The SLC1 high-affinity glutamate and neutral amino acid transporter family

Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-β-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.

The influence of recent major crater impacts on the surrounding surfaces of (21) Lutetia

We present 3-D simulations of impacts into Asteroid 21 Lutetia, the subject of a fly-by by the European Space Agency's Rosetta mission to Comet 67P/Churyumov-Gerasimenko. Using a 3-D shape model of the asteroid, impacts of sizes sufficient to reproduce the observed craters in Lutetia's North Polar Crater Cluster (NPCC) as observed by the OSIRIS experiment have been simulated using the Smoothed Particle Hydrodynamics technique. The asteroid itself has been modelled both as a homogeneous body and as a body with an iron core.

Differential effect of p47phox and gp91phox deficiency on the course of Pneumococcal Meningitis.

Bacterial meningitis is a severe inflammatory disease of the central nervous system and is characterized by massive infiltration of granulocytes into the cerebrospinal fluid (CSF). To assess the role of NADPH oxidase-derived reactive oxygen species (ROS) in pneumococcal meningitis, mice deficient in either the gp91 subunit (essential for functioning of the phagocyte enzyme) or the p47 subunit (essential for functioning of homologous enzymes in nonphagocytic cells) were intracisternally infected with live Streptococcus pneumoniae, and defined disease parameters were measured during the acute stage of infection. While none of the parameters measured (including CSF bacterial titers) were significantly different in gp91(-/-) and wild-type mice, the infection in p47(-/-) mice was associated with significantly increased inflammation of the subarachnoid and ventricular space, disruption of the blood-brain barrier, and the presence of interleukin-1 beta, tumor necrosis factor alpha, and matrix metalloproteinase 9 in the cortex. These changes were associated with approximately 10-fold-higher CSF bacterial titers in p47(-/-) mice than in wild-type mice (P < 0.001). In contrast to infection with live bacteria, the inflammatory response, including CSF leukocytosis, was significantly attenuated in p47(-/-) mice (but not gp91(-/-) mice) challenged with a fixed number of heat-inactivated pneumococci. Impairment of the host defense appeared to be responsible for the higher bacterial titers in p47(-/-) mice. Therefore, these results indicate that ROS generated by a gp91-independent NADPH oxidase(s) are important for establishing an adequate inflammatory response to pneumococcal CSF infection.

Vessel orientation-dependent sensitivity of optoacoustic imaging using a linear array transducer

For clinical optoacoustic imaging, linear probes are preferably used because they allow versatile imaging of the human body with real-time display and free-hand probe guidance. The two-dimensional (2-D) optoacoustic image obtained with this type of probe is generally interpreted as a 2-D cross-section of the tissue just as is common in echo ultrasound. We demonstrate in three-dimensional simulations, phantom experiments, and in vivo mouse experiments that for vascular imaging this interpretation is often inaccurate. The cylindrical blood vessels emit anisotropic acoustic transients, which can be sensitively detected only if the direction of acoustic radiation coincides with the probe aperture. Our results reveal for this reason that the signal amplitude of different blood vessels may differ even if the vessels have the same diameter and initial pressure distribution but different orientation relative to the imaging plane. This has important implications for the image interpretation, for the probe guidance technique, and especially in cases when a quantitative reconstruction of the optical tissue properties is required.

Validation of a magnetic resonance imaging guided stereotactic access to the ovine brainstem.

BackgroundAnatomical differences between humans and domestic mammals preclude the use of reported stereotactic approaches to the brainstem in animals. In animals, brainstem biopsies are required both for histopathological diagnosis of neurological disorders and for research purposes. Sheep are used as a translational model for various types of brain disease and therefore a species-specific approach needs to be developed. The aim of the present study was to establish a minimally invasive, accurate and reproducible stereotactic approach to the brainstem of sheep, using the magnetic resonance imaging guided BrainsightTM frameless stereotactic system.ResultsA transoccipital transcerebellar approach with an entry point in the occipital bone above the vermis between the transverse sinus and the external occipital protuberance was chosen. This approach provided access to the target site in all heads. The overall mean needle placement error was 1.85¿±¿1.22 mm.ConclusionsThe developed transoccipital transcerebellar route is short, provides accurate access to the ovine caudal cranial fossa and is a promising approach to be assessed further in live animals.

Justifying induction on modal μ-formulae

We define a rank function for formulae of the propositional modal μ-calculus such that the rank of a fixed point is strictly bigger than the rank of any of its finite approximations. A rank function of this kind is needed, for instance, to establish the collapse of the modal μ-hierarchy over transitive transition systems. We show that the range of the rank function is ωω. Further we establish that the rank is computable by primitive recursion, which gives us a uniform method to generate formulae of arbitrary rank below ωω.

