copy number variants (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory-inhibitory balance impacting both brain development and activity-dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for GLUT3 dysfunction in ADHD. Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EEG recordings during neurocognitive tasks, and ratings of food energy content. Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk. © 2017 Association for Child and Adolescent Mental Health.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

PubMed Central

Foley, A. Reghan; Menezes, Manoj P.; Pandraud, Amelie; Gonzalez, Michael A.; Al-Odaib, Ahmad; Abrams, Alexander J.; Sugano, Kumiko; Yonezawa, Atsushi; Manzur, Adnan Y.; Burns, Joshua; Hughes, Imelda; McCullagh, B. Gary; Jungbluth, Heinz; Lim, Ming J.; Lin, Jean-Pierre; Megarbane, Andre; Urtizberea, J. Andoni; Shah, Ayaz H.; Antony, Jayne; Webster, Richard; Broomfield, Alexander; Ng, Joanne; Mathew, Ann A.; O’Byrne, James J.; Forman, Eva; Scoto, Mariacristina; Prasad, Manish; O’Brien, Katherine; Olpin, Simon; Oppenheim, Marcus; Hargreaves, Iain; Land, John M.; Wang, Min X.; Carpenter, Kevin; Horvath, Rita; Straub, Volker; Lek, Monkol; Gold, Wendy; Farrell, Michael O.; Brandner, Sebastian; Phadke, Rahul; Matsubara, Kazuo; McGarvey, Michael L.; Scherer, Steven S.; Baxter, Peter S.; King, Mary D.; Clayton, Peter; Rahman, Shamima; Reilly, Mary M.; Ouvrier, Robert A.; Christodoulou, John; Züchner, Stephan; Muntoni, Francesco

2014-01-01

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms. PMID:24253200

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

PubMed

Foley, A Reghan; Menezes, Manoj P; Pandraud, Amelie; Gonzalez, Michael A; Al-Odaib, Ahmad; Abrams, Alexander J; Sugano, Kumiko; Yonezawa, Atsushi; Manzur, Adnan Y; Burns, Joshua; Hughes, Imelda; McCullagh, B Gary; Jungbluth, Heinz; Lim, Ming J; Lin, Jean-Pierre; Megarbane, Andre; Urtizberea, J Andoni; Shah, Ayaz H; Antony, Jayne; Webster, Richard; Broomfield, Alexander; Ng, Joanne; Mathew, Ann A; O'Byrne, James J; Forman, Eva; Scoto, Mariacristina; Prasad, Manish; O'Brien, Katherine; Olpin, Simon; Oppenheim, Marcus; Hargreaves, Iain; Land, John M; Wang, Min X; Carpenter, Kevin; Horvath, Rita; Straub, Volker; Lek, Monkol; Gold, Wendy; Farrell, Michael O; Brandner, Sebastian; Phadke, Rahul; Matsubara, Kazuo; McGarvey, Michael L; Scherer, Steven S; Baxter, Peter S; King, Mary D; Clayton, Peter; Rahman, Shamima; Reilly, Mary M; Ouvrier, Robert A; Christodoulou, John; Züchner, Stephan; Muntoni, Francesco; Houlden, Henry

2014-01-01

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

PubMed Central

Afshari, Parisa; Yao, Wei-Dong

2017-01-01

We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia. PMID:28886095

Expression Levels of KMT2C and SLC20A1 Identified by Information-theoretical Analysis Are Powerful Prognostic Biomarkers in Estrogen Receptor-positive Breast Cancer.

PubMed

Sato, Keiko; Akimoto, Kazunori

2017-06-01

In general, it has been considered that estrogen receptor-positive (ER + ) breast cancer has a good prognosis and is responsive to endocrine therapy. However, one third of patients with ER + breast cancer exhibit endocrine therapy resistance, and many patients develop recurrence and die 5 to 10 years after diagnosis. In ER +  breast cancer, a major problem is to distinguish those patients most likely to develop recurrence or metastatic disease within 10 years after diagnosis from those with a sufficiently good prognosis. We downloaded the messenger RNA expression data and the clinical information for 401 patients with ER +  breast cancer from the cBioPortal for Cancer Genomics. An information-theoretical approach was used to identify the prognostic factors for survival in patients with ER + breast cancer and to classify those patients according to the prognostic factors. The information-theoretical approach contributed to the identification of KMT2C and SLC20A1 as prognostic biomarkers in ER + breast cancer. We found that low KMT2C expression was associated with a poor outcome and high SLC20A1 expression was associated with a poor outcome. Both levels of KMT2C and SLC20A1 expression were significantly and strongly associated with the differentiation of survival. The 10-year survival rate for ER + patients with low KMT2C and high SLC20A1 expression was 0%. In contrast, for ER + patients with high KMT2C and low SLC20A1 expression, the 10-year survival rate was 86.78%. Our results strongly suggest that clinical examination of the expression of both KMT2C and SLC20A1 in ER + breast cancer will be very useful for the determination of prognosis and therapy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism.

PubMed

Šerý, Omar; Paclt, Ivo; Drtílková, Ivana; Theiner, Pavel; Kopečková, Marta; Zvolský, Petr; Balcar, Vladimir J

2015-06-11

ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.

6. VIEW OF SLC3W CONTROL ROOM (ROOM 105) FROM ITS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

6. VIEW OF SLC-3W CONTROL ROOM (ROOM 105) FROM ITS SOUTHEAST CORNER - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

83. DETAIL OF HONEYWELL AIRCONDITIONING CONTROLS IN SLC3E CONTROL ROOM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

83. DETAIL OF HONEYWELL AIR-CONDITIONING CONTROLS IN SLC-3E CONTROL ROOM - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

9. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: PLANS, SECTIONS, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

9. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: PLANS, SECTIONS, AND DETAILS, JANUARY 1993. - Cape Canaveral Air Station, Launch Complex 17, Facility 28425, East end of Lighthouse Road, Cape Canaveral, Brevard County, FL

8. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: ELEVATIONS AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: ELEVATIONS AND BUILDING SECTION, JULY 1992. - Cape Canaveral Air Station, Launch Complex 17, Facility 28425, East end of Lighthouse Road, Cape Canaveral, Brevard County, FL

Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family

PubMed Central

Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M.; Laederach, Juerg; Dutzler, Raimund

2017-01-01

Secondary active transporters of the SLC11/NRAMP family catalyse the uptake of iron and manganese into cells. These proteins are highly conserved across all kingdoms of life and thus likely share a common transport mechanism. Here we describe the structural and functional properties of the prokaryotic SLC11 transporter EcoDMT. Its crystal structure reveals a previously unknown outward-facing state of the protein family. In proteoliposomes EcoDMT mediates proton-coupled uptake of manganese at low micromolar concentrations. Mutants of residues in the transition-metal ion-binding site severely affect transport, whereas a mutation of a conserved histidine located near this site results in metal ion transport that appears uncoupled to proton transport. Combined with previous results, our study defines the conformational changes underlying transition-metal ion transport in the SLC11 family and it provides molecular insight to its coupling to protons. PMID:28059071

Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non‐syndromic corneal endothelial dystrophy

PubMed Central

Desir, Julie; Moya, Graciela; Reish, Orit; Van Regemorter, Nicole; Deconinck, Hilde; David, Karen L; Meire, Françoise M; Abramowicz, Marc J

2007-01-01

Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non‐syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. PMID:17220209

SLC4 family transporters in a marine diatom directly pump bicarbonate from seawater

PubMed Central

Nakajima, Kensuke; Tanaka, Atsuko; Matsuda, Yusuke

2013-01-01

Photosynthesis in marine diatoms is a vital fraction of global primary production empowered by CO2-concentrating mechanisms. Acquisition of HCO3− from seawater is a critical primary step of the CO2-concentrating mechanism, allowing marine photoautotrophic eukaryotes to overcome CO2 limitation in alkaline high-salinity water. However, little is known about molecular mechanisms governing this process. Here, we show the importance of a plasma membrane-type HCO3− transporter for CO2 acquisition in a marine diatom. Ten putative solute carrier (SLC) family HCO3− transporter genes were found in the genome of the marine pennate diatom Phaeodactylum tricornutum. Homologs also exist in marine centric species, Thalassiosira pseudonana, suggesting a general occurrence of SLC transporters in marine diatoms. Seven genes were found to encode putative mammalian-type SLC4 family transporters in P. tricornutum, and three of seven genes were specifically transcribed under low CO2 conditions. One of these gene products, PtSLC4-2, was localized at the plasmalemma and significantly stimulated both dissolved inorganic carbon (DIC) uptake and photosynthesis in P. tricornutum. DIC uptake by PtSLC4-2 was efficiently inhibited by an anion-exchanger inhibitor, 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, in a concentration-dependent manner and highly dependent on Na+ ions at concentrations over 100 mM. These results show that DIC influx into marine diatoms is directly driven at the plasmalemma by a specific HCO3− transporter with a significant halophilic nature. PMID:23297242

High rates of intestinal bicarbonate secretion in seawater tilapia (Oreochromis mossambicus).

PubMed

Ruiz-Jarabo, I; Gregório, S F; Gaetano, P; Trischitta, F; Fuentes, J

2017-05-01

Osmoregulation in fish is a complex process that requires the orchestrated cooperation of many tissues. In fish facing hyperosmotic environments, the intestinal absorption of some monovalent ions and the secretion of bicarbonate are key processes to favor water absorption. In the present study, we showed that bicarbonate levels in the intestinal fluid are several fold higher in seawater than in freshwater acclimated tilapia (Oreochromis mossambicus). In addition, we analyzed gene expression of the main molecular mechanisms involved in HCO 3 - movements i.e. slc26a6, slc26a3, slc4a4 and v-type H-ATPase sub C in the intestine of tilapia acclimated to both seawater and freshwater. Our results show an anterior/posterior functional regionalization of the intestine in tilapia in terms of expression patterns, which is affected by environmental salinity mostly in the anterior and mid intestine. Analysis of bicarbonate secretion using pH-Stat in tissues mounted in Ussing chambers reveals high rates of bicarbonate secretion in tilapia acclimated to seawater from anterior intestine to rectum ranging between ~900 and ~1700nmolHCO 3 - cm -2 h -1 . However, a relationship between the expression of slc26a6, slc26a3, slc4a4 and the rate of bicarbonate secretion seems to be compromised in the rectum. In this region, the low expression of the bicarbonate transporters could not explain the high bicarbonate secretion rates here described. However, we postulate that the elevated v-type H-ATPase mRNA expression in the rectum could be involved in this process. Copyright © 2017 Elsevier Inc. All rights reserved.

Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

PubMed

Iqbal, Zafar; Willemsen, Marjolein H; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Marouillat, Sylviane; Wienker, Thomas F; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-03-05

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Expression profiling of the solute carrier gene family in chicken intestine from the late embryonic to early post-hatch stages.

PubMed

Li, H; Gilbert, E R; Zhang, Y; Crasta, O; Emmerson, D; Webb, K E; Wong, E A

2008-08-01

Intestinal development during late embryogenesis and early post-hatch has a long-term influence on digestive and absorptive capacity in chickens. The objective of this research was to obtain a global view of intestinal solute carrier (SLC) gene family member expression from late embryogenesis until 2 weeks post-hatch with a focus on SLC genes involved in uptake of sugars and amino acids. Small intestine samples from male chicks were collected on embryonic days 18 (E18) and 20 (E20), day of hatch and days 1, 3, 7 and 14 post-hatch. The expression profiles of 162 SLC genes belonging to 41 SLC families were determined using Affymetrix chicken genome microarrays. The majority of SLC genes showed little or no difference in level of expression during E18-D14. A number of well-known intestinal transporters were upregulated between E18 and D14 including the amino acid transporters rBAT, y(+)LAT-2 and EAAT3, the peptide transporter PepT1 and the sugar transporters SGLT1, GLUT2 and GLUT5. The amino acid transporters CAT-1 and CAT-2 were downregulated. In addition, several glucose and amino acid transporters that are novel to our understanding of nutrient absorption in the chicken intestine were discovered through the arrays (SGLT6, SNAT1, SNAT2 and AST). These results represent a comprehensive characterization of the expression profiles of the SLC family of genes at different stages of development in the chicken intestine and lay the ground work for future nutritional studies.

Teleost fish models in membrane transport research: the PEPT1(SLC15A1) H+–oligopeptide transporter as a case study

PubMed Central

Romano, Alessandro; Barca, Amilcare; Storelli, Carlo; Verri, Tiziano

2014-01-01

Human genes for passive, ion-coupled transporters and exchangers are included in the so-called solute carrier (SLC) gene series, to date consisting of 52 families and 398 genes. Teleost fish genes for SLC proteins have also been described in the last two decades, and catalogued in preliminary SLC-like form in 50 families and at least 338 genes after systematic GenBank database mining (December 2010–March 2011). When the kinetic properties of the expressed proteins are studied in detail, teleost fish SLC transporters always reveal extraordinary ‘molecular diversity’ with respect to the mammalian counterparts, which reflects peculiar adaptation of the protein to the physiology of the species and/or to the environment where the species lives. In the case of the H+–oligopeptide transporter PEPT1(SLC15A1), comparative analysis of diverse teleost fish orthologs has shown that the protein may exhibit very eccentric properties in terms of pH dependence (e.g. the adaptation of zebrafish PEPT1 to alkaline pH), temperature dependence (e.g. the adaptation of icefish PEPT1 to sub-zero temperatures) and/or substrate specificity (e.g. the species-specificity of PEPT1 for the uptake of l-lysine-containing peptides). The revelation of such peculiarities is providing new contributions to the discussion on PEPT1 in both basic (e.g. molecular structure–function analyses) and applied research (e.g. optimizing diets to enhance growth of commercially valuable fish). PMID:23981715

Novel synthesis of nanocomposite for the extraction of Sildenafil Citrate (Viagra) from water and urine samples: Process screening and optimization.

PubMed

Asfaram, Arash; Ghaedi, Mehrorang; Purkait, Mihir Kumar

2017-09-01

A sensitive analytical method is investigated to concentrate and determine trace level of Sildenafil Citrate (SLC) present in water and urine samples. The method is based on a sample treatment using dispersive solid-phase micro-extraction (DSPME) with laboratory-made Mn@ CuS/ZnS nanocomposite loaded on activated carbon (Mn@ CuS/ZnS-NCs-AC) as a sorbent for the target analyte. The efficiency was enhanced by ultrasound-assisted (UA) with dispersive nanocomposite solid-phase micro-extraction (UA-DNSPME). Four significant variables affecting SLC recovery like; pH, eluent volume, sonication time and adsorbent mass were selected by the Plackett-Burman design (PBD) experiments. These selected factors were optimized by the central composite design (CCD) to maximize extraction of SLC. The results exhibited that the optimum conditions for maximizing extraction of SLC were 6.0 pH, 300μL eluent (acetonitrile) volume, 10mg of adsorbent and 6min sonication time. Under optimized conditions, virtuous linearity of SLC was ranged from 30 to 4000ngmL -1 with R 2 of 0.99. The limit of detection (LOD) was 2.50ngmL -1 and the recoveries at two spiked levels were ranged from 97.37 to 103.21% with the relative standard deviation (RSD) less than 4.50% (n=15). The enhancement factor (EF) was 81.91. The results show that the combination UAE with DNSPME is a suitable method for the determination of SLC in water and urine samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Glutamine Transporters in Mammalian Cells and Their Functions in Physiology and Cancer

PubMed Central

Bhutia, Yangzom D.; Ganapathy, Vadivel

2016-01-01

The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action. PMID:26724577

Mutation Analysis of SLC26A4 for Pendred Syndrome and Nonsyndromic Hearing Loss by High-Resolution Melting

PubMed Central

Chen, Neng; Tranebjærg, Lisbeth; Rendtorff, Nanna Dahl; Schrijver, Iris

2011-01-01

Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic heterogeneity, however, necessitates analysis of all exons and splice sites to identify mutations for individual patients. Although Sanger sequencing is the gold standard for mutation detection, screening methods supplemented with targeted sequencing can provide a cost-effective alternative. One such method, denaturing high-performance liquid chromatography, was developed for clinical mutation detection in SLC26A4. However, this method inherently cannot distinguish homozygous changes from wild-type sequences. High-resolution melting (HRM), on the other hand, can detect heterozygous and homozygous changes cost-effectively, without any post-PCR modifications. We developed a closed-tube HRM mutation detection method specific for SLC26A4 that can be used in the clinical diagnostic setting. Twenty-eight primer pairs were designed to cover all 21 SLC26A4 exons and splice junction sequences. Using the resulting amplicons, initial HRM analysis detected all 45 variants previously identified by sequencing. Subsequently, a 384-well plate format was designed for up to three patient samples per run. Blinded HRM testing on these plates of patient samples collected over 1 year in a clinical diagnostic laboratory accurately detected all variants identified by sequencing. In conclusion, HRM with targeted sequencing is a reliable, simple, and cost-effective method for SLC26A4 mutation screening and detection. PMID:21704276

Molecular cloning, mRNA expression and tissue distribution analysis of Slc7a11 gene in alpaca (Lama paco) skins associated with different coat colors.

