The transporter GAT1 plays an important role in GABA-mediated carbon-nitrogen interactions in Arabidopsis

Glutamate derived γ-aminobutyric acid (GABA) is synthetized in the cytosol prior to delivery to the mitochondria where it is catabolized via the TCA cycle. GABA accumulates under various environmental conditions, but an increasing number of studies show its involvement at the crossroad between C and N metabolism. To assess the role of GABA in modulating cellular metabolism, we exposed seedlings of A. thaliana GABA transporter gat1 mutant to full nutrition medium and media deficient in C and N combined with feeding of different concentrations (0.5 and 1 mM) of exogenous GABA. GC-MS based metabolite profiling showed an expected effect of medium composition on the seedlings metabolism of mutant and wild type alike. That being said, a significant interaction between GAT1 deficiency and medium composition was determined with respect to magnitude of change in relative amino acid levels. The effect of exogenous GABA treatment on metabolism was contingent on both the medium and the genotype, leading for instance to a drop in asparagine under full nutrition and low C conditions and glucose under all tested media, but not to changes in GABA content. We additionally assessed the effect of GAT1 deficiency on the expression of glutamate metabolism related genes and genes involved in abiotic stress responses. These results suggest a role for GAT1 in GABA-mediated metabolic alterations in the context of the C-N equilibrium of plant cells.

Size does matter: 18 amino acids at the N-terminal tip of an amino acid transporter in Leishmania determine substrate specificity

Long N-terminal tails of amino acid transporters are known to act as sensors of the internal pool of amino acids and as positive regulators of substrate flux rate. In this study we establish that N-termini of amino acid transporters can also determine substrate specificity. We show that due to alternative trans splicing, the human pathogen Leishmania naturally expresses two variants of the proline/alanine transporter, one 18 amino acid shorter than the other. We demonstrate that the longer variant (LdAAP24) translocates both proline and alanine, whereas the shorter variant (∆18LdAAP24) translocates just proline. Remarkably, co-expressing the hydrophilic N-terminal peptide of the long variant with ∆18LdAAP24 was found to recover alanine transport. This restoration of alanine transport could be mediated by a truncated N-terminal tail, though truncations exceeding half of the tail length were no longer functional. Taken together, the data indicate that the first 18 amino acids of the negatively charged N-terminal LdAAP24 tail are required for alanine transport and may facilitate the electrostatic interactions of the entire negatively charged N-terminal tail with the positively charged internal loops in the transmembrane domain, as this mechanism has been shown to underlie regulation of substrate flux rate for other transporters.

Amino Acid Export in Developing Arabidopsis Seeds Depends on UmamiT Facilitators

Essential amino acids cannot be synthesized by humans and animals. They often are limiting in plant-derived foods and determine the nutritional value of a given diet [1]. Seeds and fruits often represent the harvestable portion of plants. In order to improve the amino acid composition of these tissues, it is indispensable to understand how these substrates are transported within the plant. Amino acids result from nitrogen assimilation, which often occurs in leaves, the source tissue. They are transported via the vasculature, the xylem, and the phloem into the seeds, the so-called sink tissue, where they are stored or consumed. In seeds, several tissues are symplasmically isolated [2, 3], i.e., not connected by plasmodesmata, channels in the cell walls that enable a cytoplasmic continuum in plants [4]. Consequently, amino acids must be exported from cells into the apoplast and re-imported many times to support seed development. Several amino acid importers are known, but exporters remained elusive [5, 6]. Here, we characterize four members of the plant-specific UmamiT transporter family from Arabidopsis, related to the amino acid facilitator SIAR1 and the vacuolar auxin transporter WAT1 [7, 8]. We show that the proteins transport amino acids along their (electro)chemical potential across the plasma membrane. In seeds, they are found in tissues from which amino acids are exported. Loss-of-function mutants accumulate high levels of free amino acids in fruits and produce smaller seeds. Our results strongly suggest a crucial role for the UmamiTs in amino acid export and possibly a means to improve yield quality.