Positive affect moderates the effect of negative affect on cardiovascular disease-related hospitalizations and all-cause mortality after cardiac rehabilitation

BACKGROUND Little is known as to whether negative emotions adversely impact the prognosis of patients who undergo cardiac rehabilitation. We prospectively investigated the predictive value of state negative affect (NA) assessed at discharge from cardiac rehabilitation for prognosis and the moderating role of positive affect (PA) on the effect of NA on outcomes. METHODS A total of 564 cardiac patients (62.49 ± 11.51) completed a comprehensive three-month outpatient cardiac rehabilitation program, filling in the Global Mood Scale (GMS) at discharge. The combined endpoint was cardiovascular disease (CVD)-related hospitalizations plus all-cause mortality at follow-up. Cox regression models estimated the predictive value of NA, as well as the moderating influence of PA on outcomes. Survival models were adjusted for sociodemographic factors, traditional cardiovascular risk factors, and severity of disease. RESULTS During a mean follow-up period of 3.4 years, 71 patients were hospitalized for a CVD-related event and 15 patients died. NA score (range 0-20) was a significant and independent predictor (hazard ratio (HR) 1.091, 95% confidence interval (CI) 1.012-1.175; p = 0.023) with a three-point higher level in NA increasing the relative risk by 9.1%. Furthermore, PA interacted significantly with NA (p < 0.001). The relative risk of poor prognosis with NA was increased in patients with low PA (p = 0.012) but remained unchanged in combination with high PA (p = 0.12). CONCLUSION The combination of NA with low PA was particularly predictive of poor prognosis. Whether reduction of NA and increase of PA, particularly in those with high NA, improves outcome needs to be tested.

Institutions as key drivers of collective action in WUAs [Water User Associations] of Uzbekistan

This paper presents a multifactor approach for performance assessment of Water Users Associations (WUAs) in Uzbekistan in order to identify the drivers for improved and effi cient performance of WUAs. The study was carried out in the Fergana Valley where the WUAs were created along the South Fergana Main Canal during the last 10 years. The farmers and the employees of 20 WUAs were questioned about the WUAs’ activities and the quantitative and qualitative data were obtained. This became a base for the calculation of 36 indicators divided into 6 groups: Water supply, technical conditions, economic conditions, social and cultural conditions, organizational conditions and information conditions. All the indicators assessed with a differentiated point system adjusted for subjectivity of several of them give the total maximal result for the associations of 250 point. The WUAs of the Fergana Valley showed the score between 145 and 219 points, what refl ects a highly diverse level of the WUAs performance in the region. The analysis of the indicators revealed that the key points of the WUA’s success are the organizational and institutional conditions including the participatory factors and awareness of both the farmers and employees about the work of WUA. The research showed that the low performance of the WUAs is always explained by the low technical and economic conditions along with weak organization and information dissemination conditions. It is clear that it is complicated to improve technical and economic conditions immediately because they are cost-based and cost-induced. However, it is possible to improve the organizational conditions and to strengthen the institutional basis via formal and information institutions which will gradually lead to improvement of economic and technical conditions of WUAs. Farmers should be involved into the WUA Governance and into the process of making common decisions and solving common problems together via proper institutions. Their awareness can also be improved by leading additional trainings for increasing farmers’ agronomic and irrigation knowledge, teaching them water saving technologies and acquainting them with the use of water measuring equipment so it can bring reliable water supply, transparent budgeting and adequate as well as equitable water allocation to the water users.

The contribution of intrabolus pressure to symptoms induced by gastric banding

BACKGROUND & AIMS Mechanisms that ultimately lead to dysphagia are still not totally clear. Patients with laparoscopic gastric banding (LAGB) often complain about dysphagia, regurgitation and heartburn. Our aim was to evaluate the contribution of intrabolus pressure to symptoms of gastric banding. METHODS This study investigated 30 patients with LAGB before and 3 months after conversion to Roux-en-Y gastric bypass (RYGB), evaluating symptoms with a 7-point-Likert-scale and esophageal peristalsis, esophageal bolus transit and intrabolus pressure changes using combined impedance-manometry. RESULTS Conversion from LAGB to RYGB leads to a significant reduction in dysphagia (1.9 +/- 0.4 vs. 0.0 +/- 0.0; p< 0.01) and regurgitation (4.2 +/- 0.4 vs. 0.1 +/- 0.1; p< 0.01) symptom scores. For liquid swallows we found a modest but significant correlation between the intensity of dysphagia and intrabolus pressure (r=0.11; p<0.05) and the intensity of regurgitation and intrabolus pressure for viscous swallows (r=0.12, p<0.05) in patients with LAGB. There was a significant (p< 0.05) reduction in intrabolus pressure at 5 cm above LES before (liquid 10.6 +/-1.0; viscous 13.5 +/- 1.5) and after (liquid 6.4 +/- 0.6; viscous 10.5 +/- 0.9) conversion from LAGB to RYGB. CONCLUSION Current data suggest that intraesophageal pressure during bolus presence in the distal esophagus contributes to the development but not to the intensity of dysphagia and regurgitation.