PubMed

Tian, Xue; Meng, Xiaolin; Wang, Liangyan; Song, Yunfei; Zhang, Danli; Ji, Yuankai; Li, Xuejun; Dong, Changsheng

2015-01-25

Slc7a11 encoding solute carrier family 7 member 11 (amionic amino acid transporter light chain, xCT), has been identified to be a critical genetic regulator of pheomelanin synthesis in hair and melanocytes. To better understand the molecular characterization of Slc7a11 and the expression patterns in skin of white versus brown alpaca (lama paco), we cloned the full length coding sequence (CDS) of alpaca Slc7a11 gene and analyzed the expression patterns using Real Time PCR, Western blotting and immunohistochemistry. The full length CDS of 1512bp encodes a 503 amino acid polypeptide. Sequence analysis showed that alpaca xCT contains 12 transmembrane regions consistent with the highly conserved amino acid permease (AA_permease_2) domain similar to other vertebrates. Sequence alignment and phylogenetic analysis revealed that alpaca xCT had the highest identity and shared the same branch with Camelus ferus. Real Time PCR and Western blotting suggested that xCT was expressed at significantly high levels in brown alpaca skin, and transcripts and protein possessed the same expression pattern in white and brown alpaca skins. Additionally, immunohistochemical analysis further demonstrated that xCT staining was robustly increased in the matrix and root sheath of brown alpaca skin compared with that of white. These results suggest that Slc7a11 functions in alpaca coat color regulation and offer essential information for further exploration on the role of Slc7a11 in melanogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

11. CENTRAL ATLAS CONTROL CONSOLE IN SLC3W CONTROL ROOM. COMMUNICATIONS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

11. CENTRAL ATLAS CONTROL CONSOLE IN SLC-3W CONTROL ROOM. COMMUNICATIONS HEADSETS IN FOREGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Synthesis/literature review for determining structural layer coefficients (SLC) of bases.

DOT National Transportation Integrated Search

2014-12-01

FDOTs current method of determining a base material structural layer coefficient (SLC) is detailed in the : Materials Manual, Chapter 2.1, Structural Layer Coefficients for Flexible Pavement Base Materials. : Currently, any new base material not a...

Studying Interactions of Drugs with Cell Membrane Nutrient Transporters: New Frontiers of Proteoliposome Nanotechnology.

PubMed

Scalise, Mariafrancesca; Galluccio, Michele; Pochini, Lorena; Console, Lara; Barile, Maria; Giangregorio, Nicola; Tonazzi, Annamaria; Indiveri, Cesare

2017-01-01

Transport systems are hydrophobic proteins localized in cell membranes where they mediate transmembrane flow of nutrients, ions and any other compounds essential for cell metabolism. More than 400 transporters of the SoLuteCarrier (SLC) group are present in human cells. Transporters take contacts also with xenobiotics, thus mediating absorption and/or interaction with these exogenous compounds. Since drugs belong to xenobiotics, transporters gained interest also in drug discovery. Transporters differentially expressed in pathological conditions are exploited as drug targets. Among the methodologies for defining drug interactions, in silico ligand screening and intact cell transport assay were the most diffused, so far. The first is a predictive methodology based on docking chemicals to transporters. It presents limitations due to the small number of human transporter 3D structures that have to be constructed by homology modeling. Intact cells are used for testing effects of drugs and for validating predictions. The challenges of handling this very complex experimental system, are the interferences caused by other transporters and/or intracellular enzymes. Thus, methodologies with lower complexity are welcome. One of the most updated is the proteoliposome nanotechnology consisting in a cell mimicking phospholipid membrane in which a purified transporter is inserted. In this system, drug-transporter interaction can be studied defining kinetics and mechanisms. Several data have been obtained by proteoliposome nanotechnology. An overview of data obtained on the organic cation transporters OCTN1, OCTN2 and on the amino acid transporters ASCT2 and B0AT1 will be presented. Standardized procedures, expected to be pointed out, will enlarge the assay to High Throughput Screenings. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The D543N polymorphism of the SLC11A1/NRAMP1 gene is associated with treatment failure in male patients with pulmonary tuberculosis.

PubMed

Salinas-Delgado, Yvain; Galaviz-Hernández, Carlos; Toral, René García; Ávila Rejón, Carmen A; Reyes-Lopez, Miguel A; Martínez, Antonio Rojas; Martínez-Aguilar, Gerardo; Sosa-Macías, Martha

2015-09-01

Polymorphisms in SLC11A1/NRAMP1 have shown an important association with susceptibility to tuberculosis and progression to active disease. However, whether there is an association of these polymorphisms with treatment failure is unknown. The aim of this study was to determine the association of SLC11A1 polymorphisms with treatment failure in Mexican subjects with pulmonary tuberculosis. Thirty-three subjects with treatment failure were paired by age and body mass index with 33 patients who successfully completed treatment and were considered cured. We assessed the polymorphisms of SLC11A1 in the regions of D543N and INT4 via polymerase chain reaction real-time TaqMan® single nucleotide polymorphism (SNP) genotyping. We found that D543N (G/A genotype) was associated with treatment failure in patients with pulmonary tuberculosis [odds ratio (OR) 11.61, 95% confidence interval (CI) 3.66-36.78]. When adjusted by gender, this association remained significant in males (OR 11.09, 95% CI 3.46-35.51). In our male population, the presence of the D543N polymorphism of SLC11A1 is a risk factor for treatment failure. This finding should be confirmed in other populations.

Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.

PubMed

Mohamed, Miski; Ashikov, Angel; Guillard, Mailys; Robben, Joris H; Schmidt, Samuel; van den Heuvel, B; de Brouwer, Arjan P M; Gerardy-Schahn, Rita; Deen, Peter M T; Wevers, Ron A; Lefeber, Dirk J; Morava, Eva

2013-08-13

To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation. Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast. We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP-sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP-sialic acid in vitro. We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.

The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1.

PubMed

Bodoy, Susanna; Fotiadis, Dimitrios; Stoeger, Claudia; Kanai, Yoshikatsu; Palacín, Manuel

2013-01-01

The SLC43 family is composed of only three genes coding for the plasma membrane facilitator system l amino acid transporters LAT3 (SLC43A1; TC 2.A.1.44.1) and LAT4 (SLC43A2; TC 2.A.1.44.2), and the orphan protein EEG1 (SLC43A3; TC 2.A.1.44.3). Besides the known mechanism of transport of LAT3 and LAT4, their physiological roles still remain quite obscure. Morphants suggested a role of LAT3 in renal podocyte development in zebrafish. Expression in liver and skeletal muscle, and up-regulation by starvation suggest a role of LAT3 in the flux of branched-chain amino acids (BCAAs) from liver and skeletal muscle to the bloodstream. Finally, LAT3 is up-regulated in androgen-dependent cancers, suggesting a role in mTORC1 signaling in this type of tumors. In addition, LAT4 might contribute to the transfer of BCAAs from mother to fetus. Unfortunately, the EEG1 mouse model (EEG1(Y221∗)) described here has not yet offered a clue to the physiological role of this orphan protein. Copyright © 2012 Elsevier Ltd. All rights reserved.

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population.

PubMed

Kinnear, Craig J.; Niehaus, Dana J. H.; Moolman-Smook, Johanna C.; du Toit, Pieter L.; van Kradenberg, Jeanine; Weyers, Jakobus B.; Potgieter, Annemarie; Marais, Vanessa; Emsley, Robin A.; Knowles, James A.; Corfield, Valerie A.; Brink, Paul A.; Stein, Dan J.

2000-12-01

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.

Pregnancy rates after artificial insemination with cooled stallion spermatozoa either with or without single layer centrifugation.

PubMed

Morrell, J M; Richter, J; Martinsson, G; Stuhtmann, G; Hoogewijs, M; Roels, K; Dalin, A-M

2014-11-01

A successful outcome after artificial insemination with cooled semen is dependent on many factors, the sperm quality of the ejaculate being one. Previous studies have shown that spermatozoa with good motility, normal morphology, and good chromatin integrity can be selected by means of colloid centrifugation, particularly single layer centrifugation (SLC) using species-specific colloids. The purpose of the present study was to conduct an insemination trial with spermatozoa from "normal" ejaculates, i.e., from stallions with no known fertility problem, to determine whether the improvements in sperm quality seen in SLC-selected sperm samples compared with uncentrifuged controls in laboratory tests are reflected in an increased pregnancy rate after artificial insemination. In a multicentre study, SLC-selected sperm samples and uncentrifuged controls from eight stallions were inseminated into approximately 10 mares per treatment per stallion. Ultrasound examination was carried out approximately 16 days after insemination to detect an embryonic vesicle. The pregnancy rates per cycle were 45% for controls and 69% for SLC-selected sperm samples, which is statistically significant (P < 0.0018). Thus, the improvement in sperm quality reported previously for SLC-selected sperm samples is associated with an increase in pregnancy rate, even for ejaculates from stallions with no known fertility problem. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular evolution of the Slc15 family and its response to waterborne copper and mercury exposure in tilapia.

PubMed

Huang, Qiansheng; Vera Delgado, Juan Manuel; Seni Pinoargote, Oscar David; Llaguno, Ricardo Avellán

2015-06-01

The solute carrier 15 family (Slc15), also called oligopeptide transporter family (Pept), was well-known for its role in the cellular uptake of di/tripeptides and peptide-like molecules. Our understanding of Slc15 family has already been enlarged since the rapid increasing of genome information; however, efforts are still expected to reveal the diversification of the family in an evolutionary manner. In the study, the sequence information were collected and analyzed through eleven eukaryotic organism representatives, especially in fish species. Gene expansion was observed through the evolution of the family. Further study was carried out with the representative species-Nile tilapia (Oreochromis niloticus). Tissue expression profiles were compared among members of the Slc15 family. Generally, they were all highly expressed both in the intestine and stomach, however, different members possessed its special tissue expression pattern. The mRNA levels of all the members (except Slc15a4) decreased after fasting while refeeding could restore the expression level. The recovery ability was impaired after exposure to environmental relevant concentration of copper (Cu(2+), 160 nmol/L). By contrast, mercury (Hg(2+), 25 nmol/L) did not exert significant impact on the recovery ability. Copyright © 2015 Elsevier B.V. All rights reserved.

Association of polymorphisms in 5-HTT (SLC6A4) and MAOA genes with measures of obesity in young adults of Portuguese origin.

PubMed

Dias, Helena; Muc, Magdalena; Padez, Cristina; Manco, Licínio

2016-01-01

To investigate the association of polymorphisms in SLC6A4 and MAOA genes with overweight (including obesity). Young adults (n = 535) of Portuguese origin were genotyped for the SLC6A4 polymorphisms 5-HTTLPR and STin2 and a MAOA VNTR. BMI and body fat percentage were measured and a questionnaire was used to assess individual's sport practicing habits. In whole study sample, haplotype-based analysis revealed significant association with overweight/obesity for the individual 5-HTTLPR/Stin2 haplotype L10 (p = 0.04). In men, the MAOA 3R genotype was nominally associated with body fat (p = 0.04). In inactive individuals, overweight/obesity was found significantly associated with 5-HTTLPR L-allele (p = 0.01) and nominally associated with STin2 10-allele (p = 0.03). A significant association was also found testing for all haplotype effects (χ(2 )= 8.7; p = 0.03). We found some evidences for the association of SLC6A4 and MAOA genes with measures of obesity. Our results suggest physical inactivity accentuates the influence of SLC6A4 polymorphisms on obesity risk.

A missense mutation in solute carrier family 12, member 1 (SLC12A1) causes hydrallantois in Japanese Black cattle.

PubMed

Sasaki, Shinji; Hasegawa, Kiyotoshi; Higashi, Tomoko; Suzuki, Yutaka; Sugano, Sumio; Yasuda, Yasuaki; Sugimoto, Yoshikazu

2016-09-09

Hydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing. Shared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na(+)-K(+)-2Cl(-) in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na(+)-Cl(-) increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A). In this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na(+)-K(+)-2Cl(-) in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Disbalance of calcium regulation-related genes in broiler hearts induced by selenium deficiency.

PubMed

Zhang, Ziwei; Liu, Man; Guan, Zhenqiong; Yang, Jie; Liu, Zhonghua; Xu, Shiwen

2017-06-01

Dietary selenium (Se) deficiency may influence the calcium (Ca) homeostasis in broilers. Our objective was to investigate the effects of Se deficiency on Ca regulation-related genes in broiler hearts. In the present study, 1-day-old broilers were fed either a commercial diet (as control group) with 0.15 mg/kg Se or a Se-deficient diet (as L group) with 0.033 mg/kg Se for 35 days. We examined the mRNA expression levels of 15 Ca regulation-related genes (ITPR 1, ITPR 2, ITPR3, RyR2, RyR3, SERCA1s, SLC8A1, PMCA1, CACNA1S, TRPC1, TRPC3, stromal interacting molecule 1, ORAI1, calmodulin (CaLM) and calreticulin (CRT) in broiler hearts. Then, Kyoto Encyclopedia of Genes and Genomes analysis, protein-protein interactions (PPI) analysis and correlation analysis were performed to analyse the relationships between these genes. The results showed that the mRNA expression levels of ITPR 1, ITPR 2, RyR2, RyR3, SERCA1s, SLC8A1, PMCA1, CACNA1S, CaLM and CRT were generally decreased by Se deficiency, while mRNA expression levels of TRPC1, TRPC3, stromal interacting molecule 1, ORAI1 and ITPR3 were increased by Se deficiency. Kyoto Encyclopedia of Genes and Genomes and PPI analysis showed that these Ca regulation-related genes are involved in the Ca signalling pathway and a total of 15 PPIs with a combined score of >0.4 were obtained. In conclusion, the results demonstrated that Se deficiency might cause heart injury via modulating the Ca-related pathway genes, and then induce Ca 2+ overload in the heart of broilers.

Dietary catechins and procyanidins modulate zinc homeostasis in human HepG2 cells.

PubMed

Quesada, Isabel M; Bustos, Mario; Blay, Mayte; Pujadas, Gerard; Ardèvol, Anna; Salvadó, M Josepa; Bladé, Cinta; Arola, Lluís; Fernández-Larrea, Juan

2011-02-01

Catechins and their polymers procyanidins are health-promoting flavonoids found in edible vegetables and fruits. They act as antioxidants by scavenging reactive oxygen species and by chelating the redox-active metals iron and copper. They also behave as signaling molecules, modulating multiple cell signalling pathways and gene expression, including that of antioxidant enzymes. This study aimed at determining whether catechins and procyanidins interact with the redox-inactive metal zinc and at assessing their effect on cellular zinc homeostasis. We found that a grape-seed procyanidin extract (GSPE) and the green tea flavonoid (-)-epigallocatechin-3-gallate (EGCG) bind zinc cations in solution with higher affinity than the zinc-specific chelator Zinquin, and dose-dependently prevent zinc-induced toxicity in the human hepatocarcinoma cell line HepG2, evaluated by the lactate dehydrogenase test. GSPE and EGCG hinder intracellular accumulation of total zinc, measured by atomic flame absorption spectrometry, concomitantly increasing the level of cytoplasmic labile zinc detectable by Zinquin fluorescence. Concurrently, GSPE and EGCG inhibit the expression, evaluated at the mRNA level by quantitative reverse transcriptase-polymerase chain reaction, of zinc-binding metallothioneins and of plasma membrane zinc exporter ZnT1 (SLC30A1), while enhancing the expression of cellular zinc importers ZIP1 (SLC39A1) and ZIP4 (SLC39A4). GSPE and EGCG also produce all these effects when HepG2 cells are stimulated to import zinc by treatment with supplemental zinc or the proinflammatory cytokine interleukin-6. We suggest that extracellular complexation of zinc cations and the elevation of cytoplasmic labile zinc may be relevant mechanisms underlying the modulation of diverse cell signaling and metabolic pathways by catechins and procyanidins. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of an extracellular loop in determining the stoichiometry of Na+–HCO3− cotransporters

PubMed Central

Chen, Li-Ming; Liu, Ying; Boron, Walter F

2011-01-01

The Na+–HCO3− cotransporters (NBCs) of the solute carrier 4 family (SLC4) are critical for regulating pH in cells as well as in fluids such as blood and cerebrospinal fluid. Moreover, mutations and gene disruptions in NBC are linked to a wide range of pathologies. NBCe1 (SLC4A4) is electrogenic because it has an apparent Na+:HCO3− stoichiometry of 1:2 or 1:3, whereas NBCn1 (SLC4A7) is electroneutral because it has an apparent stoichiometry of 1:1. Because stoichiometry influences the effect of transport on membrane potential and vice versa, a central question is what structural features underlie electrogenicity versus electroneutrality. A previous study on rat NBCe1/n1 chimeras demonstrated that the structural elements determining the electrogenicity of NBCe1-A are located within the transmembrane domain, excluding the large third extracellular loop. In the present study we generated a series of chimeras of human NBCe1-A and human NBCn1-A. We found that replacing merely the predicted fourth extracellular loop (EL4) – containing 32 amino acid residues that include 7 prolines – of human NBCe1-A with EL4 of NBCn1-A creates an electroneutral NBC. The opposite switch converts an electroneutral construct to one with electrogenic properties. The introduction of an N-glycosylation site into EL4 confirms that at least a part of it is exposed to the extracellular fluid. We hypothesize that putative EL4 either contributes to the substrate-binding vestibule or indirectly influences substrate binding by interacting with one or more transmembrane segments, thereby controlling the nature of transport. PMID:21224233

A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data.

PubMed

Climer, Sharlee; Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G; Gu, C Charles

2014-11-01

Complex diseases are often associated with sets of multiple interacting genetic factors and possibly with unique sets of the genetic factors in different groups of individuals (genetic heterogeneity). We introduce a novel concept of custom correlation coefficient (CCC) between single nucleotide polymorphisms (SNPs) that address genetic heterogeneity by measuring subset correlations autonomously. It is used to develop a 3-step process to identify candidate multi-SNP patterns: (1) pairwise (SNP-SNP) correlations are computed using CCC; (2) clusters of so-correlated SNPs identified; and (3) frequencies of these clusters in disease cases and controls compared to identify disease-associated multi-SNP patterns. This method identified 42 candidate multi-SNP associations with hypertensive heart disease (HHD), among which one cluster of 22 SNPs (six genes) included 13 in SLC8A1 (aka NCX1, an essential component of cardiac excitation-contraction coupling) and another of 32 SNPs had 29 from a different segment of SLC8A1. While allele frequencies show little difference between cases and controls, the cluster of 22 associated alleles were found in 20% of controls but no cases and the other in 3% of controls but 20% of cases. These suggest that both protective and risk effects on HHD could be exerted by combinations of variants in different regions of SLC8A1, modified by variants from other genes. The results demonstrate that this new correlation metric identifies disease-associated multi-SNP patterns overlooked by commonly used correlation measures. Furthermore, computation time using CCC is a small fraction of that required by other methods, thereby enabling the analyses of large GWAS datasets. © 2014 WILEY PERIODICALS, INC.