An Increased Iliocapsularis-to-rectus-femoris Ratio Is Suggestive for Instability in Borderline Hips

BACKGROUND The iliocapsularis muscle is an anterior hip structure that appears to function as a stabilizer in normal hips. Previous studies have shown that the iliocapsularis is hypertrophied in developmental dysplasia of the hip (DDH). An easy MR-based measurement of the ratio of the size of the iliocapsularis to that of adjacent anatomical structures such as the rectus femoris muscle might be helpful in everyday clinical use. QUESTIONS/PURPOSES We asked (1) whether the iliocapsularis-to-rectus-femoris ratio for cross-sectional area, thickness, width, and circumference is increased in DDH when compared with hips with acetabular overcoverage or normal hips; and (2) what is the diagnostic performance of these ratios to distinguish dysplastic from pincer hips? METHODS We retrospectively compared the anatomy of the iliocapsularis muscle between two study groups with symptomatic hips with different acetabular coverage and a control group with asymptomatic hips. The study groups were selected from a series of patients seen at the outpatient clinic for DDH or femoroacetabular impingement. The allocation to a study group was based on conventional radiographs: the dysplasia group was defined by a lateral center-edge (LCE) angle of < 25° with a minimal acetabular index of 14° and consisted of 45 patients (45 hips); the pincer group was defined by an LCE angle exceeding 39° and consisted of 37 patients (40 hips). The control group consisted of 30 asymptomatic hips (26 patients) with MRIs performed for nonorthopaedic reasons. The anatomy of the iliocapsularis and rectus femoris muscle was evaluated using MR arthrography of the hip and the following parameters: cross-sectional area, thickness, width, and circumference. The iliocapsularis-to-rectus-femoris ratio of these four anatomical parameters was then compared between the two study groups and the control group. The diagnostic performance of these ratios to distinguish dysplasia from protrusio was evaluated by calculating receiver operating characteristic (ROC) curves and the positive predictive value (PPV) for a ratio > 1. Presence and absence of DDH (ground truth) were determined on plain radiographs using the previously mentioned radiographic parameters. Evaluation of radiographs and MRIs was performed in a blinded fashion. The PPV was chosen because it indicates how likely a hip is dysplastic if the iliocapsularis-to-rectus-femoris ratio was > 1. RESULTS The iliocapsularis-to-rectus-femoris ratio for cross-sectional area, thickness, width, and circumference was increased in hips with radiographic evidence of DDH (ratios ranging from 1.31 to 1.35) compared with pincer (ratios ranging from 0.71 to 0.90; p < 0.001) and compared with the control group, the ratio of cross-sectional area, thickness, width, and circumference was increased (ratios ranging from 1.10 to 1.15; p ranging from 0.002 to 0.039). The area under the ROC curve ranged from 0.781 to 0.852. For a one-to-one iliocapsularis-to-rectus-femoris ratio, the PPV was 89% (95% confidence interval [CI], 73%-96%) for cross-sectional area, 77% (95% CI, 61%-88%) for thickness, 83% (95% CI, 67%-92%) for width, and 82% (95% CI, 67%-91%) for circumference. CONCLUSIONS The iliocapsularis-to-rectus-femoris ratio seems to be a valuable secondary sign of DDH. This parameter can be used as an adjunct for clinical decision-making in hips with borderline hip dysplasia and a concomitant cam-type deformity to identify the predominant pathology. Future studies will need to prove this finding can help clinicians determine whether the borderline dysplasia accounts for the hip symptoms with which the patient presents. LEVEL OF EVIDENCE Level III, prognostic study.

