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SLC19A3 related disorder: Treatment implication and clinical outcome of 2 new patients.
Tonduti, D, Invernizzi, F, Panteghini, C, Pinelli, L, Battaglia, S, Fazzi, E, Zorzi, G, Moroni, I, Garavaglia, B, Chiapparini, L, et al
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2018;(2):332-335
Abstract
Encephalopathies with neostriatal involvement constitute a heterogeneous group of acquired and genetically inherited conditions that include Bilateral Striatal Necrosis (BSN) and other Striatal Lesions (SL) (Tonduti et al). We describe two new patients suffering from BSN due to biallelic SLC19A3 mutations. In the first patient vitamin supplementation was started early on, resulting in the remission of the clinical picture, and an almost complete normalization of the neuroradiological findings. In the second one treatment was started late, compliance was irregular and the resulting clinical outcome was poor. The clinical outcome of our two patients confirms and further stresses the importance of the early administration of vitamin supplementation in all patients presenting with neostriatal lesions, or clear bilateral striatal necrosis. Patient 2 didn't present any additional episode of acute decompensation after the age of 20 years despite having completely stopped treatment. This suggests the existence of an age dependency of thiamin requirement in humans.
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2.
A Delicate Connection: c-di-AMP Affects Cell Integrity by Controlling Osmolyte Transport.
Commichau, FM, Gibhardt, J, Halbedel, S, Gundlach, J, Stülke, J
Trends in microbiology. 2018;(3):175-185
Abstract
Bacteria use second-messenger molecules to adapt to their environment. Several second messengers, among them cyclic di-AMP (c-di-AMP), have been discovered and intensively studied. Interestingly, c-di-AMP is essential for growth of Gram-positive bacteria such as Bacillus subtilis, Listeria monocytogenes, and Staphylococcus aureus. Many studies demonstrated that perturbation of c-di-AMP metabolism affects the integrity of the bacterial cell envelope. Therefore, it has been assumed that the nucleotide is essential for proper cell envelope synthesis. In this Opinion paper, we propose that the cell envelope phenotypes caused by perturbations of c-di-AMP metabolism can be interpreted differently: c-di-AMP might indirectly control cell envelope integrity by modulating the turgor, a physical variable that needs to be tightly adjusted. We also discuss open questions related to c-di-AMP metabolism that need to be urgently addressed by future studies.
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3.
Mechanisms of phloem loading.
Zhang, C, Turgeon, R
Current opinion in plant biology. 2018;:71-75
Abstract
The complex form of higher plants requires continuous, balanced transport of nutrients in the phloem. The initial step of transferring sugars, amino acids, and other materials from photosynthetic cells to the conducting sieve tubes is known as phloem loading. Three phloem loading mechanisms have been described. The first involves release of sucrose into the apoplast and subsequent retrieval by the phloem. The initial release step in this process is now known to be mediated by a new class of transporters, the SWEET proteins. In the other two loading mechanisms, polymer trapping and diffusion, sucrose passes into the phloem through cytoplasmic channels, the plasmodesmata. Recent models have shed additional light on these mechanisms and their ability to sustain the growth of even the tallest trees.
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SLC19A3 Gene Defects Sorting the Phenotype and Acronyms: Review.
Alfadhel, M, Tabarki, B
Neuropediatrics. 2018;(2):83-92
Abstract
Thiamine metabolism dysfunction syndrome type 2 is also known by other terms including: "SCL19A3 gene defect," "biotin-responsive basal ganglia disease" (BBGD), and "biotin-thiamine-responsive basal ganglia disease" (BTBGD). The worldwide incidence and prevalence of this disorder are unknown, but the syndrome has primarily been reported in Saudi Arabia (52% of reported cases). It is caused by a defect in thiamine transporter 2 (hTHTR2), which is encoded by the SLC19A3 gene. The clinical presentations of these syndromes are heterogeneous and are likely related to the age of onset. They can be classified into three major categories: classical childhood BBGD; early-infantile Leigh-like syndrome/atypical infantile spasms; and adult Wernicke's-like encephalopathy. These variable phenotypes have common features in that all are triggered by stressors, such as fever, trauma, or vaccinations. Affected brain areas include the basal ganglia, cerebral cortex, thalamus, and periaqueductal regions. Free thiamine is a potential biomarker for diagnosis and monitoring of treatment. Definitive diagnosis is usually made by molecular testing for the SLC19A3 gene defect, and treatment consists of thiamine alone or in combination with biotin for life. In this report, we review all reported cases of the SLC19A3 gene defect, discuss the history, epidemiology, metabolic pathways, clinical phenotypes, biochemical abnormalities, brain pathology, diagnosis, genetic issues, and treatment of this devastating disorder. Finally, we recommend instituting an international registry to further the basic scientific and clinical research to elucidate multiple unanswered questions about SLC19A3 gene syndromes.
