Spectroscopy and dissociative recombination of the lowest rotational states of H3+

The dissociative recombination of the lowest rotational states of H3+ has been investigated at the storage ring TSR using a cryogenic 22-pole radiofrequency ion trap as injector. The H3+ was cooled with buffer gas at ~15 K to the lowest rotational levels, (J,G)=(1,0) and (1,1), which belong to the ortho and para proton-spin symmetry, respectively. The rate coefficients and dissociation dynamics of H3+(J,G) populations produced with normal- and para-H2 were measured and compared to the rate and dynamics of a hot H3+ beam from a Penning source. The production of cold H3+ rotational populations was separately studied by rovibrational laser spectroscopy using chemical probing with argon around 55 K. First results indicate a ~20% relative increase of the para contribution when using para-H2 as parent gas. The H3+ rate coefficient observed for the para-H2 source gas, however, is quite similar to the H3+ rate for the normal-H2 source gas. The recombination dynamics confirm that for both source gases, only small populations of rotationally excited levels are present. The distribution of 3-body fragmentation geometries displays a broad part of various triangular shapes with an enhancement of ~12% for events with symmetric near-linear configurations. No large dependences on internal state or collision energy are found.Comment: 10 pages, 9 figures, to be published in Journal of Physics: Conference Proceeding

Assignment of resonances in dissociative recombination of HD+ ions: high-resolution measurements compared with accurate computations

The collision-energy resolved rate coefficient for dissociative recombination of HD+ ions in the vibrational ground state is measured using the photocathode electron target at the heavy-ion storage ring TSR. Rydberg resonances associated with ro-vibrational excitation of the HD+ core are scanned as a function of the electron collision energy with an instrumental broadening below 1 meV in the low-energy limit. The measurement is compared to calculations using multichannel quantum defect theory, accounting for rotational structure and interactions and considering the six lowest rotational energy levels as initial ionic states. Using thermal equilibrium level populations at 300 K to approximate the experimental conditions, close correspondence between calculated and measured structures is found up to the first vibrational excitation threshold of the cations near 0.24 eV. Detailed assignments, including naturally broadened and overlapping Rydberg resonances, are performed for all structures up to 0.024 eV. Resonances from purely rotational excitation of the ion core are found to have similar strengths as those involving vibrational excitation. A dominant low-energy resonance is assigned to contributions from excited rotational states only. The results indicate strong modifications in the energy dependence of the dissociative recombination rate coefficient through the rotational excitation of the parent ions, and underline the need for studies with rotationally cold species to obtain results reflecting low-temperature ionized media.Comment: 15 pages, 10 figures. Paper to appear in Phys. Rev. A (version as accepted

Innovative solutions to novel drug development in mental health

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.</p

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue

Geochemical detection of carbon dioxide in dilute aquifers

<p>Abstract</p> <p>Background</p> <p>Carbon storage in deep saline reservoirs has the potential to lower the amount of CO₂emitted to the atmosphere and to mitigate global warming. Leakage back to the atmosphere through abandoned wells and along faults would reduce the efficiency of carbon storage, possibly leading to health and ecological hazards at the ground surface, and possibly impacting water quality of near-surface dilute aquifers. We use static equilibrium and reactive transport simulations to test the hypothesis that perturbations in water chemistry associated with a CO₂gas leak into dilute groundwater are important measures for the potential release of CO₂to the atmosphere. Simulation parameters are constrained by groundwater chemistry, flow, and lithology from the High Plains aquifer. The High Plains aquifer is used to represent a typical sedimentary aquifer overlying a deep CO₂storage reservoir. Specifically, we address the relationships between CO₂flux, groundwater flow, detection time and distance. The CO₂flux ranges from 10³to 2 × 10⁶t/yr (0.63 to 1250 t/m²/yr) to assess chemical perturbations resulting from relatively small leaks that may compromise long-term storage, water quality, and surface ecology, and larger leaks characteristic of short-term well failure.</p> <p>Results</p> <p>For the scenarios we studied, our simulations show pH and carbonate chemistry are good indicators for leakage of stored CO₂into an overlying aquifer because elevated CO₂yields a more acid pH than the ambient groundwater. CO₂leakage into a dilute groundwater creates a slightly acid plume that can be detected at some distance from the leak source due to groundwater flow and CO₂buoyancy. pH breakthrough curves demonstrate that CO₂leaks can be easily detected for CO₂flux ≥ 10⁴t/yr within a 15-month time period at a monitoring well screened within a permeable layer 500 m downstream from the vertical gas trace. At lower flux rates, the CO₂dissolves in the aqueous phase in the lower most permeable unit and does not reach the monitoring well. Sustained pumping in a developed aquifer mixes the CO₂-affected water with the ambient water and enhances pH signal for small leaks (10³t/yr) and reduces pH signal for larger leaks (≥ 10⁴t/yr).</p> <p>Conclusion</p> <p>The ability to detect CO₂leakage from a storage reservoir to overlying dilute groundwater is dependent on CO₂solubility, leak flux, CO₂buoyancy, and groundwater flow. Our simulations show that the most likely places to detect CO₂are at the base of the confining layer near the water table where CO₂gas accumulates and is transported laterally in all directions, and downstream of the vertical gas trace where groundwater flow is great enough to transport dissolved CO₂laterally. Our simulations show that CO₂may not rise high enough in the aquifer to be detected because aqueous solubility and lateral groundwater transport within the lower aquifer unit exceeds gas pressure build-up and buoyancy needed to drive the CO₂gas upwards.</p