Synchronization of two independently moving cameras without feature correspondences

In this work, a method that synchronizes two video sequences is proposed. Unlike previous methods, which require the existence of correspondences between features tracked in the two sequences, and/or that the cameras are static or jointly moving, the proposed approach does not impose any of these constraints. It works when the cameras move independently, even if different features are tracked in the two sequences. The assumptions underlying the proposed strategy are that the intrinsic parameters of the cameras are known and that two rigid objects, with independent motions on the scene, are visible in both sequences. The relative motion between these objects is used as clue for the synchronization. The extrinsic parameters of the cameras are assumed to be unknown. A new synchronization algorithm for static or jointly moving cameras that see (possibly) different parts of a common rigidly moving object is also proposed. Proof-of-concept experiments that illustrate the performance of these methods are presented, as well as a comparison with a state-of-the-art approach.

Antisense properties of tricyclo-DNA.

Tricyclo (tc)-DNA belongs to the class of conformationally constrained DNA analogs that show enhanced binding properties to DNA and RNA. We prepared tc-oligonucleotides up to 17 nt in length, and evaluated their binding efficiency and selectivity towards complementary RNA, their biological stability in serum, their RNase H inducing potential and their antisense activity in a cellular assay. Relative to RNA or 2'-O-Me-phosphorothioate (PS)-RNA, fully modified tc-oligodeoxynucleotides, 10-17 nt in length, show enhanced selectivity and enhanced thermal stability by approximately 1 degrees C/modification in binding to RNA targets. Tricyclodeoxyoligonucleotides are completely stable in heat-deactivated fetal calf serum at 37 degree C. Moreover, tc-DNA-RNA duplexes are not substrates for RNase H. To test for antisense effects in vivo, we used HeLa cell lines stably expressing the human beta-globin gene with two different point mutations in the second intron. These mutations lead to the inclusion of an aberrant exon in beta-globin mRNA. Lipofectamine-mediated delivery of a 17mer tc-oligodeoxynucleotide complementary to the 3'-cryptic splice site results in correction of aberrant splicing already at nanomolar concentrations with up to 100-fold enhanced efficiency relative to a 2'-O-Me-PS-RNA oligonucleotide of the same length and sequence. In contrast to 2'-O-Me-PS-RNA, tc-DNA shows antisense activity even in the absence of lipofectamine, albeit only at much higher oligonucleotide concentrations.

Der Körper als Gefäß. Eine Studie zur visuellen Anthropologie des Alten Orients

The perception of the human body as container is widespread in cognitive linguistics, psychology and anthropology and is estimated to be universal. But what can we say about the specific context of the Hebrew Bible as well as Ancient-Near-Eastern texts and material culture, and more especially about anthropomorphic vessels in the Levant? Biblical, Egyptian and Mesopotamian texts compare the human body with pottery in order to emphasize its status of having been created (Geschöpflichkeit) on the one hand, and its fragility (Zerbrechlichkeit) on the other. Not in every case does the metaphor refer to an individual. Very often, however, it is used with relation to groups of people (nations) and requires particular caution when it comes to drawing a conclusion about the embodiment. The archaeological-iconographic record demonstrates that the human body, especially the female body, was imagined as a container. The fact that vessels in the shape of female bodies are the majority can partly be explained with the association between container and pregnancy. This essay aims at stimulating the discussion about embodiment in the Ancient Near East, concepts of emotion the body as a container in the Hebrew Bible, and its relation to the material culture.

Real-time computer-based visual feedback improves visual acuity in downbeat nystagmus - a pilot study.

BACKGROUND Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements. METHODS The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison. RESULTS Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043). CONCLUSIONS This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

A Proof-Theoretic Analysis of Theories for Stratified Inductive Definitions

In this article we study subsystems SIDᵥ of the theory ID₁ in which fixed point induction is restricted to properly stratified formulas.

Deep Points Consolidation

In this paper, we present a consolidation method that is based on a new representation of 3D point sets. The key idea is to augment each surface point into a deep point by associating it with an inner point that resides on the meso-skeleton, which consists of a mixture of skeletal curves and sheets. The deep points representation is a result of a joint optimization applied to both ends of the deep points. The optimization objective is to fairly distribute the end points across the surface and the meso-skeleton, such that the deep point orientations agree with the surface normals. The optimization converges where the inner points form a coherent meso-skeleton, and the surface points are consolidated with the missing regions completed. The strength of this new representation stems from the fact that it is comprised of both local and non-local geometric information. We demonstrate the advantages of the deep points consolidation technique by employing it to consolidate and complete noisy point-sampled geometry with large missing parts.