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.

Gender differences in the association of a high quality job and self-esteem over time: A multiwave study

High self-esteem often predicts job-related outcomes, such as high job satisfaction or high status. Theoretically, high quality jobs (HQJs) should be important for self-esteem, as they enable people to use a variety of skills and attribute accomplishments to themselves, but research findings are mixed. We expected reciprocal relationships between self-esteem and HQJ. However, as work often is more important for the status of men, we expected HQJ to have a stronger influence on self-esteem for men as compared to women. Conversely, task-related achievements violate gender stereotypes for women, who may need high self-esteem to obtain HQJs. In a 4-year cross-lagged panel analysis with 325 young workers, self-esteem predicted HQJ; the lagged effect from HQJ on self-esteem was marginally significant. In line with the hypotheses, the multigroup model showed a significant path only from self-esteem to HQJ for women, and from HQJ to self-esteem for men. The reverse effect was not found for women, and only marginally significant for men. Overall, although there were some indications for reciprocal effects, our findings suggest that women need high self-esteem to obtain HQJs to a greater degree than men, and that men base their self-esteem on HQJs to a greater extent than women.

High-Pressure Behavior and Phase Stability of Al5BO9, a Mullite-Type Ceramic Material

Phase stability, elastic behavior, and pressure-induced structural evolution of synthetic boron-mullite Al5BO9 (a = 5.6780(7), b = 15.035(6), and c =7.698(3) Å, space group Cmc21, Z = 4) were investigated up to 25.6(1) GPa by in situ single-crystal synchrotron X-ray diffraction with a diamond anvil cell (DAC) under hydrostatic conditions. No evidence of phase transition was observed up to 21.7(1) GPa. At 25.6(1) GPa, the refined unit-cell parameters deviated significantly from the compressional trend, and the diffraction peaks appeared broader than at lower pressure. At 26.7(1) GPa, the diffraction pattern was not indexable, suggesting amorphization of the material or a phase transition to a high-pressure polymorph. Fitting the P–V data up to 21.7(1) GPa with a second-order Birch–Murnaghan Equation-of-State, we obtained a bulk modulus KT0 = 164(1) GPa. The axial compressibilities, here described as linearized bulk moduli, are as follows: KT0(a) = 244(9), KT0(b) = 120(4), and KT0(c) = 166(11) GPa (KT0(a):KT0(b):KT0(c) = 2.03:1:1.38). The structure refinements allowed a description of the main deformation mechanisms in response to the applied pressure. The stiffer crystallographic direction appears to be controlled by the infinite chains of edge-sharing octahedra running along [100], making the structure less compressible along the a-axis than along the b- and c-axis.

Improving the clinical prediction of psychosis by combining ultra-high risk criteria and cognitive basic symptoms

OBJECTIVE Cognitive impairments are regarded as a core component of schizophrenia. However, the cognitive dimension of psychosis is hardly considered by ultra-high risk (UHR) criteria. Therefore, we studied whether the combination of symptomatic UHR criteria and the basic symptom criterion "cognitive disturbances" (COGDIS) is superior in predicting first-episode psychosis. METHOD In a naturalistic 48-month follow-up study, the conversion rate to first-episode psychosis was studied in 246 outpatients of an early detection of psychosis service (FETZ); thereby, the association between conversion, and the combined and singular use of UHR criteria and COGDIS was compared. RESULTS Patients that met UHR criteria and COGDIS (n=127) at baseline had a significantly higher risk of conversion (hr=0.66 at month 48) and a shorter time to conversion than patients that met only UHR criteria (n=37; hr=0.28) or only COGDIS (n=30; hr=0.23). Furthermore, the risk of conversion was higher for the combined criteria than for UHR criteria (n=164; hr=0.56 at month 48) and COGDIS (n=158; hr=0.56 at month 48) when considered irrespective of each other. CONCLUSIONS Our findings support the merits of considering both COGDIS and UHR criteria in the early detection of persons who are at high risk of developing a first psychotic episode within 48months. Applying both sets of criteria improves sensitivity and individual risk estimation, and may thereby support the development of stage-targeted interventions. Moreover, since the combined approach enables the identification of considerably more homogeneous at-risk samples, it should support both preventive and basic research.

High-resolution glacial and deglacial record of atmospheric methane by continuous-flow and laser spectrometer analysis along the NEEM ice core

The Greenland NEEM (North Greenland Eemian Ice Drilling) operation in 2010 provided the first opportunity to combine trace-gas measurements by laser spectroscopic instruments and continuous-flow analysis along a freshly drilled ice core in a field-based setting. We present the resulting atmospheric methane (CH4) record covering the time period from 107.7 to 9.5 ka b2k (thousand years before 2000 AD). Companion discrete CH4 measurements are required to transfer the laser spectroscopic data from a relative to an absolute scale. However, even on a relative scale, the high-resolution CH4 data set significantly improves our knowledge of past atmospheric methane concentration changes. New significant sub-millennial-scale features appear during interstadials and stadials, generally associated with similar changes in water isotopic ratios of the ice, a proxy for local temperature. In addition to the midpoint of Dansgaard–Oeschger (D/O) CH4 transitions usually used for cross-dating, sharp definition of the start and end of these events brings precise depth markers (with ±20 cm uncertainty) for further cross-dating with other palaeo- or ice core records, e.g. speleothems. The method also provides an estimate of CH4 rates of change. The onsets of D/O events in the methane signal show a more rapid rate of change than their endings. The rate of CH4 increase associated with the onsets of D/O events progressively declines from 1.7 to 0.6 ppbv yr−1 in the course of marine isotope stage 3. The largest observed rate of increase takes place at the onset of D/O event #21 and reaches 2.5 ppbv yr−1.