A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data

PubMed Central

Climer, Sharlee; Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G.; Gu, C. Charles

2014-01-01

Complex diseases are often associated with sets of multiple interacting genetic factors and possibly with unique sets of the genetic factors in different groups of individuals (genetic heterogeneity). We introduce a novel concept of Custom Correlation Coefficient (CCC) between single nucleotide polymorphisms (SNPs) that address genetic heterogeneity by measuring subset correlations autonomously. It is used to develop a 3-step process to identify candidate multi-SNP patterns: (1) pairwise (SNP-SNP) correlations are computed using CCC; (2) clusters of so-correlated SNPs identified; and (3) frequencies of these clusters in disease cases and controls compared to identify disease-associated multi-SNP patterns. This method identified 42 candidate multi-SNP associations with hypertensive heart disease (HHD), among which one cluster of 22 SNPs (6 genes) included 13 in SLC8A1 (aka NCX1, an essential component of cardiac excitation-contraction coupling) and another of 32 SNPs had 29 from a different segment of SLC8A1. While allele frequencies show little difference between cases and controls, the cluster of 22 associated alleles were found in 20% of controls but no cases and the other in 3% of controls but 20% of cases. These suggest that both protective and risk effects on HHD could be exerted by combinations of variants in different regions of SLC8A1, modified by variants from other genes. The results demonstrate that this new correlation metric identifies disease-associated multi-SNP patterns overlooked by commonly used correlation measures. Furthermore, computation time using CCC is a small fraction of that required by other methods, thereby enabling the analyses of large GWAS datasets. PMID:25168954

68. GENERAL VIEW OF SOUTH AND EAST SIDES OF SLC3W ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

68. GENERAL VIEW OF SOUTH AND EAST SIDES OF SLC-3W LIQUID OXYGEN APRON. CABLE TRAYS IN FOREGROUND - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

An examination of the association between 5-HTTLPR, combat exposure, and PTSD diagnosis among U.S. veterans.

PubMed

Liu, Yutao; Garrett, Melanie E; Dennis, Michelle F; Green, Kimberly T; Ashley-Koch, Allison E; Hauser, Michael A; Beckham, Jean C; Kimbrel, Nathan A

2015-01-01

To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans. The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the SLC6A4 gene. A structured clinical interview was used to diagnose PTSD. Combat and civilian trauma exposure were assessed with validated self-report instruments. Logistic regression was used to test for main effects of 5-HTTLPR on PTSD diagnosis as well as gene x environment (GxE) interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure. Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample. The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found.

Transport via SLC5A8 with Subsequent Inhibition of Histone Deacetylases HDAC1 and HDAC3 Underlies the Antitumor Activity of 3-Bromopyruvate

PubMed Central

Thangaraju, Muthusamy; Karunakaran, Senthil K.; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D.; Ganapathy, Vadivel

2009-01-01

Background 3-Bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of ATP production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The present studies have uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. Methods Transport of 3-bromopyruvate via SLC5A8, a tumor suppressor and a Na+-coupled electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by FACS analysis and colony formation assay. Acetylation status of histone H4 was evaluated by Western blot. Results 3-Bromopyruvate is a transportable substrate for SLC5A8, with the transport process being Na+-coupled and electrogenic. MCF7 cells do not express SLC5A8 and are not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells undergo apoptosis in the presence of 3-bromopyruvate. This cell death is associated with inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identify HDAC1 and HDAC3 as the targets for 3-bromopyruvate. Conclusions 3-Bromopyruvate is transported into cells actively via the tumor suppressor SLC5A8 and the process is energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells leads to apoptosis, and the mechanism involves inhibition of HDAC1/HDAC3. PMID:19637353

Polymorphisms at the 3' untranslated region of SLC11A1 gene are associated with protection to Brucella infection in goats.

PubMed

Iacoboni, Paola A; Hasenauer, Flavia C; Caffaro, M Eugenia; Gaido, Analia; Rossetto, Cristina; Neumann, Roberto D; Salatin, Antonio; Bertoni, Emiliano; Poli, Mario A; Rossetti, Carlos A

2014-08-15

Goats are susceptible to brucellosis and the detection of Brucella-infected animals is carried out by serological tests. In other ruminant species, polymorphisms in microsatellites (Ms) of 3' untranslated region (3'UTR) of the solute carrier family 11 member A1 (SLC11A1) gene were associated with resistance to Brucella abortus infection. Goats present two polymorphic Ms at the 3'UTR end of SLC11A1 gene, called regions A and B. Here, we evaluated if polymorphisms in regions A and/or B are associated with Brucella infection in goats. Serum (for the detection of Brucella-specific antibodies) and hair samples (for DNA isolation and structure analysis of the SLC11A1 gene) were randomly collected from 229 adult native goats from the northwest of Argentina. Serological status was evaluated by buffer plate antigen test (BPAT) complemented by the fluorescent polarization assay (FPA), and the genotype of the 3'UTR of the SLC11A1 gene was determined by capillary electrophoresis and confirmed by sequence analysis. Polymorphisms in regions A and B of the 3'UTR SLC11A1 gene were found statistically significant associated with protection to Brucella infection. Specifically, the association study indicates statistical significance of the allele A15 and B7/B7 genotype with absence of Brucella-specific antibodies (p=0.0003 and 0.0088, respectively). These data open a promising opportunity for limiting goat brucellosis through selective breeding of animals based on genetic markers associated with natural resistance to B. melitensis infection. Copyright © 2014 Elsevier B.V. All rights reserved.

Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion

PubMed Central

Knauf, Felix; Ko, Narae; Jiang, Zhirong; Robertson, William G.; Van Itallie, Christina M.; Anderson, James M.

2011-01-01

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [14C]oxalate simultaneously with the flux of [3H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular “leak” pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion. PMID:22021714

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder.

PubMed

Chandley, Michelle J; Szebeni, Katalin; Szebeni, Attila; Crawford, Jessica; Stockmeier, Craig A; Turecki, Gustavo; Miguel-Hidalgo, Jose Javier; Ordway, Gregory A

2013-07-01

Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression. These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

PubMed Central

Robert, Stephanie M.; Buckingham, Susan C.; Campbell, Susan L.; Robel, Stefanie; Holt, Kenneth T.; Ogunrinu-Babarinde, Toyin; Warren, Paula Province; White, David M.; Reid, Meredith A.; Eschbacher, Jenny M.; Berens, Michael E.; Lahti, Adrienne C.; Nabors, Louis B.; Sontheimer, Harald

2015-01-01

Glioma is the most common malignant primary brain tumor. Their rapid growth is aided by tumor-mediated release of glutamate, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc− (SXC), responsible for the cellular synthesis of glutathione. However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient tissue and tissues propagated in mice, we found that approximately 50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to annotated genomic data in the REMBRANDT database. In a clinical pilot study we used Magnetic Resonance Spectroscopy (MRS) to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the FDA-approved SXC inhibitor, sulfasalazine. In 9 glioma patients with biopsy-confirmed expression of SXC, we found that its expression positively correlates with glutamate release, which is acutely inhibited with oral sulfasalazine. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and peritumoral seizures. PMID:26019222

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth.

PubMed

Fumagalli, Monica; Provenzi, Livio; De Carli, Pietro; Dessimone, Francesca; Sirgiovanni, Ida; Giorda, Roberto; Cinnante, Claudia; Squarcina, Letizia; Pozzoli, Uberto; Triulzi, Fabio; Brambilla, Paolo; Borgatti, Renato; Mosca, Fabio; Montirosso, Rosario

2018-01-01

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.

Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation.

PubMed

Ashikov, Angel; Abu Bakar, Nurulamin; Wen, Xiao-Yan; Niemeijer, Marco; Rodrigues Pinto Osorio, Glentino; Brand-Arzamendi, Koroboshka; Hasadsri, Linda; Hansikova, Hana; Raymond, Kimiyo; Vicogne, Dorothée; Simon, Marleen E H; Pfundt, Rolph; Timal, Sharita; Beumers, Roel; Biot, Christophe; Smeets, Roel; Kersten, Marjan; Huijben, Karin; Linders, Peter T A; van den Bogaart, Geert; van Hijum, Sacha A F T; Rodenburg, Richard; van den Heuvel, Lambertus P; van Spronsen, Francjan; Honzik, Tomas; Foulquier, Francois; van Scherpenzeel, Monique; Lefeber, Dirk J

2018-06-05

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi.Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.

DNA methylation of amino acid transporter genes in the human placenta.

PubMed

Simner, C; Novakovic, B; Lillycrop, K A; Bell, C G; Harvey, N C; Cooper, C; Saffery, R; Lewis, R M; Cleal, J K

2017-12-01

Placental transfer of amino acids via amino acid transporters is essential for fetal growth. Little is known about the epigenetic regulation of amino acid transporters in placenta. This study investigates the DNA methylation status of amino acid transporters and their expression across gestation in human placenta. BeWo cells were treated with 5-aza-2'-deoxycytidine to inhibit methylation and assess the effects on amino acid transporter gene expression. The DNA methylation levels of amino acid transporter genes in human placenta were determined across gestation using DNA methylation array data. Placental amino acid transporter gene expression across gestation was also analysed using data from publically available Gene Expression Omnibus data sets. The expression levels of these transporters at term were established using RNA sequencing data. Inhibition of DNA methylation in BeWo cells demonstrated that expression of specific amino acid transporters can be inversely associated with DNA methylation. Amino acid transporters expressed in term placenta generally showed low levels of promoter DNA methylation. Transporters with little or no expression in term placenta tended to be more highly methylated at gene promoter regions. The transporter genes SLC1A2, SLC1A3, SLC1A4, SLC7A5, SLC7A11 and SLC7A10 had significant changes in enhancer DNA methylation across gestation, as well as gene expression changes across gestation. This study implicates DNA methylation in the regulation of amino acid transporter gene expression. However, in human placenta, DNA methylation of these genes remains low across gestation and does not always play an obvious role in regulating gene expression, despite clear evidence for differential expression as gestation proceeds. Copyright © 2017. Published by Elsevier Ltd.

Regulators of Slc4 bicarbonate transporter activity

PubMed Central

Thornell, Ian M.; Bevensee, Mark O.

2015-01-01

The Slc4 family of transporters is comprised of anion exchangers (AE1-4), Na+-coupled bicarbonate transporters (NCBTs) including electrogenic Na/bicarbonate cotransporters (NBCe1 and NBCe2), electroneutral Na/bicarbonate cotransporters (NBCn1 and NBCn2), and the electroneutral Na-driven Cl-bicarbonate exchanger (NDCBE), as well as a borate transporter (BTR1). These transporters regulate intracellular pH (pHi) and contribute to steady-state pHi, but are also involved in other physiological processes including CO2 carriage by red blood cells and solute secretion/reabsorption across epithelia. Acid-base transporters function as either acid extruders or acid loaders, with the Slc4 proteins moving HCO−3 either into or out of cells. According to results from both molecular and functional studies, multiple Slc4 proteins and/or associated splice variants with similar expected effects on pHi are often found in the same tissue or cell. Such apparent redundancy is likely to be physiologically important. In addition to regulating pHi, a HCO−3 transporter contributes to a cell's ability to fine tune the intracellular regulation of the cotransported/exchanged ion(s) (e.g., Na+ or Cl−). In addition, functionally similar transporters or splice variants with different regulatory profiles will optimize pH physiology and solute transport under various conditions or within subcellular domains. Such optimization will depend on activated signaling pathways and transporter expression profiles. In this review, we will summarize and discuss both well-known and more recently identified regulators of the Slc4 proteins. Some of these regulators include traditional second messengers, lipids, binding proteins, autoregulatory domains, and less conventional regulators. The material presented will provide insight into the diversity and physiological significance of multiple members within the Slc4 gene family. PMID:26124722

Regulators of Slc4 bicarbonate transporter activity.

PubMed

Thornell, Ian M; Bevensee, Mark O

2015-01-01

The Slc4 family of transporters is comprised of anion exchangers (AE1-4), Na(+)-coupled bicarbonate transporters (NCBTs) including electrogenic Na/bicarbonate cotransporters (NBCe1 and NBCe2), electroneutral Na/bicarbonate cotransporters (NBCn1 and NBCn2), and the electroneutral Na-driven Cl-bicarbonate exchanger (NDCBE), as well as a borate transporter (BTR1). These transporters regulate intracellular pH (pHi) and contribute to steady-state pHi, but are also involved in other physiological processes including CO2 carriage by red blood cells and solute secretion/reabsorption across epithelia. Acid-base transporters function as either acid extruders or acid loaders, with the Slc4 proteins moving HCO(-) 3 either into or out of cells. According to results from both molecular and functional studies, multiple Slc4 proteins and/or associated splice variants with similar expected effects on pHi are often found in the same tissue or cell. Such apparent redundancy is likely to be physiologically important. In addition to regulating pHi, a HCO(-) 3 transporter contributes to a cell's ability to fine tune the intracellular regulation of the cotransported/exchanged ion(s) (e.g., Na(+) or Cl(-)). In addition, functionally similar transporters or splice variants with different regulatory profiles will optimize pH physiology and solute transport under various conditions or within subcellular domains. Such optimization will depend on activated signaling pathways and transporter expression profiles. In this review, we will summarize and discuss both well-known and more recently identified regulators of the Slc4 proteins. Some of these regulators include traditional second messengers, lipids, binding proteins, autoregulatory domains, and less conventional regulators. The material presented will provide insight into the diversity and physiological significance of multiple members within the Slc4 gene family.

Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4.

PubMed

Rose, Jane; Muskett, Julie A; King, Kelly A; Zalewski, Christopher K; Chattaraj, Parna; Butman, John A; Kenna, Margaret A; Chien, Wade W; Brewer, Carmen C; Griffith, Andrew J

2017-07-01

To characterize the severity and natural history of hearing loss, and the prevalence of having a cochlear implant in a maturing cohort of individuals with enlarged vestibular aqueduct (EVA) and zero or one mutant allele of SLC26A4. Prospective cohort study of subjects ascertained between 1998 and 2015 at the National Institutes of Health Clinical Center. Study subjects were 127 individuals (median age, 8 years; range, 0-59 years) with EVA in at least one ear. Ears with EVA and zero or one mutant allele of SLC26A4 had mean 0.5/1/2/4-kHz pure-tone averages of 62.6 and 52.9 dB HL, respectively, in contrast to EVA ears with two mutant alleles of SLC26A4 (88.1 dB HL; P < .01). This association was independent of age, sex, or side of EVA (P < .001). Natural history of hearing loss was not associated with number of mutant alleles (P = .94). The prevalence of having a cochlear implant was nine (12%) of 76, two (13%) of 15, and 12 (38%) of 32 subjects with zero, one, and two mutant alleles, respectively (P = .00833). This association was not independent (P = .534) but reflected underlying correlations with age at time of first audiogram (P = .003) or severity of hearing loss (P = .000). Ears with EVA and zero or one mutant allele of SLC26A4 have less severe hearing loss, no difference in prevalence of fluctuation, and a lower prevalence of cochlear implantation in comparison to ears with two mutant alleles of SLC26A4. NA Laryngoscope, 127:E238-E243, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Evolutionary Relationships and Functional Diversity of Plant Sulfate Transporters

PubMed Central

Takahashi, Hideki; Buchner, Peter; Yoshimoto, Naoko; Hawkesford, Malcolm J.; Shiu, Shin-Han

2011-01-01

Sulfate is an essential nutrient cycled in nature. Ion transporters that specifically facilitate the transport of sulfate across the membranes are found ubiquitously in living organisms. The phylogenetic analysis of known sulfate transporters and their homologous proteins from eukaryotic organisms indicate two evolutionarily distinct groups of sulfate transport systems. One major group named Tribe 1 represents yeast and fungal SUL, plant SULTR, and animal SLC26 families. The evolutionary origin of SULTR family members in land plants and green algae is suggested to be common with yeast and fungal SUL and animal anion exchangers (SLC26). The lineage of plant SULTR family is expanded into four subfamilies (SULTR1–SULTR4) in land plant species. By contrast, the putative SULTR homologs from Chlorophyte green algae are in two separate lineages; one with the subfamily of plant tonoplast-localized sulfate transporters (SULTR4), and the other diverged before the appearance of lineages for SUL, SULTR, and SLC26. There also was a group of yet undefined members of putative sulfate transporters in yeast and fungi divergent from these major lineages in Tribe 1. The other distinct group is Tribe 2, primarily composed of animal sodium-dependent sulfate/carboxylate transporters (SLC13) and plant tonoplast-localized dicarboxylate transporters (TDT). The putative sulfur-sensing protein (SAC1) and SAC1-like transporters (SLT) of Chlorophyte green algae, bryophyte, and lycophyte show low degrees of sequence similarities with SLC13 and TDT. However, the phylogenetic relationship between SAC1/SLT and the other two families, SLC13 and TDT in Tribe 2, is not clearly supported. In addition, the SAC1/SLT family is absent in the angiosperm species analyzed. The present study suggests distinct evolutionary trajectories of sulfate transport systems for land plants and green algae. PMID:22629272

Evolutionary relationships and functional diversity of plant sulfate transporters.