Comparison between magnetic resonance imaging and computed tomography of the lung in patients with cystic fibrosis with regard to clinical, laboratory, and pulmonary functional parameters

OBJECTIVE To evaluate whether magnetic resonance imaging (MRI) is effective as computed tomography (CT) in determining morphologic and functional pulmonary changes in patients with cystic fibrosis (CF) in association with multiple clinical parameters. MATERIALS AND METHODS Institutional review board approval and patient written informed consent were obtained. In this prospective study, 30 patients with CF (17 men and 13 women; mean (SD) age, 30.2 (9.2) years; range, 19-52 years) were included. Chest CT was acquired by unenhanced low-dose technique for clinical purposes. Lung MRI (1.5 T) comprised T2- and T1-weighted sequences before and after the application of 0.1-mmol·kg gadobutrol, also considering lung perfusion imaging. All CT and MR images were visually evaluated by using 2 different scoring systems: the modified Helbich and the Eichinger scores. Signal intensity of the peribronchial walls and detected mucus on T2-weighted images as well as signal enhancement of the peribronchial walls on contrast-enhanced T1-weighted sequences were additionally assessed on MRI. For the clinical evaluation, the pulmonary exacerbation rate, laboratory, and pulmonary functional parameters were determined. RESULTS The overall modified Helbich CT score had a mean (SD) of 15.3 (4.8) (range, 3-21) and median of 16.0 (interquartile range [IQR], 6.3). The overall modified Helbich MR score showed slightly, not significantly, lower values (Wilcoxon rank sum test and Student t test; P > 0.05): mean (SD) of 14.3 (4.7) (range, 3-20) and median of 15.0 (IQR, 7.3). Without assessment of perfusion, the overall Eichinger score resulted in the following values for CT vs MR examinations: mean (SD), 20.3 (7.2) (range, 4-31); and median, 21.0 (IQR, 9.5) vs mean (SD), 19.5 (7.1) (range, 4-33); and median, 20.0 (IQR, 9.0). All differences between CT and MR examinations were not significant (Wilcoxon rank sum tests and Student t tests; P > 0.05). In general, the correlations of the CT scores (overall and different imaging parameters) to the clinical parameters were slightly higher compared to the MRI scores. However, if all additional MRI parameters were integrated into the scoring systems, the correlations reached the values of the CT scores. The overall image quality was significantly higher for the CT examinations compared to the MRI sequences. CONCLUSIONS One major diagnostic benefit of lung MRI in CF is the possible acquisition of several different morphologic and functional imaging features without the use of any radiation exposure. Lung MRI shows reliable associations with CT and clinical parameters, which suggests its implementation in CF for routine diagnosis, which would be particularly important in follow-up imaging over the long term.

Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874.

Historische Entwicklungen im Wohlfahrtswesen der Schweiz

In diesem Handbuch werden Themen, Handlungsfelder und Organisationen des Schweizer Sozialwesens «sichtbar» gemacht: historische Entwicklungen, aktuelle Herausforderungen, Abhängigkeiten und Zusammenhänge. Fachpersonen aus den Organisationen des Schweizer Sozialwesens sowie Wissenschaftler und Wissenschaftlerinnen aus Hochschulen zeigen auf, welchen Einfluss Entscheidungen in der Sozial- und Bildungspolitik auf die Lebensverhältnisse der Bevölkerung haben und welchen Beitrag das Sozialwesen an das Wohl aller leistet. Exemplarisch verdeutlicht werden die Besonderheiten des Schweizer Sozialwesens anhand der Sozialversicherungen, der öffentlichen und privaten sozialen Dienste sowie der Sozialen Arbeit als Profession und Disziplin. Beiträge über Subsidiarität, Integration, Lebensqualität, Staatlichkeit und Zivilgesellschaft, Effizienz- und Wirkungsorientierung, Risikominimierung, Prävention, soziale Ungleichheit, Eigenverantwortung und Selbstbestimmung schaffen einen Überblick über aktuelle soziale Problemlagen in der Schweiz und darauf zielende Konzepte. Das Handbuch wurde für die 2. Auflage überarbeitet und ergänzt. Es ist ein unentbehrliches Nachschlagewerk für alle, die sich mit dem Sozialwesen auseinandersetzen: Fachleute aus dem sozialen Bereich, Politikerinnen und Politiker, Studierende, Medienschaffende und weitere interessierte Personen.