Depression, antidepressants and driving safety.

BackgroundThe purpose of this study was to review to review the reported associations of depression and antidepressants with motor vehicle crashes.PurposeA literature search for material published in the English language between January, 1995, and October, 2015, in bibliographic databases was combined with a search for other relevant material referenced in the retrieved articles.MethodsRetrieved articles were systematically reviewed for inclusion criteria: 19 epidemiological studies (17 case-control and 2 cohort studies) fulfilled the inclusion criteria by estimating the crash risk associated with depression and/or psychotropic medications in naturalistic settings.ResultsThe estimates of the odds ratio (OR) of crash involvement associated with depression ranged from 1.78 to 3.99. All classes of antidepressants were reported to have side effects with the potential to affect driving safety. The majority of studies of antidepressant effects on driving reported an elevated crash risk, and ORs ranged from 1.19 to 2.03 for all crashes, and 3.19 for fatal crashes. In meta-analysis, depression was associated with approximately 2-fold increased crash risk (summary OR = 1.90; 95% CI, 1.06 to 3.39), and antidepressants were associated with approximately 40% increased crash risk (summary OR = 1.40; 95%CI, 1.18 to 1.66).ConclusionBased on the findings of the studies reviewed, depression, antidepressants or the combination of depression and antidepressants may pose a potential hazard to driving safety. More research is needed to understand the individual contributions of depression and the medications used to treat depression

Role of the conserved aspartate and phenylalanine residues in prokaryotic and mitochondrial elongation factor Ts in guanine nucleotide exchange

AbstractThe guanine nucleotide exchange reaction catalyzed by elongation factor Ts is proposed to arise from the intrusion of the side chains of D80 and F81 near the Mg2+ binding site in EF-Tu. D80A and F81A mutants of E. coli EF-Ts were 2–3-fold less active in promoting GDP exchange with E. coli EF-Tu while the D80AF81A mutant was nearly 10-fold less active. The D84 and F85 mutants of EF-Tsmt were 5–10-fold less active in stimulating the activity of EF-Tumt. The double mutation completely abolished the activity of EF-Tsmt

Tomato EF-Tsmt, a functional mitochondrial translation elongation factor from higher plants

Ethylene-induced ripening in tomato (Lycopersicon esculentum) resulted in the accumulation of a transcript designated LeEF-Tsmt that encodes a protein with significant homology to bacterial Ts translational elongation factor (EF-Ts). Transient expression in tobacco and sunflower protoplasts of full-length and truncated LeEF-Tsmt- GFP fusion constructs and confocal microscopy observations clearly demonstrated the targeting of LeEF-Tsmt to mitochondria and not to chloroplasts and the requirement for a signal peptide for the proper sorting of the protein. Escherichia coli recombinant LeEF-Tsmt co-eluted from Ni-NTA resins with a protein corresponding to the molecular weight of the elongation factor EF-Tu of E. coli, indicating an interaction with bacterial EF-Tu. Increasing the GDP concentration in the extraction buffer reduced the amount of EF-Tu in the purified LeEF-Tsmt fraction. The purified LeEF-Tsmt stimulated the poly(U)-directed polymerization of phenylalanine 10-fold in the presence of EF-Tu. Furthermore, LeEF-Tsmt was capable of catalysing the nucleotide exchange reaction with E. coli EF-Tu. Altogether, these data demonstrate that LeEF-Tsmt encodes a functional mitochondrial EF-Ts. LeEFTsmt represents the first mitochondrial elongation factor to be isolated and functionally characterized in higher plants

A Relation-Centric Query Engine for the Foundational Model of Anatomy

The Foundational Model of Anatomy (FMA), a detailed representation of the structural organization of the human body, was constructed to support the development of software applications requiring knowledge of anatomy. The FMA's focus on the structural relationships between anatomical entities distinguishes it from other current anatomical knowledge sources. We developed Emily, a query engine for the FMA, to enable users to explore the richness and depth of these relationships. Preliminary analysis suggests that Emily is capable of correctly processing real world anatomical queries provided they have been translated into a constrained form suitable for processing by the query engine

Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies

Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.United States. Defense Advanced Research Projects Agency (Grant W911NF-12-2- 0039)National Institutes of Health (U.S.) (Grant 4-UH3-TR000496-0

Application of finite element modeling and viscoelasticity theory in characterization and prediction of dielectric relaxation process in polymer nanodielectrics