PubMed

Takahashi, Hideki; Buchner, Peter; Yoshimoto, Naoko; Hawkesford, Malcolm J; Shiu, Shin-Han

2011-01-01

Sulfate is an essential nutrient cycled in nature. Ion transporters that specifically facilitate the transport of sulfate across the membranes are found ubiquitously in living organisms. The phylogenetic analysis of known sulfate transporters and their homologous proteins from eukaryotic organisms indicate two evolutionarily distinct groups of sulfate transport systems. One major group named Tribe 1 represents yeast and fungal SUL, plant SULTR, and animal SLC26 families. The evolutionary origin of SULTR family members in land plants and green algae is suggested to be common with yeast and fungal SUL and animal anion exchangers (SLC26). The lineage of plant SULTR family is expanded into four subfamilies (SULTR1-SULTR4) in land plant species. By contrast, the putative SULTR homologs from Chlorophyte green algae are in two separate lineages; one with the subfamily of plant tonoplast-localized sulfate transporters (SULTR4), and the other diverged before the appearance of lineages for SUL, SULTR, and SLC26. There also was a group of yet undefined members of putative sulfate transporters in yeast and fungi divergent from these major lineages in Tribe 1. The other distinct group is Tribe 2, primarily composed of animal sodium-dependent sulfate/carboxylate transporters (SLC13) and plant tonoplast-localized dicarboxylate transporters (TDT). The putative sulfur-sensing protein (SAC1) and SAC1-like transporters (SLT) of Chlorophyte green algae, bryophyte, and lycophyte show low degrees of sequence similarities with SLC13 and TDT. However, the phylogenetic relationship between SAC1/SLT and the other two families, SLC13 and TDT in Tribe 2, is not clearly supported. In addition, the SAC1/SLT family is absent in the angiosperm species analyzed. The present study suggests distinct evolutionary trajectories of sulfate transport systems for land plants and green algae.

A simple and effective method for filling gaps in Landsat ETM+ SLC-off images

USGS Publications Warehouse

Chen, Jin; Zhu, Xiaolin; Vogelmann, James E.; Gao, Feng; Jin, Suming

2011-01-01

The scan-line corrector (SLC) of the Landsat 7 Enhanced Thematic Mapper Plus (ETM+) sensor failed in 2003, resulting in about 22% of the pixels per scene not being scanned. The SLC failure has seriously limited the scientific applications of ETM+ data. While there have been a number of methods developed to fill in the data gaps, each method has shortcomings, especially for heterogeneous landscapes. Based on the assumption that the same-class neighboring pixels around the un-scanned pixels have similar spectral characteristics, and that these neighboring and un-scanned pixels exhibit similar patterns of spectral differences between dates, we developed a simple and effective method to interpolate the values of the pixels within the gaps. We refer to this method as the Neighborhood Similar Pixel Interpolator (NSPI). Simulated and actual SLC-off ETM+ images were used to assess the performance of the NSPI. Results indicate that NSPI can restore the value of un-scanned pixels very accurately, and that it works especially well in heterogeneous regions. In addition, it can work well even if there is a relatively long time interval or significant spectral changes between the input and target image. The filled images appear reasonably spatially continuous without obvious striping patterns. Supervised classification using the maximum likelihood algorithm was done on both gap-filled simulated SLC-off data and the original "gap free" data set, and it was found that classification results, including accuracies, were very comparable. This indicates that gap-filled products generated by NSPI will have relevance to the user community for various land cover applications. In addition, the simple principle and high computational efficiency of NSPI will enable processing large volumes of SLC-off ETM+ data.

Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia.

PubMed

Yasuda, T; Yamaguchi, N; Kobayashi, K; Nishi, I; Horinouchi, H; Jalil, M A; Li, M X; Ushikai, M; Iijima, M; Kondo, I; Saheki, T

2000-12-01

Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-specific deficiency of argininosuccinate synthetase (ASS) protein. We have recently identified the gene responsible for CTLN2, viz., SLC25A13, which encodes a calcium-binding mitochondrial carrier protein, designated citrin, and found five mutations of the SLC25A13 gene in CTLN2 patients. In the present study, we have identified two novel mutations, 1800ins1 and R605X, in SLC25A13 mRNA and the SLC25A13 gene. Diagnostic analysis for the seven mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies has revealed that 102 patients had one or two of the seven mutations and 93 patients were homozygotes or compound heterozygotes. These results indicate that CTLN2 is caused by an abnormality in the SLC25A13 gene, and that our criteria for CTLN2 before DNA diagnosis are correct. Five of 22 patients from consanguineous unions have been shown to be compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes is calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. We have detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the seven mutations by Western blot analysis with anti-human citrin antibody. From these findings, we hypothesize that CTLN2 is caused by a complete deletion of citrin, although the mechanism of ASS deficiency is still unknown.

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice.

PubMed

Hutchens, Steven; Liu, Chunyi; Jursa, Thomas; Shawlot, William; Chaffee, Beth K; Yin, Weiling; Gore, Andrea C; Aschner, Michael; Smith, Donald R; Mukhopadhyay, Somshuvra

2017-06-09

Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Association analysis of SLC30A8 rs13266634 and rs16889462 polymorphisms with type 2 diabetes mellitus and repaglinide response in Chinese patients.

PubMed

Huang, Qiong; Yin, Ji-Ye; Dai, Xing-Ping; Wu, Jing; Chen, Xiang; Deng, Cai-Shu; Yu, Min; Gong, Zhi-Cheng; Zhou, Hong-Hao; Liu, Zhao-Qian

2010-12-01

Genome-wide association studies (GWASs) identified that SLC30A8 genetic polymorphism was a risk of type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with T2DM susceptibility and repaglinide therapeutic efficacy in Chinese T2DM patients. We conducted a case-control study of 443 T2DM patients and 229 healthy volunteers to identify SLC30A8 rs13266634 and rs16889462 genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-eight patients were randomly selected and underwent an 8-week repaglinide treatment (3 mg/d). Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbAlc), fasting serum insulin (FINS), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), serum triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c) were determined before and after repaglinide treatment. SLC30A8 rs13266634 risk C allele frequency was higher in T2DM patients than in healthy controls (P < 0.05). There was a better repaglinide response on FINS (P < 0.05) and PINS (P < 0.01) in patients with rs13266634 CT+TT genotypes compared with CC genotype carriers. Patients with rs16889462 GA genotype showed an enhanced repaglinide efficacy on FPG (P < 0.01), PPG (P < 0.01) and HbAlc (P < 0.05) compared with GG genotype individuals. SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with repaglinide therapeutic efficacy in Chinese T2DM patients.

The Balance of HCO3- Secretion vs. Reabsorption in the Endometrial Epithelium Regulates Uterine Fluid pH

PubMed Central

Xie, Zhang-Dong; Guo, Yi-Min; Ren, Mei-Juan; Yang, Jichun; Wang, Shao-Fang; Xu, Tong-Hui; Chen, Li-Ming; Liu, Ying

2018-01-01

Uterine fluid contains a high concentration of HCO3- which plays an essential role in sperm capacitation and fertilization. In addition, the HCO3- concentration in uterine fluid changes periodically during the estrous cycle. It is well-known that the endometrial epithelium contains machineries involving the apical SLC26 family anion exchangers for secreting HCO3- into the uterine fluid. In the present study, we find for the first time that the electroneutral Na+/HCO3- cotransporter NBCn1 is expressed at the apical membrane of the endometrial epithelium. The protein abundance of the apical NBCn1 and that of the apical SLC26A4 and SLC26A6 are reciprocally regulated during the estrous cycle in the uterus. NBCn1 is most abundant at diestrus, whereas SLC26A4/A6 are most abundant at proestrus/estrus. In the ovariectomized mice, the expression of uterine NBCn1 is inhibited by β-estradiol, but stimulated by progesterone, whereas that of uterine SLC26A4/A6 is stimulated by β-estradiol. In vivo perfusion studies show that the endometrial epithelium is capable of both secreting and reabsorbing HCO3-. Moreover, the activity for HCO3- secretion by the endometrial epithelium is significantly higher at estrus than it is at diestrus. The opposite is true for HCO3- reabsorption. We conclude that the endometrial epithelium simultaneously contains the activity for HCO3- secretion involving the apical SLC26A4/A6 and the activity for HCO3- reabsorption involving the apical NBCn1, and that the acid-base homeostasis in the uterine fluid is regulated by the finely-tuned balance of the two activities. PMID:29422866

Morphological study on dental caries induced in WBN/KobSlc rats (Rattus norvegicus) fed a standard laboratory diet.

PubMed

Fukuzato, Yoko; Matsuura, Tetsuro; Ozaki, Kiyokazu; Matsuura, Masahiro; Sano, Tomoya; Nakahara, Yutaka; Kodama, Yasushi; Nakagawa, Akihito; Okamura, Sumie; Suido, Hirohisa; Torii, Kayo; Makino, Taketoshi; Narama, Isao

2009-10-01

In our previous studies, WBN/KobSlc was characterized as a rat strain in which only males began to develop pancreatitis, and then presented with diabetic symptoms. In the course of studying their pancreatic inflammation, we detected molar caries in prediabetic males feeding on a standard diet (CRF-1) widely used for experimental animals. The purpose of this study is to confirm whether the WBN/KobSlc strain is caries-susceptible to the diet reported to be non-cariogenic, and to examine the effect of a prediabetic condition on their dental caries. For a morphological study, 25 male WBN/KobSlc rats aged 3.2-7.8 months and 24 females of the same strain aged 3.3-6.6 months were used, along with 10 males and 10 females of 8.2-month-old F344 rats. Marked dental caries were detected in the mandibular molars of male and female WBN/KobSlc rats regardless of pancreatitis, although no similar changes were observed in any teeth of the F344 strain fed the same diet. Soft X-ray examination revealed that the caries began in the crown and progressed horizontally and vertically, and that a severe radiolucent lesion extensively expanded to the entire crown, corresponding to a macroscopically deleted molar. The caries had gradually developed mainly in the second mandibular molar from more than 3.5 months of age, while none were seen in any rats before that time. The WBN/KobSlc rats were caries-susceptible even to the standard laboratory diet, and pancreatitis was not directly associated with the onset of dental caries in this strain.

Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients.

PubMed

Barbosa, M; Lopes, A; Mota, C; Martins, E; Oliveira, J; Alves, S; De Bonis, P; Mota, M do Céu; Dias, C; Rodrigues-Santos, P; Fortuna, A M; Quelhas, D; Lacerda, L; Bisceglia, L; Cardoso, M L

2012-01-01

Cystinuria is a rare autosomal inherited disorder characterized by impaired transport of cystine and dibasic aminoacids in the proximal renal tubule. Classically, cystinuria is classified as type I (silent heterozygotes) and non-type I (heterozygotes with urinary hyperexcretion of cystine). Molecularly, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). The goal of this study is to provide a comprehensive clinical, biochemical and molecular characterization of a cohort of 12 Portuguese patients affected with cystinuria in order to provide insight into genotype-phenotype correlations. We describe seven type I and five non-type I patients. Regarding the molecular classification, seven patients were type A and five were type B. In SLC3A1 gene, two large genomic rearrangements and 13 sequence variants, including four new variants c.611-2A>C; c.1136+44G>A; c.1597T (p.Y533N); c.*70A>G, were found. One large genomic rearrangement was found in SLC7A9 gene as well as 24 sequence variants including 3 novel variants: c.216C>T (p.C72C), c.1119G>A (p.S373S) and c.*82C>T. In our cohort the most frequent pathogenic mutations were: large rearrangements (33.3% of mutant alleles) and a missense mutation c.1400T>C (p.M467T) (11.1%). This report expands the spectrum of SLC3A1 and SLC7A9 mutations and provides guidance in the clinical implementation of molecular assays in routine genetic counseling of Portuguese patients affected with cystinuria. © 2011 John Wiley & Sons A/S.

Sex determines which section of the SLC6A4 gene is linked to obsessive-compulsive symptoms in normal Chinese college students.

PubMed

Lei, Xuemei; Chen, Chuansheng; He, Qinghua; Chen, Chunhui; Moyzis, Robert K; Xue, Gui; Chen, Xiongying; Cao, Zhongyu; Li, Jin; Li, He; Zhu, Bi; Chun Hsu, Anna Shan; Li, Sufang; Li, Jun; Dong, Qi

2012-09-01

Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3' UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD. Published by Elsevier Ltd.

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

PubMed Central

Tavares, Catarina; Eloy, Catarina; Melo, Miguel; Gaspar da Rocha, Adriana; Pestana, Ana; Batista, Rui; Rios, Elisabete; Sobrinho Simões, Manuel

2018-01-01

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression. PMID:29757257

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression.

PubMed

Tavares, Catarina; Eloy, Catarina; Melo, Miguel; Gaspar da Rocha, Adriana; Pestana, Ana; Batista, Rui; Bueno Ferreira, Luciana; Rios, Elisabete; Sobrinho Simões, Manuel; Soares, Paula

2018-05-13

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.

Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

PubMed Central

2013-01-01

Background In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. Methods Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. Results Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross-validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. Conclusions Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of β-carotene with lipid metabolism is exciting for future study. PMID:23656756

Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration

PubMed Central

Baas, Dominique C.; Ho, Lintje; Tanck, Michael W.T.; Fritsche, Lars G.; Merriam, Joanna E.; van het Slot, Ruben; Koeleman, Bobby P.C.; Gorgels, Theo G.M.F.; van Duijn, Cornelia M.; Uitterlinden, André G.; de Jong, Paulus T.V.M.; Hofman, Albert; ten Brink, Jacoline B.; Vingerling, Johannes R.; Klaver, Caroline C.W.; Dean, Michael; Weber, Bernhard H. F.; Allikmets, Rando; Hageman, Gregory S.

2012-01-01

Purpose Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress–mediated AMD pathology. Methods Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Würzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. Results In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. Conclusions No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists. PMID:22509097

Polymorphisms in sodium-dependent vitamin C transporter genes and plasma, aqueous humor and lens nucleus ascorbate concentrations in an ascorbate depleted setting.

PubMed

Senthilkumari, Srinivasan; Talwar, Badri; Dharmalingam, Kuppamuthu; Ravindran, Ravilla D; Jayanthi, Ramamurthy; Sundaresan, Periasamy; Saravanan, Charu; Young, Ian S; Dangour, Alan D; Fletcher, Astrid E

2014-07-01

We have previously reported low concentrations of plasma ascorbate and low dietary vitamin C intake in the older Indian population and a strong inverse association of these with cataract. Little is known about ascorbate levels in aqueous humor and lens in populations habitually depleted of ascorbate and no studies in any setting have investigated whether genetic polymorphisms influence ascorbate levels in ocular tissues. Our objectives were to investigate relationships between ascorbate concentrations in plasma, aqueous humor and lens and whether these relationships are influenced by Single Nucleotide Polymorphisms (SNPs) in sodium-dependent vitamin C transporter genes (SLC23A1 and SLC23A2). We enrolled sixty patients (equal numbers of men and women, mean age 63 years) undergoing small incision cataract surgery in southern India. We measured ascorbate concentrations in plasma, aqueous humor and lens nucleus using high performance liquid chromatography. SLC23A1 SNPs (rs4257763, rs6596473) and SLC23A2 SNPs (rs1279683 and rs12479919) were genotyped using a TaqMan assay. Patients were interviewed for lifestyle factors which might influence ascorbate. Plasma vitamin C was normalized by a log10 transformation. Statistical analysis used linear regression with the slope of the within-subject associations estimated using beta (β) coefficients. The ascorbate concentrations (μmol/L) were: plasma ascorbate, median and inter-quartile range (IQR), 15.2 (7.8, 34.5), mean (SD) of aqueous humor ascorbate, 1074 (545) and lens nucleus ascorbate, 0.42 (0.16) (μmol/g lens nucleus wet weight). Minimum allele frequencies were: rs1279683 (0.28), rs12479919 (0.30), rs659647 (0.48). Decreasing concentrations of ocular ascorbate from the common to the rare genotype were observed for rs6596473 and rs12479919. The per allele difference in aqueous humor ascorbate for rs6596473 was -217 μmol/L, p < 0.04 and a per allele difference in lens nucleus ascorbate of -0.085 μmol/g, p < 0.02 for rs12479919. The β coefficients for the regression of log10 plasma ascorbate on aqueous humor ascorbate were higher for the GG genotype of rs6596473: GG, β = 1460 compared to carriage of the C allele, CG, β = 1059, CC, β = 1132, p interaction = 0.1. In conclusion we found that compared to studies in well-nourished populations, ascorbate concentrations in the plasma, aqueous humor and lens nucleus were low. We present novel findings that polymorphisms in SLC23A1/2 genes influenced ascorbate concentration in aqueous humor and lens nucleus. Copyright © 2014 Elsevier Ltd. All rights reserved.

Preliminary results on heavy flavor physics at SLD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Usher, T.

1994-12-01

The author reports on preliminary heavy flavor physics results from the SLD detector at the SLAC Linear Collider. Efficient tagging of b{bar b} events is achieved with an impact parameter technique that takes advantage of the small and stable interaction point of the SLC and all charged tracks in Z{sup 0} decays. This technique is applied to samples of Z{sup 0} events collected during the 1992 and 1993 physics runs. Preliminary measurements of the ratio R{sub b} = {Gamma}(Z{sup 0} {yields} b{bar b})/{Gamma}(Z{sup 0} {yields} hadrons) and the average B hadron lifetime <{tau}{sub B}> are reported. In a sample ofmore » 27K Z{sup 0} events, values of R{sub b} = 0.235 {+-} 0.006(stat.) {+-} 0.018(syst.) and <{tau}{sub B}> = 1.53 {+-} 0.006(stat.) {+-} 0.018(syst.) are obtained. In addition, the first measurement of the left-right asymmetry A{sub b} is reported. Using a sample of 38K Z{sup 0} events with a luminosity weighted electron polarization of 62%, the author obtains a preliminary value of A{sub b} = 0.94 {+-} 0.006(stat.) {+-} 0.018(syst.).« less

8. VIEW OF SLC3W CONTROL ROOM (ROOM 105) FROM ITS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. VIEW OF SLC-3W CONTROL ROOM (ROOM 105) FROM ITS NORTHEAST CORNER. TELEMETRY ROOM VISIBLE THROUGH WINDOWS IN SOUTH WALL. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

7. VIEW OF SLC3W CONTROL ROOM (ROOM 105) FROM ITS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

7. VIEW OF SLC-3W CONTROL ROOM (ROOM 105) FROM ITS SOUTHWEST CORNER. NOTE RAISED FLATFORM IN CENTER OF ROOM. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family.