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Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions.
Stopfer, P, Giessmann, T, Hohl, K, Hutzel, S, Schmidt, S, Gansser, D, Ishiguro, N, Taub, ME, Sharma, A, Ebner, T, et al
British journal of clinical pharmacology. 2018;(9):1941-1949
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Abstract
AIMS: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin. METHODS In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug. RESULTS Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI. CONCLUSIONS Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.
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Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.
Katsube, T, Miyazaki, S, Narukawa, Y, Hernandez-Illas, M, Wajima, T
European journal of clinical pharmacology. 2018;(7):931-938
Abstract
PURPOSE Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters. METHODS DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates. RESULTS Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71-1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated. CONCLUSIONS Cefiderocol has no clinically significant DDI potential via drug transporters.
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Low affinity uniporter carrier proteins can increase net substrate uptake rate by reducing efflux.
Bosdriesz, E, Wortel, MT, Haanstra, JR, Wagner, MJ, de la Torre Cortés, P, Teusink, B
Scientific reports. 2018;(1):5576
Abstract
Many organisms have several similar transporters with different affinities for the same substrate. Typically, high-affinity transporters are expressed when substrate is scarce and low-affinity ones when it is abundant. The benefit of using low instead of high-affinity transporters remains unclear, especially when additional nutrient sensors are present. Here, we investigate two hypotheses. It was previously hypothesized that there is a trade-off between the affinity and the catalytic efficiency of transporters, and we find some but no definitive support for it. Additionally, we propose that for uptake by facilitated diffusion, at saturating substrate concentrations, lowering the affinity enhances the net uptake rate by reducing substrate efflux. As a consequence, there exists an optimal, external-substrate-concentration dependent transporter affinity. A computational model of Saccharomyces cerevisiae glycolysis shows that using the low affinity HXT3 transporter instead of the high affinity HXT6 enhances the steady-state flux by 36%. We tried to test this hypothesis with yeast strains expressing a single glucose transporter modified to have either a high or a low affinity. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low-affinity transport systems.
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Organic Chemistry Research on the Mechanistic Elucidation of Iron Acquisition in Barley.
Namba, K, Murata, Y
Biological & pharmaceutical bulletin. 2018;(10):1502-1507
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Abstract
An organic chemistry approach to the mechanistic elucidation of iron acquisition in graminaceous plants is introduced here. To elucidate this detailed mechanism using phytosiderophores, the efficient synthesis of 2'-deoxymugineic acid (DMA), a phytosiderophore of rice, was established. The synthetic DMA was confirmed to have similar iron transport activity to that of natural mugineic acid (MA). It was also revealed that the addition of synthetic DMA, along with iron, to a rice hydroponic solution enabled the rice to grow well even under an alkaline condition, and DMA clearly showed its high potential as a fertilizer to improve food production. On the other hand, the 2'-hydroxy group of MA was confirmed to serve as a point of introduction for labeling, allowing the synthesis of various mugineic acid derivatives as molecular probes. The incorporation of fluorescent mugineic acid into cells allowed them to be clearly observed by fluorescence confocal analysis, and this provided the first direct experimental evidence of transporter-mediated internalization of mugineic acid into cells.
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Transport of Amino Acids across the Vacuolar Membrane of Yeast: Its Mechanism and Physiological Role.
Kawano-Kawada, M, Kakinuma, Y, Sekito, T
Biological & pharmaceutical bulletin. 2018;(10):1496-1501
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Abstract
In yeast cells growing under nutrient-rich condition approximately 50% of total amino acids are accumulated in the vacuoles; however, the composition of amino acids in the cytosol and in the vacuoles is quite different. The vacuoles, like lysosomes, degrade proteins transported into their lumen and produce amino acids. These amino acids should be quickly excreted to the cytosol under nutrient starvation condition and recycled for de novo protein synthesis. These suggest that specific machineries that transport amino acids into and out of the vacuoles operate at the vacuolar membrane. Several families of transporter involved in the vacuolar compartmentalization of amino acids have been identified and characterized using budding yeast Saccharomyces cerevisiae. In this review, we describe the vacuolar amino acid transporters identified so far and introduce recent findings on their activity and physiological function.
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Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.
Lorés-Motta, L, Riaz, M, Grunin, M, Corominas, J, van Asten, F, Pauper, M, Leenders, M, Richardson, AJ, Muether, P, Cree, AJ, et al
JAMA ophthalmology. 2018;(8):875-884
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Abstract
IMPORTANCE Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. OBJECTIVE To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. DESIGN, SETTING, AND PARTICIPANTS In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. MAIN OUTCOMES AND MEASURES Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. RESULTS Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. CONCLUSIONS AND RELEVANCE We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.