Nanodielectrics, typically defined as polymer composites with nanosized ceramic fillers, have demonstrated significant improvements in electrical endurance, breakdown strength and dielectric constant relative to their constituent materials, which leads to enhanced energy storage capabilities. The key role played by the large interfacial area surrounding nanofillers proves to be essential to the enhancement, yet quantitative models to predict the altered dielectric properties in the interfacial area are rarely seen. In this presentation, we apply a finite element modeling approach, originally developed for viscoelasticity analysis, to predict the frequency and temperature dependence of dielectric permittivity spectra in polymer nanodielectrics containing functionalized silica fillers. The dispersion state of nanofillers in the finite element model is determined from descriptor-based analysis of scanning electron micrographs, and the interfacial area surrounding the fillers is explicitly configured into the geometry. The dielectric permittivity spectra of the polymer matrix are imported into the model using a series of Debye relaxation functions. The analogy between dielectric permittivity and viscoelastic modulus allows for a simple mathematical conversion between the two physically distinct quantities, which enables the usage of Prony Series when fitting the dielectric spectrum. With the assistance of a earlier developed algorithm to fit the viscoelastic modulus, the parameters of Debye relaxation series function are obtained. Using the above morphology and physical property inputs, dielectric spectroscopy experiments over a range of frequencies and temperatures can be simulated. Properties of the interfacial region are obtained through an iterative comparison between model output and experimental results. It is observed that the distribution of dielectric relaxation times of the interface could be expressed using those of the polymer matrix multiplied by frequency shift factors that vary with different functionalization of the silica filler surfaces. Our results indicate that surface energy parameters of the filler and the polymer matrix can vary the dielectric response of the composites, which is consistent with earlier observations of the viscoelastic properties of polymer nanocomposites. Further discussion on the results also provides insight into the underlying dielectric relaxation mechanism in the interfacial area

Testing Apps With Real-World Inputs

To test mobile apps, one requires realistic and coherent test inputs. The Link approach for Web testing has shown that knowledge bases such as DBPedia can be a reliable source of semantically coherent inputs. In this paper, we adapt and extend the Link approach towards test generation for mobile applications: (1) We identify and match descriptive labels with input fields, based on the Gestalt principles of human perception; (2) We then use natural language processing techniques to extract the concept associated with the label; (3) We use this concept to query a knowledge base for candidate input values; (4) We cluster the UI elements according to their functionality into input and actions, filling the input elements first and then interacting with the actions. Our evaluation shows that leveraging knowledge bases for testing mobile apps with realistic inputs is effective. On average, our approach covered 9% more statements than randomly generated text inputs

Widespread recombination, reassortment, and transmission of unbalanced compound viral genotypes in natural arenavirus infections.

Arenaviruses are one of the largest families of human hemorrhagic fever viruses and are known to infect both mammals and snakes. Arenaviruses package a large (L) and small (S) genome segment in their virions. For segmented RNA viruses like these, novel genotypes can be generated through mutation, recombination, and reassortment. Although it is believed that an ancient recombination event led to the emergence of a new lineage of mammalian arenaviruses, neither recombination nor reassortment has been definitively documented in natural arenavirus infections. Here, we used metagenomic sequencing to survey the viral diversity present in captive arenavirus-infected snakes. From 48 infected animals, we determined the complete or near complete sequence of 210 genome segments that grouped into 23 L and 11 S genotypes. The majority of snakes were multiply infected, with up to 4 distinct S and 11 distinct L segment genotypes in individual animals. This S/L imbalance was typical: in all cases intrahost L segment genotypes outnumbered S genotypes, and a particular S segment genotype dominated in individual animals and at a population level. We corroborated sequencing results by qRT-PCR and virus isolation, and isolates replicated as ensembles in culture. Numerous instances of recombination and reassortment were detected, including recombinant segments with unusual organizations featuring 2 intergenic regions and superfluous content, which were capable of stable replication and transmission despite their atypical structures. Overall, this represents intrahost diversity of an extent and form that goes well beyond what has been observed for arenaviruses or for viruses in general. This diversity can be plausibly attributed to the captive intermingling of sub-clinically infected wild-caught snakes. Thus, beyond providing a unique opportunity to study arenavirus evolution and adaptation, these findings allow the investigation of unintended anthropogenic impacts on viral ecology, diversity, and disease potential