PubMed

Mackenzie, Bryan; Erickson, Jeffrey D

2004-02-01

The sodium-coupled neutral amino acid transporters (SNAT) of the SLC38 gene family resemble the classically-described System A and System N transport activities in terms of their functional properties and patterns of regulation. Transport of small, aliphatic amino acids by System A subtypes (SNAT1, SNAT2, and SNAT4) is rheogenic and pH sensitive. The System N subtypes SNAT3 and SNAT5 also countertransport H(+), which may be key to their operation in reverse, and have narrower substrate profiles than do the System A subtypes. Glutamine emerges as a favored substrate throughout the family, except for SNAT4. The SLC38 transporters undoubtedly play many physiological roles including the transfer of glutamine from astrocyte to neuron in the CNS, ammonia detoxification and gluconeogenesis in the liver, and the renal response to acidosis. Probing their regulation has revealed additional roles, and recent work has considered SLC38 transporters as therapeutic targets in neoplasia.

Stallion spermatozoa selected by single layer centrifugation are capable of fertilization after storage for up to 96 h at 6°C prior to artificial insemination

PubMed Central

2012-01-01

Background One of the challenges faced by equine breeders is ensuring delivery of good quality semen doses for artificial insemination when the mare is due to ovulate. Single Layer Centrifugation (SLC) has been shown to select morphologically normal spermatozoa with intact chromatin and good progressive motility from the rest of the ejaculate, and to prolong the life of these selected spermatozoa in vitro. The objective of the present study was a proof of concept, to determine whether fertilizing ability was retained in SLC-selected spermatozoa during prolonged storage. Findings Sixteen mares were inseminated with SLC-selected sperm doses that had been cooled and stored at 6°C for 48 h, 72 h or 96 h. Embryos were identified in 11 mares by ultrasound examination 16–18 days after presumed ovulation. Conclusion SLC-selected stallion spermatozoa stored for up to 96 h are capable of fertilization. PMID:22788670

Changes in oil content of transgenic soybeans expressing the yeast SLC1 gene.

PubMed

Rao, Suryadevara S; Hildebrand, David

2009-10-01

The wild type (Wt) and mutant form of yeast (sphingolipid compensation) genes, SLC1 and SLC1-1, have been shown to have lysophosphatidic acid acyltransferase (LPAT) activities (Nageic et al. in J Biol Chem 269:22156-22163, 1993). Expression of these LPAT genes was reported to increase oil content in transgenic Arabidopsis and Brassica napus. It is of interest to determine if the TAG content increase would also be seen in soybeans. Therefore, the wild type SLC1 was expressed in soybean somatic embryos under the control of seed specific phaseolin promoter. Some transgenic somatic embryos and in both T2 and T3 transgenic seeds showed higher oil contents. Compared to controls, the average increase in triglyceride values went up by 1.5% in transgenic somatic embryos. A maximum of 3.2% increase in seed oil content was observed in a T3 line. Expression of the yeast Wt LPAT gene did not alter the fatty acid composition of the seed oil.

Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease.

PubMed

Stark, Klaus; Reinhard, Wibke; Grassl, Martina; Erdmann, Jeanette; Schunkert, Heribert; Illig, Thomas; Hengstenberg, Christian

2009-11-05

Recently, a large meta-analysis including over 28,000 participants identified nine different loci with association to serum uric acid (UA) levels. Since elevated serum UA levels potentially cause gout and are a possible risk factor for coronary artery disease (CAD) and myocardial infarction (MI), we performed two large case-control association analyses with participants from the German MI Family Study. In the first study, we assessed the association of the qualitative trait gout and ten single nucleotide polymorphisms (SNP) markers that showed association to UA serum levels. In the second study, the same genetic polymorphisms were analyzed for association with CAD. A total of 683 patients suffering from gout and 1,563 healthy controls from the German MI Family Study were genotyped. Nine SNPs were identified from a recently performed genome-wide meta-analysis on serum UA levels (rs12129861, rs780094, rs734553, rs2231142, rs742132, rs1183201, rs12356193, rs17300741 and rs505802). Additionally, the marker rs6855911 was included which has been associated with gout in our cohort in a previous study. SNPs rs734553 and rs6855911, located in SLC2A9, and SNP rs2231142, known to be a missense polymorphism in ABCG2, were associated with gout (p=5.6*10(-7), p=1.1*10(-7), and p=1.3*10(-3), respectively). Other SNPs in the genes PDZK1, GCKR, LRRC16A, SLC17A1-SLC17A3, SLC16A9, SLC22A11 and SLC22A12 failed the significance level. None of the ten markers were associated with risk to CAD in our study sample of 1,473 CAD cases and 1,241 CAD-free controls. SNP markers in SLC2A9 and ABCG2 genes were found to be strongly associated with the phenotype gout. However, not all SNP markers influencing serum UA levels were also directly associated with the clinical manifestation of gout in our study sample. In addition, none of these SNPs showed association with the risk to CAD in the German MI Family Study.

Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans

PubMed Central

Voruganti, Venkata Saroja; Kent, Jack W.; Debnath, Subrata; Cole, Shelley A.; Haack, Karin; Göring, Harald H. H.; Carless, Melanie A.; Curran, Joanne E.; Johnson, Matthew P.; Almasy, Laura; Dyer, Thomas D.; MacCluer, Jean W.; Moses, Eric K.; Abboud, Hanna E.; Mahaney, Michael C.; Blangero, John; Comuzzie, Anthony G.

2013-01-01

Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10−7). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3–7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10−3) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10−6) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors. PMID:24379826

The development of cat testicular sperm cryopreservation protocols: Effects of tissue fragments or sperm cell suspension.

PubMed

Chatdarong, Kaywalee; Thuwanut, Paweena; Morrell, Jane M

2016-01-15

In endangered animals that have been found dead or sterilized for medical reasons, testis is the ultimate source of haploid DNA or sperm. Thus, preservation of testicular sperm may be performed to rescue their genetics. The aim of this study was to evaluate protocols for testicular sperm freezing: as tissue fragments or cell suspension in domestic cats as a model. A pair of testes from each cat (n = 9) were cut into eight equal pieces. Four randomly selected pieces were cryopreserved as: (1) tissue pieces using two-step freezing; (2) tissue pieces using a slow passive cooling device (CoolCell); (3) sperm suspension after single-layer centrifugation (SLC) through colloids; and (4) sperm suspension without being processed through SLC. A testicular piece from each cat served as fresh control. Testicular sperm membrane and DNA integrity were evaluated before, and after, the cryopreservation process. In addition, spermatogenic cell types (testicular sperm, spermatogonia, spermatocyte, and spermatid) present in the suspension samples were counted before and after SLC. The results found that testicular sperm membrane integrity in the suspension after SLC process was higher than that in the fragment form neither using the two-step nor CoolCell freezing, both before and after freezing (before freezing: 92.3 ± 3.4 vs. 81 ± 4.5 and 80.0 ± 7.0; after freezing: 84.5 ± 4.6 vs. 71.2 ± 12 and 76.2 ± 4.6; P ≤ 0.05). Testicular sperm DNA integrity was, however, not different among groups. Furthermore, the samples processed through the SLC had higher ration of sperm cells: other spermatogenic cells than those were not processed through the SLC (88.9 ± 3.8 vs. 30 ± 7.9; P ≤ 0.05). In summary, testicular sperm cryopreserved as a minced suspension is considered suitable in terms of preventing sperm membrane integrity, and SLC is considered a selection tool for enriching haploid sperm cells from castrated or postmortem cats. Copyright © 2016 Elsevier Inc. All rights reserved.

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

PubMed Central

Raffler, Johannes; Friedrich, Nele; Arnold, Matthias; Kacprowski, Tim; Rueedi, Rico; Altmaier, Elisabeth; Bergmann, Sven; Budde, Kathrin; Gieger, Christian; Homuth, Georg; Pietzner, Maik; Römisch-Margl, Werner; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wallaschofski, Henri; Nauck, Matthias; Völker, Uwe; Kastenmüller, Gabi; Suhre, Karsten

2015-01-01

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases. PMID:26352407

Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study

PubMed Central

Zhou, Kaixin; Donnelly, Louise A.; Kimber, Charlotte H.; Donnan, Peter T.; Doney, Alex S.F.; Leese, Graham; Hattersley, Andrew T.; McCarthy, Mark I.; Morris, Andrew D.; Palmer, Colin N.A.; Pearson, Ewan R.

2009-01-01

OBJECTIVE Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance. RESULTS A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56). CONCLUSIONS The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes. PMID:19336679

Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against High-Grade Gliomas.

PubMed

Azzalin, Alberto; Nato, Giulia; Parmigiani, Elena; Garello, Francesca; Buffo, Annalisa; Magrassi, Lorenzo

2017-04-01

Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glucose antiporter type 2 (SGLT2/SLC5A2) superfamily, phlorizin (PHZ), in decreasing glucose consumption and cell proliferation of human and murine glioblastoma cells. We found in vitro that RTV, active on at least three different GLUT/SLC2A transporters, was more effective than IDV, a specific inhibitor of GLUT4/SLC2A4, both in decreasing glucose consumption and lactate production and in inhibiting growth of U87MG and Hu197 human glioblastoma cell lines and primary cultures of human glioblastoma. PHZ was inactive on the same cells. Similar results were obtained when cells were grown in adherence or as 3D multicellular tumor spheroids. RTV treatment but not IDV treatment induced AMP-activated protein kinase (AMPKα) phosphorylation that paralleled the decrease in glycolytic activity and cell growth. IDV, but not RTV, induced an increase in GLUT1/SLC2A1 whose activity could compensate for the inhibition of GLUT4/SLC2A4 by IDV. RTV and IDV pass poorly the blood brain barrier and are unlikely to reach sufficient liquoral concentrations in vivo to inhibit glioblastoma growth as single agents. Isobologram analysis of the association of RTV or IDV and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide (TMZ) indicated synergy only with RTV on inhibition of glioblastoma cells. Finally, we tested in vivo the combination of RTV and BCNU on established GL261 tumors. This drug combination increased the overall survival and allowed a five-fold reduction in the dose of BCNU. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome.

PubMed

Gerards, Mike; Kamps, Rick; van Oevelen, Jo; Boesten, Iris; Jongen, Eveline; de Koning, Bart; Scholte, Hans R; de Angst, Isabel; Schoonderwoerd, Kees; Sefiani, Abdelaziz; Ratbi, Ilham; Coppieters, Wouter; Karim, Latifa; de Coo, René; van den Bosch, Bianca; Smeets, Hubert

2013-03-01

Leigh syndrome is an early onset, often fatal progressive neurodegenerative disorder caused by mutations in the mitochondrial or nuclear DNA. Until now, mutations in more than 35 genes have been reported to cause Leigh syndrome, indicating an extreme genetic heterogeneity for this disorder, but still only explaining part of the cases. The possibility of whole exome sequencing enables not only mutation detection in known candidate genes, but also the identification of new genes associated with Leigh syndrome in small families and isolated cases. Exome sequencing was combined with homozygosity mapping to identify the genetic defect in a Moroccan family with fatal Leigh syndrome in early childhood and specific magnetic resonance imaging abnormalities in the brain. We detected a homozygous nonsense mutation (c.20C>A; p.Ser7Ter) in the thiamine transporter SLC19A3. In vivo overexpression of wild-type SLC19A3 showed an increased thiamine uptake, whereas overexpression of mutant SLC19A3 did not, confirming that the mutation results in an absent or non-functional protein. Seventeen additional patients with Leigh syndrome were screened for mutations in SLC19A3 using conventional Sanger sequencing. Two unrelated patients, both from Moroccan origin and one from consanguineous parents, were homozygous for the same p.Ser7Ter mutation. One of these patients showed the same MRI abnormalities as the patients from the first family. Strikingly, patients receiving thiamine had an improved life-expectancy. One patient in the third family deteriorated upon interruption of the thiamine treatment and recovered after reinitiating. Although unrelated, all patients came from the province Al Hoceima in Northern Morocco. Based on the recombination events the mutation was estimated to have occurred 1250-1750 years ago. Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome, who might benefit from high doses of thiamine and/or biotin. Especially, Moroccan patients with Leigh syndrome should be tested for the c.20C>A founder mutation in SLC19A3.

Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions

PubMed Central

Lu, Hang; Lu, Zhiqiang; Li, Xue; Li, Gentao; Qiao, Yilin

2017-01-01

Background Herb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities. Methods HEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract of Juncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on the in vivo pharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3. Results More than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50 values being <5 µg/ml. Juncus effusus showed a strong inhibition to OAT3 in vitro, and markedly altered the in vivo pharmacokinetic parameters of furosemide in rats. Conclusion The present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs. PMID:28560096

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

PubMed

Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L; Jacobs, Suzanne B R; Grarup, Niels; Burtt, Noël P; Mahajan, Anubha; Fuchsberger, Christian; Atzmon, Gil; Benediktsson, Rafn; Blangero, John; Bowden, Don W; Brandslund, Ivan; Brosnan, Julia; Burslem, Frank; Chambers, John; Cho, Yoon Shin; Christensen, Cramer; Douglas, Desirée A; Duggirala, Ravindranath; Dymek, Zachary; Farjoun, Yossi; Fennell, Timothy; Fontanillas, Pierre; Forsén, Tom; Gabriel, Stacey; Glaser, Benjamin; Gudbjartsson, Daniel F; Hanis, Craig; Hansen, Torben; Hreidarsson, Astradur B; Hveem, Kristian; Ingelsson, Erik; Isomaa, Bo; Johansson, Stefan; Jørgensen, Torben; Jørgensen, Marit Eika; Kathiresan, Sekar; Kong, Augustine; Kooner, Jaspal; Kravic, Jasmina; Laakso, Markku; Lee, Jong-Young; Lind, Lars; Lindgren, Cecilia M; Linneberg, Allan; Masson, Gisli; Meitinger, Thomas; Mohlke, Karen L; Molven, Anders; Morris, Andrew P; Potluri, Shobha; Rauramaa, Rainer; Ribel-Madsen, Rasmus; Richard, Ann-Marie; Rolph, Tim; Salomaa, Veikko; Segrè, Ayellet V; Skärstrand, Hanna; Steinthorsdottir, Valgerdur; Stringham, Heather M; Sulem, Patrick; Tai, E Shyong; Teo, Yik Ying; Teslovich, Tanya; Thorsteinsdottir, Unnur; Trimmer, Jeff K; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Vaziri-Sani, Fariba; Voight, Benjamin F; Wilson, James G; Boehnke, Michael; McCarthy, Mark I; Njølstad, Pål R; Pedersen, Oluf; Groop, Leif; Cox, David R; Stefansson, Kari; Altshuler, David

2014-04-01

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

A novel variant in the SLC12A1 gene in two families with antenatal Bartter syndrome.

PubMed

Breinbjerg, Anders; Siggaard Rittig, Charlotte; Gregersen, Niels; Rittig, Søren; Hvarregaard Christensen, Jane

2017-01-01

Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalaemia and metabolic alkalosis. We present two apparently nonrelated cases with antenatal Bartter syndrome type I, due to a novel variant in the SLC12A1 gene encoding the bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 in the thick ascending limb of the loop of Henle. Blood samples were received from the two cases and 19 of their relatives, and deoxyribonucleic acid was extracted. The coding regions of the SLC12A1 gene were amplified using polymerase chain reaction, followed by bidirectional direct deoxyribonucleic acid sequencing. Each affected child in the two families was homozygous for a novel inherited variant in the SLC12A1gene, c.1614T>A. The variant predicts a change from a tyrosine codon to a stop codon (p.Tyr538Ter). The two cases presented antenatally and at six months of age, respectively. The two cases were homozygous for the same variant in the SLC12A1 gene, but presented clinically at different ages. This could eventually be explained by the presence of other gene variants or environmental factors modifying the phenotypes. The phenotypes of the patients were similar to other patients with antenatal Bartter syndrome. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins

PubMed Central

Yamashita, Tetsuji; Hakizimana, Pierre; Wu, Siva; Hassan, Ahmed; Jacob, Stefan; Temirov, Jamshid; Fang, Jie; Mellado-Lagarde, Marcia; Gursky, Richard; Horner, Linda; Leibiger, Barbara; Leijon, Sara; Centonze, Victoria E.; Berggren, Per-Olof; Frase, Sharon; Auer, Manfred; Brownell, William E.; Fridberger, Anders; Zuo, Jian

2015-01-01

Nature’s fastest motors are the cochlear outer hair cells (OHCs). These sensory cells use a membrane protein, Slc26a5 (prestin), to generate mechanical force at high frequencies, which is essential for explaining the exquisite hearing sensitivity of mammalian ears. Previous studies suggest that Slc26a5 continuously diffuses within the membrane, but how can a freely moving motor protein effectively convey forces critical for hearing? To provide direct evidence in OHCs for freely moving Slc26a5 molecules, we created a knockin mouse where Slc26a5 is fused with YFP. These mice and four other strains expressing fluorescently labeled membrane proteins were used to examine their lateral diffusion in the OHC lateral wall. All five proteins showed minimal diffusion, but did move after pharmacological disruption of membrane-associated structures with a cholesterol-depleting agent and salicylate. Thus, our results demonstrate that OHC lateral wall structure constrains the mobility of plasma membrane proteins and that the integrity of such membrane-associated structures are critical for Slc26a5’s active and structural roles. The structural constraint of membrane proteins may exemplify convergent evolution of cellular motors across species. Our findings also suggest a possible mechanism for disorders of cholesterol metabolism with hearing loss such as Niemann-Pick Type C diseases. PMID:26352669

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

PubMed

Srour, M; Hamdan, F F; Gan-Or, Z; Labuda, D; Nassif, C; Oskoui, M; Gana-Weisz, M; Orr-Urtreger, A; Rouleau, G A; Michaud, J L

2015-07-01

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID. © 2015 John Wiley | Clinical Exome Genome Reports.

SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

PubMed Central

Park, Julien H.; Hogrebe, Max; Grüneberg, Marianne; DuChesne, Ingrid; von der Heiden, Ava L.; Reunert, Janine; Schlingmann, Karl P.; Boycott, Kym M.; Beaulieu, Chandree L.; Mhanni, Aziz A.; Innes, A. Micheil; Hörtnagel, Konstanze; Biskup, Saskia; Gleixner, Eva M.; Kurlemann, Gerhard; Fiedler, Barbara; Omran, Heymut; Rutsch, Frank; Wada, Yoshinao; Tsiakas, Konstantinos; Santer, René; Nebert, Daniel W.; Rust, Stephan; Marquardt, Thorsten

2015-01-01

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders. PMID:26637979

Culture medium, gas atmosphere and MAPK inhibition affect regulation of RNA-binding protein targets during mouse preimplantation development.

PubMed

Calder, Michele D; Watson, Patricia H; Watson, Andrew J

2011-11-01

During oogenesis, mammalian oocytes accumulate maternal mRNAs that support the embryo until embryonic genome activation. RNA-binding proteins (RBP) may regulate the stability and turnover of maternal and embryonic mRNAs. We hypothesised that varying embryo culture conditions, such as culture medium, oxygen tension and MAPK inhibition, affects regulation of RBPs and their targets during preimplantation development. STAU1, ELAVL1, KHSRP and ZFP36 proteins and mRNAs were detected throughout mouse preimplantation development, whereas Elavl2 mRNA decreased after the two-cell stage. Potential target mRNAs of RBP regulation, Gclc, Slc2a1 and Slc7a1 were detected during mouse preimplantation development. Gclc mRNA was significantly elevated in embryos cultured in Whitten's medium compared with embryos cultured in KSOMaa, and Gclc mRNA was elevated under high-oxygen conditions. Inhibition of the p38 MAPK pathway reduced Slc7a1 mRNA expression while inhibition of ERK increased Slc2a1 mRNA expression. The half-lives of the potential RBP mRNA targets are not regulated in parallel; Slc2a1 mRNA displayed the longest half-life. Our results indicate that mRNAs and proteins encoding five RBPs are present during preimplantation development and more importantly, demonstrate that expression of RBP target mRNAs are regulated by culture medium, gas atmosphere and MAPK pathways.

Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis.

PubMed

Rajagopal, Abbhirami; Braslavsky, Débora; Lu, James T; Kleppe, Soledad; Clément, Florencia; Cassinelli, Hamilton; Liu, David S; Liern, Jose Miguel; Vallejo, Graciela; Bergadá, Ignacio; Gibbs, Richard A; Campeau, Phillipe M; Lee, Brendan H

2014-11-01

Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis. The goal of this study was to identify genetic causes of the clinical findings in the two siblings. Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified. Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies. A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484G>A, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1. The homozygous G>A transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition.

Differential Natural Selection of Human Zinc Transporter Genes between African and Non-African Populations

PubMed Central

Zhang, Chao; Li, Jing; Tian, Lei; Lu, Dongsheng; Yuan, Kai; Yuan, Yuan; Xu, Shuhua

2015-01-01

Zinc transporters play important roles in all eukaryotes by maintaining the rational zinc concentration in cells. However, the diversity of zinc transporter genes (ZTGs) remains poorly studied. Here, we investigated the genetic diversity of 24 human ZTGs based on the 1000 Genomes data. Some ZTGs show small population differences, such as SLC30A6 with a weighted-average FST (WA-FST = 0.015), while other ZTGs exhibit considerably large population differences, such as SLC30A9 (WA-FST = 0.284). Overall, ZTGs harbor many more highly population-differentiated variants compared with random genes. Intriguingly, we found that SLC30A9 was underlying natural selection in both East Asians (EAS) and Africans (AFR) but in different directions. Notably, a non-synonymous variant (rs1047626) in SLC30A9 is almost fixed with 96.4% A in EAS and 92% G in AFR, respectively. Consequently, there are two different functional haplotypes exhibiting dominant abundance in AFR and EAS, respectively. Furthermore, a strong correlation was observed between the haplotype frequencies of SLC30A9 and distributions of zinc contents in soils or crops. We speculate that the genetic differentiation of ZTGs could directly contribute to population heterogeneity in zinc transporting capabilities and local adaptations of human populations in regard to the local zinc state or diets, which have both evolutionary and medical implications. PMID:25927708

The single-center experience with the standardization of single-site laparoscopic colectomy for right-sided colon cancer.

PubMed

Takahashi, Hidekazu; Takemasa, Ichiro; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Yamamoto, Hirofumi; Matsuda, Chu; Mizushima, Tsunekazu; Doki, Yuichiro; Mori, Masaki

2017-08-01

Complete mesocolic excision (CME) with central vascular ligation (CVL) has been widely accepted as a surgical treatment for right-sided colon cancer. Single-site laparoscopic colectomy (SLC) is associated with reduced pain and improved cosmesis, in comparison to the multi-site laparoscopic colectomy (MCL). Although the feasibility of CME + CVL under MCL has been reported, SLC for right-sided colon cancer is generally challenging. The purpose of this study is to demonstrate our efforts to standardize the SLC for right-sided colon cancer. This retrospective study enrolled 202 consecutive patients with right-sided colon cancer who underwent laparoscopic colectomy for right-sided colon cancer, using an inferior approach and intraoperative navigation surgery, between 2008 and 2014. The patients were divided into 3 groups, based on the period of treatment, as follows: Period I (2008-2009, n = 56), Period II (2010-2011, n = 70), and Period III (2012-2014, n = 76). The patient's baseline characteristics did not differ among the three periods. The ratio of SLC significantly increased with the passage of the time. The short-term outcomes were similar among the three periods. As for oncological clearance, there was a significant increase in the number of resected lymph nodes with the passage of the time (P < 0.05). We successfully standardized SLC for right-sided colon cancer.

Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.

PubMed

Tanegashima, Kosuke; Sato-Miyata, Yukiko; Funakoshi, Masabumi; Nishito, Yasumasa; Aigaki, Toshiro; Hara, Takahiko

2017-01-01

We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon β-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9-mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that β-OHB is a HDAC inhibitor and show that β-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Genetics Home Reference: Amish lethal microcephaly

MedlinePlus

... occurs in approximately 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population. Related Information What information about a genetic condition can statistics provide? Why ... in the SLC25A19 gene cause Amish lethal microcephaly . The SLC25A19 ...

Zinc transport and diabetes risk.

PubMed

Pearson, Ewan

2014-04-01

Genome-wide association studies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk. A rare variant association study has now established the direction of effect, surprisingly showing that loss-of-function mutations in SLC30A8 are protective against diabetes.

9. PAYLOAD CONTROL CONSOLE NEAR EAST WALL OF SLC3W CONTROL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

9. PAYLOAD CONTROL CONSOLE NEAR EAST WALL OF SLC-3W CONTROL ROOM. PAYLOAD CONTROLS INSTALLED IN CONSOLE BY THE PAYLOAD SPONSOR PRIOR TO EACH LAUNCH. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant.

PubMed

Zhao, Zheng; Song, Zhangjun; Wang, Xuwei; Sun, Haifeng; Yang, Xiaomin; Yuan, Yong; Yu, Pan

2017-01-01

ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2 - ROS1 fusion variant, which was different from the two common SLC34A2 - ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal.

Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant

PubMed Central

Zhao, Zheng; Song, Zhangjun; Wang, Xuwei; Sun, Haifeng; Yang, Xiaomin; Yuan, Yong; Yu, Pan

2017-01-01

ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant, which was different from the two common SLC34A2-ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal. PMID:28860822

1. GENERAL VIEW OF SLC3W SHOWING SOUTH FACE AND EAST ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF SLC-3W SHOWING SOUTH FACE AND EAST SIDE OF A-FRAME MOBILE SERVICE TOWER (MST). MST IN SERVICE POSITION OVER LAUNCHER AND FLAME BUCKET. CABLE TRAYS BETWEEN LAUNCH OPERATIONS BUILDING (BLDG. 763) AND SLC-3W IN FOREGROUND. LIQUID OXYGEN APRON VISIBLE IMMEDIATELY EAST (RIGHT) OF MST; FUEL APRON VISIBLE IMMEDIATELY WEST (LEFT) OF MST. A PORTION OF THE FLAME BUCKET VISIBLE BELOW THE SOUTH FACE OF THE MST. CAMERA TOWERS VISIBLE EAST OF MST BETWEEN ROAD AND CABLE TRAY, AND SOUTH OF MST NEAR LEFT MARGIN OF PHOTOGRAPH. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

The competition of densification and structure ordering during crystallization of HCP-Mg in the framework of layering

NASA Astrophysics Data System (ADS)

Luo, Jie; Jiang, Yewei; Yu, Ronggang; Wu, Yongquan

2017-06-01

In this paper, we performed an NPT molecular dynamics simulation of crystallization process of HCP-Mg to probe the competition between densification and structural ordering. Two opposite layering patterns, i.e. outward and inward, were designed for analysis. From the perspective of solid-like cluster (SLC) itself, structural ordering always precedes densification; but from the perspective of SLC's precursor, structural ordering always lags behind densification; the reversion occurs at the closest two liquid layers around SLC. We call it dip-rebound phenomenon. This phenomenon is a completely new finding. It resolves, to some extent, recent debate about whether densification or structural ordering triggers crystallization.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

PubMed

Brezo, J; Bureau, A; Mérette, C; Jomphe, V; Barker, E D; Vitaro, F; Hébert, M; Carbonneau, R; Tremblay, R E; Turecki, G

2010-08-01

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.

13. DETAIL OF CENTER OF CENTRAL CONTROL CONSOLE IN SLC3W ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

13. DETAIL OF CENTER OF CENTRAL CONTROL CONSOLE IN SLC-3W CONTROL ROOM SHOWING USAF LAUNCH CONTROLLER AND ASSISTANT USAF LAUNCH CONTROLLER PANELS. CONSOLES AND CHAIRS NEAR NORTH WALL IN BACKGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Zinc and its transporters, pancreatic beta cells, and insulin metabolism

USDA-ARS?s Scientific Manuscript database

Zinc is an essential trace metal for life. Two families of zinc transporters, SLC30A (ZnT) and SLC39A (ZIP) are required for maintaining cellular zinc homeostasis. ZnTs function to decrease cytoplasmic zinc concentrations whereas ZIPs do the opposite. Expression of zinc transporters can be tissue/ce...

Small Learning Communities Sense of Belonging to Reach At-Risk Students of Promise

ERIC Educational Resources Information Center

Hackney, Debbie

2011-01-01

The research design is a quantitative causal comparative method. The Florida Comprehensive Assessment Test (FCAT) which measures student scores included assessments in mathematics and reading. The design study called for an examination of how type of small learning community (SLC) or the type non-SLC high school environment affected student…

Young Children's Musical Activities in the Home

ERIC Educational Resources Information Center

Blackburn, Carolyn

2017-01-01

The association between human speech, language and communication (SLC) and participation in music is manifest in music education and psychology literature in a number of ways. Research studies into young children's SLC are numerous and policy focus on this area of children's learning and development and their later literacy has been intense. By…

Organizational Strategic Learning Capability: Exploring the Dimensions

ERIC Educational Resources Information Center

Moon, Hanna; Sejong, Wendy; Valentine, Tom

2017-01-01

Purpose: How to build and enhance the strategic learning capability (SLC) of an organization becomes crucial to both research and practice. This study was designed with the purpose to conceptualize SLC by translating and interpreting the related literature to develop empirical dimensions that could be tested and used in a survey instrument.…

Small Learning Communities: 2000-2003. Evaluation Brief

ERIC Educational Resources Information Center

Heath, Debra

2005-01-01

The purpose of this program evaluation was to identify the effects of Small Learning Community (SLC) reforms on school climate, student attitudes and student performance. Eight SLC programs in five Albuquerque high schools were studied for one to four years, depending on each program's date of inception. Data were collected from students,…

Calcium oxalate stone formation in the inner ear as a result of an Slc26a4 mutation.

PubMed

Dror, Amiel A; Politi, Yael; Shahin, Hashem; Lenz, Danielle R; Dossena, Silvia; Nofziger, Charity; Fuchs, Helmut; Hrabé de Angelis, Martin; Paulmichl, Markus; Weiner, Steve; Avraham, Karen B

2010-07-09

Calcium oxalate stone formation occurs under pathological conditions and accounts for more than 80% of all types of kidney stones. In the current study, we show for the first time that calcium oxalate stones are formed in the mouse inner ear of a genetic model for hearing loss and vestibular dysfunction in humans. The vestibular system within the inner ear is dependent on extracellular tiny calcium carbonate minerals for proper function. Thousands of these biominerals, known as otoconia, are associated with the utricle and saccule sensory maculae and are vital for mechanical stimulation of the sensory hair cells. We show that a missense mutation within the Slc26a4 gene abolishes the transport activity of its encoded protein, pendrin. As a consequence, dramatic changes in mineral composition, size, and shape occur within the utricle and saccule in a differential manner. Although abnormal giant carbonate minerals reside in the utricle at all ages, in the saccule, a gradual change in mineral composition leads to a formation of calcium oxalate in adult mice. By combining imaging and spectroscopy tools, we determined the profile of mineral composition and morphology at different time points. We propose a novel mechanism for the accumulation and aggregation of oxalate crystals in the inner ear.

GLUT1 deficiency syndrome as a cause of encephalopathy that includes cognitive disability, treatment-resistant infantile epilepsy and a complex movement disorder.

PubMed

Graham, John M

2012-05-01

Glucose transporter-1 (GLUT1) deficiency syndrome is caused by heterozygous mutations in the SLC2A1 gene, resulting in impaired glucose transport into the brain. It is characterized by a low glucose concentration in the cerebrospinal fluid (hypoglycorrhachia) in the absence of hypoglycemia, in combination with low to normal lactate in the cerebrospinal fluid (CSF). It often results in treatment-resistant infantile epilepsy with progressive developmental disabilities and a complex movement disorder. Recognizing GLUT1 deficiency syndrome is important, since initiation of a ketogenic diet can reduce the frequency of seizures and the severity of the movement disorder. There can be a considerable delay in diagnosing GLUT1 deficiency syndrome, and this point is illustrated by the natural history of this disorder in a 21-year-old woman with severe, progressive neurological disabilities. Her encephalopathy consisted of treatment-resistant seizures, a complex movement disorder, progressive intellectual disability, and deceleration of her head growth after late infancy. Focused evaluation at age 21 revealed GLUT1 deficiency caused by a novel heterozygous missence mutation in exon 7 (c.938C > A; p.Ser313Try) in SLC2A1 as the cause for her disabilities. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

[Importance of the hyperuricaemia, gout and gender nosological features in the activity of general practitioner - family doctor].

PubMed

Rudichenko, V M

2012-01-01

In this article there were analyzed gender data about features of hyperuricaemia and gout: women are much older at the onset of gout arthritis (one of main reasons, probably, makes menopause by itself), have more associated comorbid deseases as hypertension and kidney failure and drinks less alcoholic beverages. It was noticed, that typical localisation of the lesion on the first toe is less often in women, and women are more inclined to use diuretics among medical drugs. Abovementioned clinical features are of some importance for the broad activity of general practitioners - family doctors. Gender features of polyarthicular gout are not uniformed. Scientific researches confirmed possibility of the genetic basis of the uric acid metabolism, which influences some fenotypical features of the organism. Several genes are known for their influence on serum uric acid: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A3, SLC16A9 and SLC22A12. However, conclusions of the research works confirm the necessity of scientific clarification of the importance of different factors of gender differences.

Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man.

PubMed

Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Alvarez-Sala-Walther, Luis-Antonio; Cuadrado-Grande, Nuria; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

2011-03-01

The most common form of hemochromatosis is caused by mutations in the HFE gene. Rare forms of the disease are caused by mutations in other genes. We present a patient with hyperferritinemia and iron overload, and facial flushing. Magnetic resonance imaging was performed to measure hepatic iron overload, and a molecular study of the genes involved in iron metabolism was undertaken. The iron overload was similar to that observed in HFE hemochromatosis, and the patient was double heterozygous for two novel mutations, c.-20G>A and c.718A>G (p.K240E), in the HFE and ferroportin (FPN1 or SLC40A1) genes, respectively. Hyperferritinemia and facial flushing improved after phlebotomy. Two of the patient's children were also studied, and the daughter was heterozygous for the mutation in the SLC40A1 gene, although she did not have hyperferritinemia. The patient presented a mild iron overload phenotype probably because of the two novel mutations in the HFE and SLC40A1 genes. © 2011 John Wiley & Sons A/S.

A Case of Brown-Vialetto-Van Laere Syndrome Due To a Novel Mutation in SLC52A3 Gene

PubMed Central

Thulasi, Venkatraman; Veerapandiyan, Aravindhan; Pletcher, Beth A.; Tong, Chun M.