Interaction and uptake of exosomes by ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Exosomes consist of membrane vesicles that are secreted by several cell types, including tumors and have been found in biological fluids. Exosomes interact with other cells and may serve as vehicles for the transfer of protein and RNA among cells.</p> <p>Methods</p> <p>SKOV3 exosomes were labelled with carboxyfluoresceine diacetate succinimidyl-ester and collected by ultracentrifugation. Uptake of these vesicles, under different conditions, by the same cells from where they originated was monitored by immunofluorescence microscopy and flow cytometry analysis. Lectin analysis was performed to investigate the glycosylation properties of proteins from exosomes and cellular extracts.</p> <p>Results</p> <p>In this work, the ovarian carcinoma SKOV3 cell line has been shown to internalize exosomes from the same cells via several endocytic pathways that were strongly inhibited at 4°C, indicating their energy dependence. Partial colocalization with the endosome marker EEA1 and inhibition by chlorpromazine suggested the involvement of clathrin-dependent endocytosis. Furthermore, uptake inhibition in the presence of 5-ethyl-N-isopropyl amiloride, cytochalasin D and methyl-beta-cyclodextrin suggested the involvement of additional endocytic pathways. The uptake required proteins from the exosomes and from the cells since it was inhibited after proteinase K treatments. The exosomes were found to be enriched in specific mannose- and sialic acid-containing glycoproteins. Sialic acid removal caused a small but non-significant increase in uptake. Furthermore, the monosaccharides D-galactose, α-L-fucose, α-D-mannose, D-N-acetylglucosamine and the disaccharide β-lactose reduced exosomes uptake to a comparable extent as the control D-glucose.</p> <p>Conclusions</p> <p>In conclusion, exosomes are internalized by ovarian tumor cells via various endocytic pathways and proteins from exosomes and cells are required for uptake. On the other hand, exosomes are enriched in specific glycoproteins that may constitute exosome markers. This work contributes to the knowledge about the properties and dynamics of exosomes in cancer.</p

Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression

Emergency department triage: an ethical analysis

<p>Abstract</p> <p>Background</p> <p>Emergency departments across the globe follow a triage system in order to cope with overcrowding. The intention behind triage is to improve the emergency care and to prioritize cases in terms of clinical urgency.</p> <p>Discussion</p> <p>In emergency department triage, medical care might lead to adverse consequences like delay in providing care, compromise in privacy and confidentiality, poor physician-patient communication, failing to provide the necessary care altogether, or even having to decide whose life to save when not everyone can be saved. These consequences challenge the ethical quality of emergency care. This article provides an ethical analysis of "routine" emergency department triage. The four principles of biomedical ethics - viz. respect for autonomy, beneficence, nonmaleficence and justice provide the starting point and help us to identify the ethical challenges of emergency department triage. However, they do not offer a <it>comprehensive </it>ethical view. To address the ethical issues of emergency department triage from a more comprehensive ethical view, the care ethics perspective offers additional insights.</p> <p>Summary</p> <p>We integrate the results from the analysis using four principles of biomedical ethics into care ethics perspective on triage and propose an integrated clinically and ethically based framework of emergency department triage planning, as seen from a comprehensive ethics perspective that incorporates both the principles-based and care-oriented approach.</p