Measured electron contribution to Shuttle plasma environment: Abbreviated update

The differential energy spectra of electrons between 1 and 100 eV were measured by an electron spectrometer flown on an early shuttle. This energy range was scanned in 64 incremental steps with a resolution of 7%. The most striking feature that was observed throughout these spectra was a relatively flat distribution of the higher energy electrons out to 100 eV. This is in contrast to normal ambient spectra which consistently show a rapid decline in quantitative flux beyond 50 to 55 eV. The lower energy (1 to 2 eV) end of these spectra showed steep thermal trails comparable to normal ambient spectral structure. In general, daytime fluxes were significantly higher than those obtained during nighttime measurements. Quantitative flux excursions which may possibly be associated with thruster firing were frequently observed. Spectral structure suggestive of the N2 vibrational excitation energy loss mechanism was also seen in the data from some measurement periods. Examples of these spectra are shown and possible correlations are discussed

Metamorphic Domain-Specific Languages: A Journey Into the Shapes of a Language

External or internal domain-specific languages (DSLs) or (fluent) APIs? Whoever you are -- a developer or a user of a DSL -- you usually have to choose your side; you should not! What about metamorphic DSLs that change their shape according to your needs? We report on our 4-years journey of providing the "right" support (in the domain of feature modeling), leading us to develop an external DSL, different shapes of an internal API, and maintain all these languages. A key insight is that there is no one-size-fits-all solution or no clear superiority of a solution compared to another. On the contrary, we found that it does make sense to continue the maintenance of an external and internal DSL. The vision that we foresee for the future of software languages is their ability to be self-adaptable to the most appropriate shape (including the corresponding integrated development environment) according to a particular usage or task. We call metamorphic DSL such a language, able to change from one shape to another shape

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype

A Trouble Shared Is a Trouble Halved: Social Context and Status Affect Pain in Mouse Dyads

In mice behavioral response to pain is modulated by social status. Recently, social context also has been shown to affect pain sensitivity. In our study, we aimed to investigate the effects of interaction between status and social context in dyads of outbred CD-1 male mice in which the dominance/submission relationship was stable. Mice were assessed for pain response in a formalin (1% concentration) test either alone (individually tested-IT), or in pairs of dominant and subordinate mice. In the latter condition, they could be either both injected (BI) or only one injected (OI) with formalin. We observed a remarkable influence of social context on behavioral response to painful stimuli regardless of the social status of the mice. In the absence of differences between OI and IT conditions, BI mice exhibited half as much Paw-licking behavior than OI group. As expected, subordinates were hypoalgesic in response to the early phase of the formalin effects compared to dominants. Clear cut-differences in coping strategies of dominants and subordinates appeared. The former were more active, whereas the latter were more passive. Finally, analysis of behavior of the non-injected subjects (the observers) in the OI dyads revealed that dominant observers were more often involved in Self-grooming behavior upon observation of their subordinate partner in pain. This was not the case for subordinate mice observing the pain response of their dominant partner. In contrast, subordinate observers Stared at the dominant significantly more frequently compared to observer dominants in other dyads. The observation of a cagemate in pain significantly affected the observer's behavior. Additionally, the quality of observer's response was also modulated by the dominance/submission relationship

Effect of obesity on constant workrate exercise in hyperinflated men with COPD

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD.</p> <p>Methods</p> <p>Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET.</p> <p>Results and discussion</p> <p>FEV₁% predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO₂in L·min^-1was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories.</p> <p>Conclusions</p> <p>OB and OW patients with COPD had a higher peak VO₂than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.</p

Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acid A (GABA A ) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABA A -receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65554/1/j.1528-1157.1994.tb05955.x.pd