2017-01-01

Brown-Vialetto-Van Laere syndrome is a rare disorder characterized by motor, sensory, and cranial neuronopathies, associated with mutations in SLC52A2 and SLC52A3 genes that code for human riboflavin transporters RFVT2 and RFVT3, respectively. The authors describe the clinical course of a 6-year-old girl with Brown-Vialetto-Van Laere syndrome and a novel homozygous mutation c.1156T>C in the SLC52A3 gene, who presented at the age of 2.5 years with progressive brain stem dysfunction including ptosis, facial weakness, hearing loss, dysphagia, anarthria with bilateral vocal cord paralysis, and ataxic gait. She subsequently developed respiratory failure requiring tracheostomy and worsening dysphagia necessitating a gastrostomy. Following riboflavin supplementation, resolution of facial diplegia and ataxia, improvements in ptosis, and bulbar function including vocalization and respiration were noted. However, her sensorineural hearing loss remained unchanged. Similar to other cases of Brown-Vialetto-Van Laere syndrome, our patient responded favorably to early riboflavin supplementation with significant but not complete neurologic recovery. PMID:28856173

A Case of Brown-Vialetto-Van Laere Syndrome Due To a Novel Mutation in SLC52A3 Gene: Clinical Course and Response to Riboflavin.

PubMed

Thulasi, Venkatraman; Veerapandiyan, Aravindhan; Pletcher, Beth A; Tong, Chun M; Ming, Xue

2017-01-01

Brown-Vialetto-Van Laere syndrome is a rare disorder characterized by motor, sensory, and cranial neuronopathies, associated with mutations in SLC52A2 and SLC52A3 genes that code for human riboflavin transporters RFVT2 and RFVT3, respectively. The authors describe the clinical course of a 6-year-old girl with Brown-Vialetto-Van Laere syndrome and a novel homozygous mutation c.1156T>C in the SLC52A3 gene, who presented at the age of 2.5 years with progressive brain stem dysfunction including ptosis, facial weakness, hearing loss, dysphagia, anarthria with bilateral vocal cord paralysis, and ataxic gait. She subsequently developed respiratory failure requiring tracheostomy and worsening dysphagia necessitating a gastrostomy. Following riboflavin supplementation, resolution of facial diplegia and ataxia, improvements in ptosis, and bulbar function including vocalization and respiration were noted. However, her sensorineural hearing loss remained unchanged. Similar to other cases of Brown-Vialetto-Van Laere syndrome, our patient responded favorably to early riboflavin supplementation with significant but not complete neurologic recovery.

Whole-genome analysis of a patient with early-stage small-cell lung cancer.

PubMed

Han, J-Y; Lee, Y-S; Kim, B C; Lee, G K; Lee, S; Kim, E-H; Kim, H-M; Bhak, J

2014-12-01

We performed whole-genome sequencing (WGS) of a case of early-stage small-cell lung cancer (SCLC) to analyze the genomic features. WGS revealed a lot of single-nucleotide variations (SNVs), small insertion/deletions and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Somatic mutations were found in TP53 and CREBBP. Novel nonsynonymous (ns) SNVs in C6ORF103 and SLC5A4 genes were also found. Sanger sequencing of the SLC5A4 gene in 23 independent SCLC samples showed another nsSNV in the SLC5A4 gene, indicating that nsSNVs in the SLC5A4 gene are recurrent in SCLC. WGS of an early-stage SCLC identified novel recurrent mutations and validated known variations, including copy number variations. These findings provide insight into the genomic landscape contributing to SCLC development.

Removal of bacteria from boar ejaculates by Single Layer Centrifugation can reduce the use of antibiotics in semen extenders.

PubMed

Morrell, J M; Wallgren, M

2011-01-01

There is considerable interest world-wide in reducing the use of antibiotics to stem the development of antibiotic-resistant strains of bacteria. An alternative to the routine addition of antibiotics to semen extenders in livestock breeding would be to separate the spermatozoa from bacterial contaminants in the semen immediately after collection. The present study was designed to determine whether such separation was possible by Single Layer Centrifugation (SLC) using the colloid Androcoll™-P. The results showed that complete removal (6 out of 10 samples), or considerable reduction of bacterial contaminants (4 out of 10 samples) was possible with this method. The type of bacteria and/or the length of time between collection and SLC-processing affected the removal of bacteria, with motile flagellated bacteria being more likely to be present after SLC than non-flagellated bacteria. Although further studies are necessary, these preliminary results suggest that the use of SLC when processing boar semen for AI doses might enable antibiotic usage in semen extenders to be reduced. Copyright © 2010 Elsevier B.V. All rights reserved.

Furosemide loading test in a case of homozygous solute carrier family 12, member 1 (SLC12A1) mutation (g.62382825G>A, p.Pro372Leu) in Japanese Black cattle.

PubMed

Hasegawa, Kiyotoshi; Sasaki, Shinji; Sakamoto, Yoichi; Takano, Akifumi; Takayama, Megumi; Higashi, Tomoko; Sugimoto, Yoshikazu; Yasuda, Yasuaki

2017-10-01

Hydrallantois is the excessive accumulation of fluid in the allantoic cavity in a pregnant animal and is associated with fetal death. We recently identified a recessive missense mutation in the solute carrier family 12, member 1 (SLC12A1) gene (g.62382825G>A, p.Pro372Leu) that is associated with hydrallantois in Japanese Black cattle. Unexpectedly, we found a case of the homozygous risk-allele for SLC12A1 in a calf, using a PCR-based direct DNA sequencing test. The homozygote was outwardly healthy up to 3 months of age and the mother did not exhibit any clinical symptoms of hydrallantois. In order to validate these observations, we performed confirmation tests for the genotype and a diuretic loading test using furosemide, which inhibits the transporter activity of the SLC12A1 protein. The results showed that the calf was really homozygous for the risk-allele. In the homozygous calf, administration of furosemide did not alter urinary Na + or Cl - levels, in contrast to the heterozygote and wild-type calves in which these were significantly increased. These results demonstrate that the SLC12A1 (g.62382825G>A, p.Pro372Leu) is a hypomorphic or loss-of-function mutation and the hydrallantois with this mutation shows incomplete penetrance in Japanese Black cattle. © 2017 Japanese Society of Animal Science.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

PubMed Central

Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L.; Jacobs, Suzanne B. R.; Grarup, Niels; Burtt, Noël P.; Mahajan, Anubha; Fuchsberger, Christian; Atzmon, Gil; Benediktsson, Rafn; Blangero, John; Bowden, Don W.; Brandslund, Ivan; Brosnan, Julia; Burslem, Frank; Chambers, John; Cho, Yoon Shin; Christensen, Cramer; Douglas, Desirée A.; Duggirala, Ravindranath; Dymek, Zachary; Farjoun, Yossi; Fennell, Timothy; Fontanillas, Pierre; Forsén, Tom; Gabriel, Stacey; Glaser, Benjamin; Gudbjartsson, Daniel F.; Hanis, Craig; Hansen, Torben; Hreidarsson, Astradur B.; Hveem, Kristian; Ingelsson, Erik; Isomaa, Bo; Johansson, Stefan; Jørgensen, Torben; Jørgensen, Marit Eika; Kathiresan, Sekar; Kong, Augustine; Kooner, Jaspal; Kravic, Jasmina; Laakso, Markku; Lee, Jong-Young; Lind, Lars; Lindgren, Cecilia M; Linneberg, Allan; Masson, Gisli; Meitinger, Thomas; Mohlke, Karen L; Molven, Anders; Morris, Andrew P.; Potluri, Shobha; Rauramaa, Rainer; Ribel-Madsen, Rasmus; Richard, Ann-Marie; Rolph, Tim; Salomaa, Veikko; Segrè, Ayellet V.; Skärstrand, Hanna; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Sulem, Patrick; Tai, E Shyong; Teo, Yik Ying; Teslovich, Tanya; Thorsteinsdottir, Unnur; Trimmer, Jeff K.; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Vaziri-Sani, Fariba; Voight, Benjamin F.; Wilson, James G.; Boehnke, Michael; McCarthy, Mark I.; Njølstad, Pål R.; Pedersen, Oluf; Groop, Leif; Cox, David R.; Stefansson, Kari; Altshuler, David

2014-01-01

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention. PMID:24584071

The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter

PubMed Central

Abplanalp, Jeannette; Laczko, Endre; Philp, Nancy J.; Neidhardt, John; Zuercher, Jurian; Braun, Philipp; Schorderet, Daniel F.; Munier, Francis L.; Verrey, François; Berger, Wolfgang; Camargo, Simone M.R.; Kloeckener-Gruissem, Barbara

2013-01-01

Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis–Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition. PMID:23578822

The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter.

PubMed

Abplanalp, Jeannette; Laczko, Endre; Philp, Nancy J; Neidhardt, John; Zuercher, Jurian; Braun, Philipp; Schorderet, Daniel F; Munier, Francis L; Verrey, François; Berger, Wolfgang; Camargo, Simone M R; Kloeckener-Gruissem, Barbara

2013-08-15

Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis-Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition.

Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism

PubMed Central

Cross, Sarah; Kim, Soo-Jeong; Weiss, Lauren A.; Delahanty, Ryan J.; Sutcliffe, James S.; Leventhal, Bennett L.; Cook, Edwin H.; Veenstra-VanderWeele, Jeremy

2009-01-01

Elevated platelet serotonin (5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood serotonin (5-HT), 5-HT binding affinity for the serotonin transporter (Km), 5-HT uptake (Vmax), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in twenty-four first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (Km, p = 0.005) and 5-HT uptake rate (Vmax, p = 0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p = 0.046). These initial studies of indices of the 5-HT system with several SNPs at loci in this system generate hypotheses for testing in other samples. PMID:17406648

Single layer centrifugation-selected boar spermatozoa are capable of fertilization in vitro

PubMed Central

2013-01-01

Background Good quality spermatozoa are important to achieve fertilization, viable embryos and offspring. Single Layer Centrifugation (SLC) through a colloid (Androcoll-P) selects good quality spermatozoa. However, it has not been established previously whether porcine spermatozoa selected by this method maintain their fertility. Methods The semen was prepared either by SLC or by standard centrifugation (control) and used for in vitro fertilization (IVF) at oocyte:spermatozoa ratios of 1:50; 1:100 and 1:300 (or 4 x 103, 8 x 103 and 24 x 103 spermatozoa/ml) to evaluate their subsequent ability to generate blastocysts. In addition, sperm motility was assessed by computer assisted sperm motility analysis. Results Total and progressive motility were significantly higher in sperm samples prepared by SLC compared to uncentrifuged samples. Sperm binding ability, polyspermy, cleavage and blastocyst rates were affected by the oocyte:sperm ratio, but not by sperm treatment. Conclusion The use of SLC does not adversely affect the in vitro fertilizing and embryo-generating ability of the selected spermatozoa compared to their unselected counterparts, but further modifications in the IVF conditions would be needed to improve the monospermy in IVF systems. Since SLC did not appear to have a negative effect on sperm fertilizing ability, and may in fact select for spermatozoa with a greater potential for fertilization, an in vivo trial to determine the usefulness of this sperm preparation technique prior to artificial insemination is warranted. PMID:23497680

Exome Sequencing Identifies a Novel Homozygous Mutation in the Phosphate Transporter SLC34A1 in Hypophosphatemia and Nephrocalcinosis

PubMed Central

Rajagopal, Abbhirami; Braslavsky, Débora; Lu, James T.; Kleppe, Soledad; Clément, Florencia; Cassinelli, Hamilton; Liu, David S.; Liern, Jose Miguel; Vallejo, Graciela; Bergadá, Ignacio; Gibbs, Richard A.; Campeau, Phillipe M.

2014-01-01

Context: Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis. Objective: The goal of this study was to identify genetic causes of the clinical findings in the two siblings. Design: Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified. Patients and Other Participants: Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies. Results: A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484G>A, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1. Conclusions: The homozygous G>A transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition. PMID:25050900

SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.

PubMed

Park, Julien H; Hogrebe, Max; Grüneberg, Marianne; DuChesne, Ingrid; von der Heiden, Ava L; Reunert, Janine; Schlingmann, Karl P; Boycott, Kym M; Beaulieu, Chandree L; Mhanni, Aziz A; Innes, A Micheil; Hörtnagel, Konstanze; Biskup, Saskia; Gleixner, Eva M; Kurlemann, Gerhard; Fiedler, Barbara; Omran, Heymut; Rutsch, Frank; Wada, Yoshinao; Tsiakas, Konstantinos; Santer, René; Nebert, Daniel W; Rust, Stephan; Marquardt, Thorsten

2015-12-03

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2).

PubMed

Guissart, Claire; Drouot, Nathalie; Oncel, Ibrahim; Leheup, Bruno; Gershoni-Barush, Ruth; Muller, Jean; Ferdinandusse, Sacha; Larrieu, Lise; Anheim, Mathieu; Arslan, Elif Acar; Claustres, Mireille; Tranchant, Christine; Topaloglu, Haluk; Koenig, Michel

2016-08-01

Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21-p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown-Vialleto-Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2)

PubMed Central

Guissart, Claire; Drouot, Nathalie; Oncel, Ibrahim; Leheup, Bruno; Gershoni-Barush, Ruth; Muller, Jean; Ferdinandusse, Sacha; Larrieu, Lise; Anheim, Mathieu; Arslan, Elif Acar; Claustres, Mireille; Tranchant, Christine; Topaloglu, Haluk; Koenig, Michel

2016-01-01

Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21–p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown–Vialleto–Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation. PMID:26669662

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

PubMed

Patriquin, Michelle A; Hamon, Sara C; Harding, Mark J; Nielsen, Ellen M; Newton, Thomas F; De La Garza, Richard; Nielsen, David A

2017-10-01

This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Bicarbonate Transport During Enamel Maturation.

PubMed

Yin, Kaifeng; Paine, Michael L

2017-11-01

Amelogenesis (tooth enamel formation) is a biomineralization process consisting primarily of two stages (secretory stage and maturation stage) with unique features. During the secretory stage, the inner epithelium of the enamel organ (i.e., the ameloblast cells) synthesizes and secretes enamel matrix proteins (EMPs) into the enamel space. The protein-rich enamel matrix forms a highly organized architecture in a pH-neutral microenvironment. As amelogenesis transitions to maturation stage, EMPs are degraded and internalized by ameloblasts through endosomal-lysosomal pathways. Enamel crystallite formation is initiated early in the secretory stage, however, during maturation stage the more rapid deposition of calcium and phosphate into the enamel space results in a rapid expansion of crystallite length and mineral volume. During maturation-stage amelogenesis, the pH value of enamel varies considerably from slightly above neutral to acidic. Extracellular acid-base balance during enamel maturation is tightly controlled by ameloblast-mediated regulatory networks, which include significant synthesis and movement of bicarbonate ions from both the enamel papillary layer cells and ameloblasts. In this review we summarize the carbonic anhydrases and the carbonate transporters/exchangers involved in pH regulation in maturation-stage amelogenesis. Proteins that have been shown to be instrumental in this process include CA2, CA6, CFTR, AE2, NBCe1, SLC26A1/SAT1, SLC26A3/DRA, SLC26A4/PDS, SLC26A6/PAT1, and SLC26A7/SUT2. In addition, we discuss the association of miRNA regulation with bicarbonate transport in tooth enamel formation.

Genetic variations in the MCT1 (SLC16A1) gene in the Chinese population of Singapore.

PubMed

Lean, Choo Bee; Lee, Edmund Jon Deoon

2009-01-01

MCT1(SLC16A1) is the first member of the monocarboxylate transporter (MCT) and its family is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study identifies genetic variations in SLC16A1 in the ethnic Chinese group of the Singaporean population (n=95). The promoter, coding region and exon-intron junctions of the SLC16A1 gene encoding the MCT1 transporter were screened for genetic variation in the study population by DNA sequencing. Seven genetic variations of SLC16A1, including 4 novel ones, were found: 2 in the promoter region, 2 in the coding exons (both nonsynonymous variations), 2 in the 3' untranslated region (3'UTR) and 1 in the intron. Of the two mutations detected in the promoter region, the -363-855T>C is a novel mutation. The 1282G>A (Val(428)Ile) is a novel SNP and was found as heterozygotic in 4 subjects. The 1470T>A (Asp(490)Glu) was found to be a common polymorphism in this study. Lastly, IVS3-17A>C in intron 3 and 2258 (755)A>G in 3'UTR are novel mutations found to be common polymorphisms in the local Chinese population. To our knowledge, this is the first report of a comprehensive analysis on the MCT1 gene in any population.

Implementation of Scientific Community Laboratories and Their Effect on Student Conceptual Learning, Attitudes, and Understanding of Uncertainty

NASA Astrophysics Data System (ADS)

Lark, Adam

Scientific Community Laboratories, developed by The University of Maryland, have shown initial promise as laboratories meant to emulate the practice of doing physics. These laboratories have been re-created by incorporating their design elements with the University of Toledo course structure and resources. The laboratories have been titled the Scientific Learning Community (SLC) Laboratories. A comparative study between these SLC laboratories and the University of Toledo physics department's traditional laboratories was executed during the fall 2012 semester on first semester calculus-based physics students. Three tests were executed as pre-test and post-tests to capture the change in students' concept knowledge, attitudes, and understanding of uncertainty. The Force Concept Inventory (FCI) was used to evaluate students' conceptual changes through the semester and average normalized gains were compared between both traditional and SLC laboratories. The Colorado Learning Attitudes about Science Survey for Experimental Physics (E-CLASS) was conducted to elucidate students' change in attitudes through the course of each laboratory. Finally, interviews regarding data analysis and uncertainty were transcribed and coded to track changes in the way students understand uncertainty and data analysis in experimental physics after their participation in both laboratory type. Students in the SLC laboratories showed a notable an increase conceptual knowledge and attitudes when compared to traditional laboratories. SLC students' understanding of uncertainty showed most improvement, diverging completely from students in the traditional laboratories, who declined throughout the semester.

Glutaminolysis and carcinogenesis of oral squamous cell carcinoma.

PubMed

Cetindis, Marcel; Biegner, Thorsten; Munz, Adelheid; Teriete, Peter; Reinert, Siegmar; Grimm, Martin

2016-02-01

Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I-III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I-III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4.