Comparison of globules prepared from high dilutions of various starting materials by ultraviolet light spectroscopy

Background: High and ultra-high dilutions of various starting materials, e.g. copper sulfate, Hypericum perforatum and sulfur, showed significant differences in ultraviolet light (UV) transmission from controls and amongst different dilution levels [1,2]. Verum and placebo globules of Aconitum napellus 30c or calcium carbonate/quercus e cortice 6x from the same packs as used in previous clinical trials and dissolved in water could be distinguished by UV spectroscopy [3]. However, it was unclear whether the differences in UV absorbance originated from specific characteristics of the starting materials, from differences in the production of verum and placebo globules, and/or other unknown interference factors. Aims: The aim of this study was to investigate whether globules produced with high and ultra-high dilutions (6x, 12x, 30c, 200c, 200CF (centesimal discontinuous fluxion), 10,000CF) of various starting materials (Aconitum napellus, Atropa belladonna, phosphorus, sulfur, Apis mellifica, quartz) could be distinguished by UV spectroscopy. Methodology: The globules were specially produced for this study by Spagyros AG (Gümligen, Switzerland) and differed only in the starting materials of the dilutions (but not in the batch of globules or ethanol used). Globules were dissolved in water at 10 mg/ml, in quadruplicates, approximately 22 h prior to the measurements. Absorbance of the samples in the UV range (from 190 to 340 nm) was measured in a randomized order with a Shimadzu double beam UV-1800 spectrophotometer equipped with an auto sampler. Samples of each starting material were prepared and measured on 5 independent days. The daily variations of the spectrophotometer as well as the drift during the measurements were corrected for. The average absorbance from 200 to 340 nm was compared among various starting materials within equal dilution levels using a Kruskal-Wallis test. Results: Statistically significant differences were found among 30c (Figure 1), 200c and 200CF dilutions of the various starting materials. No differences were found among 6x, 12x and 10,000CF dilutions. Conclusions: Globules prepared from high dilutions of various starting materials may show significantly different UV absorbance when dissolved in water. References [1] Wolf U, Wolf M, Heusser P, Thurneysen A, Baumgartner S. Homeopathic preparations of quartz, sulfur and copper sulfate assessed by UV-spectroscopy. Evid Based Complement Alternat Med. 2011;2011:692798. [2] Klein SD, Sandig A, Baumgartner S, Wolf U. Differences in median ultraviolet light transmissions of serial homeopathic dilutions of copper sulfate, Hypericum perforatum, and sulfur. Evid Based Complement Alternat Med. 2013;2013:370609. [3] Klein SD, Wolf U. Investigating homeopathic verum and placebo globules with ultraviolet spectroscopy. Forsch Komplementmed. 2013, accepted.

Dusty punch cards and an eternal enigma: high-density lipoproteins and atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged.

A single-centre cohort of patients with systemic light chain AL-amyloidosis treated with conventional chemotherapy or with high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has been reported to confer better prognosis in systemic light chain AL-amyloidosis as compared with conventional chemotherapy. However, only limited data are available so far on treatment and outcome of AL-amyloidosis patients in Switzerland. METHODS Within a single-centre cohort of patients with biopsy confirmed AL-amyloidosis diagnosed between January 1995 and December 2012, we aimed to investigate treatment effects in patients treated with conventional chemotherapy versus HDCT with ASCT. RESULTS We identified 50 patients with AL-amyloidosis treated with conventional chemotherapy and 13 patients who received HDCT with ASCT. Clinical characteristics differed between the groups for the age of the patients (59 years for patients with ASCT/HDCT vs 69 years; p= 0.0006) and the troponin-T value (0.015 μg/l vs 0.08 μg/l; p = 0.0279). Patients with ASCT showed a trend towards better overall survival, with median survival not yet reached compared with 53 months in patients on conventional chemotherapy (p = 0.0651). CONCLUSION Our results suggest that light chain AL-amyloidosis patients considered fit to undergo HDCT and ASCT may have a better outcome than patients treated exclusively with conventional chemotherapy regimens; however, the better performance status of patients receiving HDCT may have added to this treatment effect.

Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity

BACKGROUND Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4. METHODS The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses. RESULTS The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. CONCLUSIONS Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

Quantitative depth profiling of Ce 3+ in Pt/CeO 2 by in situ high-energy XPS in a hydrogen atmosphere

The redox property of ceria is a key factor in the catalytic activity of ceria-based catalysts. The oxidation state of well-defined ceria nanocubes in gas environments was analysed in situ by a novel combination of near-ambient pressure X-ray Photoelectron Spectroscopy (XPS) and high-energy XPS at a synchrotron X-ray source. In situ high-energy XPS is a promising new tool to determine the electronic structure of matter under defined conditions. The aim was to quantitatively determine the degree of cerium reduction in a nano-structured ceria-supported platinum catalyst as a function of the gas environment. To obtain a non-destructive depth profile at near-ambient pressure, in situ high-energy XPS analysis was performed by varying the kinetic energy of photoelectrons from 1 to 5 keV, and, thus, the probing depth. In ceria nanocubes doped with platinum, oxygen vacancies formed only in the uppermost layers of ceria in an atmosphere of 1 mbar hydrogen and 403 K. For pristine ceria nanocubes, no change in the cerium oxidation state in various hydrogen or oxygen atmospheres was observed as a function of probing depth. In the absence of platinum, hydrogen does not dissociate and, thus, does not lead to reduction of ceria.

Duration of unspecific prodromal and clinical high risk states, and early help-seeking in first-admission psychosis patients

PURPOSE Prevention of psychosis requires both presence of clinical high risk (CHR) criteria and early help-seeking. Previous retrospective studies of the duration of untreated illness (i.e. prodrome plus psychosis) did not distinguish between prodromal states with and without CHR symptoms. Therefore, we examined the occurrence of CHR symptoms and first help-seeking, thereby considering effects of age at illness-onset. METHODS Adult patients first admitted for psychosis (n = 126) were retrospectively assessed for early course of illness and characteristics of first help-seeking. RESULTS One-hundred and nine patients reported a prodrome, 58 with CHR symptoms. In patients with an early illness-onset before age 18 (n = 45), duration of both illness and psychosis were elongated, and CHR symptoms more frequent (68.9 vs. 33.3 %) compared to those with adult illness-onset. Only 29 patients reported help-seeking in the prodrome; this was mainly self-initiated, especially in patients with an early illness-onset. After the onset of first psychotic symptoms, help-seeking was mainly initiated by others. State- and age-independently, mental health professionals were the main first point-of-call (54.0 %). CONCLUSIONS Adult first-admission psychosis patients with an early, insidious onset of symptoms before age 18 were more likely to recall CHR symptoms as part of their prodrome. According to current psychosis-risk criteria, these CHR symptoms, in principle, would have allowed the early detection of psychosis. Furthermore, compared to patients with an adult illness-onset, patients with an early illness-onset were also more likely to seek help on their own account. Thus, future awareness strategies to improve CHR detection might be primarily related to young persons and self-perceived subtle symptoms.

Loss of bone strength in HLA-B27 transgenic rats is characterized by a high bone turnover and is mainly osteoclast-driven

Objective Although osteopenia is frequent in spondyloarthritis (SpA), the underlying cellular mechanisms and association with other symptoms are poorly understood. This study aimed to characterize bone loss during disease progression, determine cellular alterations, and assess the contribution of inflammatory bowel disease (IBD) to bone loss in HLA-B27 transgenic rats. Methods Bones of 2-, 6-, and 12-month-old non-transgenic, disease-free HLA-B7 and disease-associated HLA-B27 transgenic rats were examined using peripheral quantitative computed tomography, μCT, and nanoindentation. Cellular characteristics were determined by histomorphometry and ex vivo cultures. The impact of IBD was determined using [21-3 x 283-2]F1 rats, which develop arthritis and spondylitis, but not IBD. Results HLA-B27 transgenic rats continuously lost bone mass with increasing age and had impaired bone material properties, leading to a 3-fold decrease in bone strength at 12 months of age. Bone turnover was increased in HLA-B27 transgenic rats, as evidenced by a 3-fold increase in bone formation and a 6-fold increase in bone resorption parameters. Enhanced osteoclastic markers were associated with a larger number of precursors in the bone marrow and a stronger osteoclastogenic response to RANKL or TNFα. Further, IBD-free [21-3 x 283-2]F1 rats also displayed decreased total and trabecular bone density. Conclusions HLA-B27 transgenic rats lose an increasing amount of bone density and strength with progressing age, which is primarily mediated via increased bone remodeling in favor of bone resorption. Moreover, IBD and bone loss seem to be independent features of SpA in HLA-B27 transgenic rats.

Parton energy loss and momentum broadening at NLO in high temperature QCD plasmas

We present an overview of a perturbative-kinetic approach to jet propagation, energy loss, and momentum broadening in a high temperature quark–gluon plasma. The leading-order kinetic equations describe the interactions between energetic jet-particles and a non-abelian plasma, consisting of on-shell thermal excitations and soft gluonic fields. These interactions include ↔ scatterings, collinear bremsstrahlung, and drag and momentum diffusion. We show how the contribution from the soft gluonic fields can be factorized into a set of Wilson line correlators on the light-cone. We review recent field-theoretical developments, rooted in the causal properties of these correlators, which simplify the calculation of the appropriate Wilson lines in thermal field theory. With these simplifications lattice measurements of transverse momentum broadening have become possible, and the kinetic equations describing parton transport have been extended to next-to-leading order in the coupling g.