PubMed

Tóth, Lola; Fábos, Beáta; Farkas, Katalin; Sulák, Adrienn; Tripolszki, Kornélia; Széll, Márta; Nagy, Nikoletta

2017-03-15

Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities. OCA type IV (OCA4, OMIM 606574) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene. This gene encodes a membrane-associated transport protein, which regulates tyrosinase activity and, thus, melanin content by changing melanosomal pH and disrupting the incorporation of copper into tyrosinase. Here we report two Hungarian siblings affected by an unusual OCA4 phenotype. After genomic DNA was isolated from peripheral blood of the patients, the coding regions of the SLC45A2 gene were sequenced. In silico tools were applied to identify the functional impact of the newly detected mutations. Direct sequencing of the SLC45A2 gene revealed two novel, heterozygous mutations, one missense (c.1226G > A, p.Gly409Asp) and one nonsense (c.1459C > T, p.Gln437*), which were present in both patients, suggesting the mutations were compound heterozygous. In silico tools suggest that these variations are disease causing mutations. The newly identified mutations may affect the transmembrane domains of the protein, and could impair transport function, resulting in decreases in both melanosomal pH and tyrosinase activity. Our study provides expands on the mutation spectrum of the SLC45A2 gene and the genetic background of OCA4.

Genetic analysis and literature review of Chinese patients with familial renal glucosuria: Identification of a novel SLC5A2 mutation.

PubMed

Wang, Xiaojing; Yu, Miao; Wang, Tong; Zhang, Huabing; Ping, Fan; Zhang, Qian; Xu, Jianping; Feng, Kai; Xiao, Xinhua

2017-06-01

Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria with normal blood glucose. SLC5A2 gene mutation was the causative of FRG. Molecular genetic analysis of SLC5A2 gene by Sanger sequencing was conducted in two unrelated non-consanguineous Chinese families with isolated glucosuria. Extensive laboratory test and physical examination were performed. In silico algorithms were used to explore the potential effect of novel mutation on SGLT2 function. We also summarized the reported SLC5A2 mutations in the Chinese patients with FRG. A novel missense mutation (c.877A>T, p.Ser293Cys) in exon 3 was detected in proband 1 with weight loss accompanying by glucosuria and in her father with normal phenotype. In family 2, a previously reported compound heterozygous mutation (c.229G>C, p.Gly77Arg; c.1540C>T, p.Pro514Ser) was identified, and her healthy parents were heterozygous mutation carriers. The p.S293C mutation was predicted to be pathogenic. No hot spot mutation was found in reported Chinese patients with FRG. The novel pathogenic SLC5A2 mutation p.S293C was responsible for the onset of FRG. Our study further confirmed the co-dominant inheritance trait with variable penetrance and expanded the clinical and genetic spectrum of FRG. Copyright © 2017 Elsevier B.V. All rights reserved.

Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations.

PubMed

Yao, Jun; Qian, Xuli; Bao, Jingxiao; Wei, Qinjun; Lu, Yajie; Zheng, Heng; Cao, Xin; Xing, Guangqian

2015-06-02

A Chinese family was identified with clinical features of enlarged vestibular aqueduct syndrome (EVAS). The mutational analysis showed that the proband (III-2) had EVAS with bilateral sensorineural hearing loss and carried a rare compound heterozygous mutation of SLC26A4 (IVS7-2A>G, c.2167C>G), which was inherited from the same mutant alleles of IVS7-2A>G heterozygous father and c.2167C>G heterozygous mother. Compared with another confirmed pathogenic biallelic mutation in SLC26A4 (IVS7-2A>G, c.2168A>G), these two biallelic mutations shared one common mutant allele and the same codon of the other mutant allele, but led to different changes of amino acid (p.H723D, p.H723R) and both resulted in the deafness phenotype. Structure-modeling indicated that these two mutant alleles changed the shape of pendrin protein encoded by SLC26A4 with increasing randomness in conformation, and might impair pendrin's ability as an anion transporter. The molecular dynamics simulations also revealed that the stability of mutant pendrins was reduced with increased flexibility of backbone atoms, which was consistent with the structure-modeling results. These evidences indicated that codon 723 was a hot-spot region in SLC26A4 with a significant impact on the structure and function of pendrin, and acted as one of the genetic factors responsible for the development of hearing loss.

Pharmacogenetic studies update in type 2 diabetes mellitus

PubMed Central

Singh, Shalini; Usman, Kauser; Banerjee, Monisha

2016-01-01

Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment. PMID:27555891

Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.

PubMed

Thangaraju, Muthusamy; Karunakaran, Senthil K; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D; Ganapathy, Vadivel

2009-10-15

3-bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of adenosine triphosphate production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The current studies uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. The transport of 3-bromopyruvate by sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), a tumor suppressor and a sodium (Na+)-coupled, electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by fluorescence-activated cell-sorting analysis and colony-formation assay. The acetylation status of histone H4 was evaluated by Western blot analysis. 3-Bromopyruvate is a transportable substrate for SLC5A8, and that transport process is Na+-coupled and electrogenic. MCF7 cells did not express SLC5A8 and were not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells underwent apoptosis in the presence of 3-bromopyruvate. This cell death was associated with the inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identified HDAC1 and HDAC3 as the targets for 3-bromopyruvate. 3-Bromopyruvate was transported into cells actively through the tumor suppressor SLC5A8, and the process was energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells led to apoptosis, and the mechanism involved the inhibition of HDAC1/HDAC3. Copyright (c) 2009 American Cancer Society.

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms

PubMed Central

2012-01-01

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability. PMID:23234264

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

PubMed

Cheillan, David; Joncquel-Chevalier Curt, Marie; Briand, Gilbert; Salomons, Gajja S; Mention-Mulliez, Karine; Dobbelaere, Dries; Cuisset, Jean-Marie; Lion-François, Laurence; Portes, Vincent Des; Chabli, Allel; Valayannopoulos, Vassili; Benoist, Jean-François; Pinard, Jean-Marc; Simard, Gilles; Douay, Olivier; Deiva, Kumaran; Afenjar, Alexandra; Héron, Delphine; Rivier, François; Chabrol, Brigitte; Prieur, Fabienne; Cartault, François; Pitelet, Gaëlle; Goldenberg, Alice; Bekri, Soumeya; Gerard, Marion; Delorme, Richard; Tardieu, Marc; Porchet, Nicole; Vianey-Saban, Christine; Vamecq, Joseph

2012-12-13

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

Effect of heat stress on the gene expression of ion transporters/channels in the uterus of laying hens during eggshell formation.

PubMed

Bahadoran, Shahab; Dehghani Samani, Amir; Hassanpour, Hossein

2018-01-01

Heat stress is a problem in laying hens as it decreases egg quality by decreasing eggshell mineralization. Heat stress alters gene expression, hence our aim was to investigate effects of heat stress on gene expression of ion transport elements involving in uterine mineralization (TRPV6, CALB1, ITPR3, SCNN1G, SLC4A4, KCNJ15, SLC4A9, and CLCN2) by real time quantitative PCR. Forty 23-week-old White Leghorn laying hens were housed in two rooms. The control group (n = 20) was maintained at 21-23 °C, and the heat stress group (n = 20) was exposed to 36-38 °C for 8 weeks. All parameters of egg quality including egg weight, surface area, volume, and eggshell weight, thickness, ash weight, and calcium content were decreased in the heat stress group compared to the control group (by 26.9%, 32.7%, 44.1%, 38.4%, 31.7%, 39.4%, and 11.1%, respectively). Total plasma calcium was decreased by 13.4%. Levels of ITPR3, SLC4A4, and SLC4A9 transcripts in the uterine lining were decreased in the heat stress group compared to the control group (by 61.4%, 66.1%, and 66.1%, respectively). CALB1 transcript level was increased (by 34.2 fold) in the heat stress group of hens compared to controls. TRPV6, SCNN1G, KCNJ15, and CLCN2 transcript levels did not significantly differ between control and heat stress groups of laying hens. It is concluded that the down-expression of ITPR3, SLC4A4, and SLC4A9 genes may impair transportation of Cl - , HCO 3 - , and Na + in eggshell mineralization during heat stress. Increased CALB1 gene expression may increase resistance of uterine cells to detrimental effects of heat stress.

Identification of a founder mutation for Pendred syndrome in families from northwest Iran.

PubMed

Mohseni, Marzieh; Honarpour, Asal; Mozafari, Reza; Davarnia, Behzad; Najmabadi, Hossein; Kahrizi, Kimia

2014-11-01

Mutations in the SLC26A4 gene cause both Pendred syndrome and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB4 locus. The SLC26A4 mutations vary among different communities. Previous studies have shown that mutations in the SLC26A4 gene are responsible for the more common syndromic hereditary hearing loss in Iran. This study assesses the possibility of a founder mutation for Pendred syndrome in northwest Iran. In this study, we performed comprehensive clinical and genetic evaluations in two unrelated families from northwest Iran with nine members affected by hearing loss (HL). After testing short tandem repeat (STR) markers to confirm linkage to the SLC26A4 locus, we screened the SLC26A4 gene by Sanger sequencing of all 21 exons, exon-intron boundaries and the promoter region for any causative mutation. We identified the same causative mutation in these two families as we had detected earlier in two other Azeri families from northwest Iran. To investigate the possibility of a founder effect in these four families, we conducted haplotype analysis, and 14 single nucleotide polymorphisms (SNPs) throughout the SLC26A4 gene were genotyped. Patients in the two families showed the phenotype of Pendred syndrome. A known frameshift mutation (c.965insA, p.N322Fs7X) in exon 8 was identified in the two families, which was the same mutation that we detected previously in two other Azeri families. The results of haplotype analysis showed that all 15 patients from four families shared the founder mutation. Common haplotypes were not observed in noncarrier members. Based on the results of our two studies, the c.965insA mutation has only been described in Iranian families from northwest Iran, so there is evidence for a founder mutation originating in this part of Iran. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Functional identification of the promoter of SLC4A5, a gene associated with cardiovascular and metabolic phenotypes in the HERITAGE Family Study.

PubMed

Stütz, Adrian M; Teran-Garcia, Margarita; Rao, D C; Rice, Treva; Bouchard, Claude; Rankinen, Tuomo

2009-11-01

The sodium bicarbonate cotransporter gene SLC4A5, associated earlier with cardiovascular phenotypes, was tested for associations in the HERITAGE Family Study, and possible mechanisms were investigated. Twelve tag-single nucleotide polymorphisms (SNPs) covering the SLC4A5 gene were analyzed in 276 Black and 503 White healthy, sedentary subjects. Associations were tested using a variance components-based (QTDT) method with data adjusted for age, sex and body size. In Whites, rs6731545 and rs7571842 were significantly associated with resting and submaximal exercise pulse pressure (PP) (0.0004

Molecular basis of essential amino acid transport from studies of insect nutrient amino acid transporters of the SLC6 family (NAT-SLC6)

PubMed Central

Boudko, Dmitri Y.

2012-01-01

Two protein families that represent major components of essential amino acid transport in insects have been identified. They are annotated as the SLC6 and SLC7 families of transporters according to phylogenetic proximity to characterized amino acid transporters (HUGO nomenclature). Members of these families have been identified as important apical and basolateral parts of transepithelial essential amino acid absorption in the metazoan alimentary canal. Synergistically, they play critical physiological roles as essential substrate providers to diverse metabolic processes, including generic protein synthesis. This review briefly clarifies the requirements for amino acid transport and a variety of amino acid transport mechanisms, including the aforementioned families. Further it focuses on the large group of Nutrient Amino acid Transporters (NATs), which comprise a recently identified subfamily of the Neurotransmitter Sodium Symporter family (NSS or SLC6). The first insect NAT, cloned from the caterpillar gut, has a broad substrate spectrum similar to mammalian B0 transporters. Several new NAT-SLC6 members have been characterized in an effort to explore mechanisms for the essential amino acid absorption in model dipteran insects. The identification and functional characterization of new B0-like and narrow specificity transporters of essential amino acids in fruit fly and mosquitoes leads to a fundamentally important insight: that NATs evolved and act together as the integrated active core of a transport network that mediates active alimentary absorption and systemic distribution of essential amino acids. This role of NATs is projected from the most primitive prokaryotes to the most complex metazoan organisms, and represents an interesting platform for unraveling the molecular evolution of amino acid transport and modeling amino acid transport disorders. The comparative study of NATs elucidates important adaptive differences between essential amino acid transportomes of invertebrate and vertebrate organisms, outlining a new possibility for selective targeting of essential amino acid absorption mechanisms to control medically and economically important arthropods and other invertebrate organisms. PMID:22230793

Diversity in the glucose transporter-4 gene (SLC2A4) in humans reflects the action of natural selection along the old-world primates evolution.

PubMed

Tarazona-Santos, Eduardo; Fabbri, Cristina; Yeager, Meredith; Magalhaes, Wagner C; Burdett, Laurie; Crenshaw, Andrew; Pettener, Davide; Chanock, Stephen J

2010-03-23

Glucose is an important source of energy for living organisms. In vertebrates it is ingested with the diet and transported into the cells by conserved mechanisms and molecules, such as the trans-membrane Glucose Transporters (GLUTs). Members of this family have tissue specific expression, biochemical properties and physiologic functions that together regulate glucose levels and distribution. GLUT4 -coded by SLC2A4 (17p13) is an insulin-sensitive transporter with a critical role in glucose homeostasis and diabetes pathogenesis, preferentially expressed in the adipose tissue, heart muscle and skeletal muscle. We tested the hypothesis that natural selection acted on SLC2A4. We re-sequenced SLC2A4 and genotyped 104 SNPs along a approximately 1 Mb region flanking this gene in 102 ethnically diverse individuals. Across the studied populations (African, European, Asian and Latin-American), all the eight common SNPs are concentrated in the N-terminal region upstream of exon 7 ( approximately 3700 bp), while the C-terminal region downstream of intron 6 ( approximately 2600 bp) harbors only 6 singletons, a pattern that is not compatible with neutrality for this part of the gene. Tests of neutrality based on comparative genomics suggest that: (1) episodes of natural selection (likely a selective sweep) predating the coalescent of human lineages, within the last 25 million years, account for the observed reduced diversity downstream of intron 6 and, (2) the target of natural selection may not be in the SLC2A4 coding sequence. We propose that the contrast in the pattern of genetic variation between the N-terminal and C-terminal regions are signatures of the action of natural selection and thus follow-up studies should investigate the functional importance of different regions of the SLC2A4 gene.

Functional identification of the promoter of SLC4A5, a gene associated with cardiovascular and metabolic phenotypes in the HERITAGE Family Study

PubMed Central

Stütz, Adrian M; Teran-Garcia, Margarita; Rao, D C; Rice, Treva; Bouchard, Claude; Rankinen, Tuomo

2009-01-01

The sodium bicarbonate cotransporter gene SLC4A5, associated earlier with cardiovascular phenotypes, was tested for associations in the HERITAGE Family Study, and possible mechanisms were investigated. Twelve tag-single nucleotide polymorphisms (SNPs) covering the SLC4A5 gene were analyzed in 276 Black and 503 White healthy, sedentary subjects. Associations were tested using a variance components-based (QTDT) method with data adjusted for age, sex and body size. In Whites, rs6731545 and rs7571842 were significantly associated with resting and submaximal exercise pulse pressure (PP) (0.0004

Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study1234

PubMed Central

Voruganti, V Saroja; Laston, Sandra; Haack, Karin; Mehta, Nitesh R; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G

2015-01-01

Background: Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children. Objective: The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study. Design: We conducted a genomewide association study with 1.1 million genetic markers in 815 children. Results: We found serum uric acid to be significantly heritable [h2 ± SD = 0.45 ± 0.08, P = 5.8 × 10−11] and associated with SLC2A9 variants (P values between 10−16 and 10−7). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (ρG = 0.45, P = 0.002), percentage of body fat (ρG = 0.28, P = 0.04), fat mass (ρG = 0.34, P = 0.02), waist circumference (ρG = 0.42, P = 0.003), and waist-to-height ratio (ρG = 0.46, P = 0.001). Conclusions: Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children. PMID:25833971

Two Variants in SLC24A5 Are Associated with “Tiger-Eye” Iris Pigmentation in Puerto Rican Paso Fino Horses

PubMed Central

Mack, Maura; Kowalski, Elizabeth; Grahn, Robert; Bras, Dineli; Penedo, Maria Cecilia T.; Bellone, Rebecca

2017-01-01

A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF) horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS) with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 × 10−5). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA) type 6 (OCA6), which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del), which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse. PMID:28655738

GABBR1 and SLC6A1, two genes involved in modulation of GABA synaptic transmission influence risk for alcoholism; results from three ethnically diverse populations

PubMed Central

Enoch, Mary-Anne; Hodgkinson, Colin A.; Shen, Pei-Hong; Gorodetsky, Elena; Marietta, Cheryl A.; Roy, Alex; Goldman, David

2015-01-01

Background Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal GABA transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore variants in these genes might predict risk/resilience for alcoholism. Methods This study included three populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid ASPD, 181 controls; a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag SNPs were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. Results We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all three populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, i.e. the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism whereas carriers of the IND allele and either rs29220 homozygote were more resilient. Conclusions Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist. PMID:26727527

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene

PubMed Central

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L.; Noori, Hamid R.; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C.; Schloss, Patrick

2017-01-01

ABSTRACT The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. PMID:28167616

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene.

PubMed

Vengeliene, Valentina; Bespalov, Anton; Roßmanith, Martin; Horschitz, Sandra; Berger, Stefan; Relo, Ana L; Noori, Hamid R; Schneider, Peggy; Enkel, Thomas; Bartsch, Dusan; Schneider, Miriam; Behl, Berthold; Hansson, Anita C; Schloss, Patrick; Spanagel, Rainer

2017-04-01

The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene ( Slc6a3 _N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3 _N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity. © 2017. Published by The Company of Biologists Ltd.