Ethical Decision Making Behind the Wheel – A Driving Simulator Study

Over the past several years, there has been considerable debate surrounding ethical decision making in situations resulting in inevitable casualties. Given enough time and all other things being equal, studies show that drivers will typically decide to strike the fewest number of pedestrians in scenarios where there is a choice between striking several versus one or no pedestrians. However, it is unclear whether drivers behave similarly under situations of time pressure. In our experiment in a driving simulator, 32 drivers were given up to 2 s to decide which group of pedestrians to avoid among groups of larger (5) or smaller (≤1) number of pedestrians. Our findings suggest that while people frequently choose utilitarian decisions in the typical, abstract manifestations of the Trolley Problems, drivers can fail to make utilitarian decisions in simulated driving environments under a restricted period of time representative of the time they would have to make the same decision in the real world (2 s). Analysis of eye movement data shows that drivers are less likely to glance at left and right sides of crosswalks under situations of time duress. Our results raise critical engineering and ethical questions. From a cognitive engineering standpoint, we need to know how long at minimum a driver needs to make simple, moral decisions in different scenarios. From an ethical standpoint, we may need to evaluate whether automated vehicle algorithms can aid decision making on our behalf when there is not enough time for a driver to make a moral decision

A noncanonical auxin-sensing mechanism is required for organ morphogenesis in Arabidopsis

Tissue patterning in multicellular organisms is the output of precise spatio–temporal regulation of gene expression coupled with changes in hormone dynamics. In plants, the hormone auxin regulates growth and development at every stage of a plant's life cycle. Auxin signaling occurs through binding of the auxin molecule to a TIR1/AFB F-box ubiquitin ligase, allowing interaction with Aux/IAA transcriptional repressor proteins. These are subsequently ubiquitinated and degraded via the 26S proteasome, leading to derepression of auxin response factors (ARFs). How auxin is able to elicit such a diverse range of developmental responses through a single signaling module has not yet been resolved. Here we present an alternative auxin-sensing mechanism in which the ARF ARF3/ETTIN controls gene expression through interactions with process-specific transcription factors. This noncanonical hormone-sensing mechanism exhibits strong preference for the naturally occurring auxin indole 3-acetic acid (IAA) and is important for coordinating growth and patterning in diverse developmental contexts such as gynoecium morphogenesis, lateral root emergence, ovule development, and primary branch formation. Disrupting this IAA-sensing ability induces morphological aberrations with consequences for plant fitness. Therefore, our findings introduce a novel transcription factor-based mechanism of hormone perception in plants. Note that there is a CORRIGENDUM to this article: http://eprints.whiterose.ac.uk/132306/ http://genesdev.cshlp.org/content/31/17/1821.ful

The positive effect of selective prostaglandin E2 receptor EP2 and EP4 blockade on cystogenesis in vitro is counteracted by increased kidney inflammation in vivo

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major cause of end-stage kidney disease in man. The central role of cyclic adenosine monophosphate (cAMP) in ADPKD pathogenesis has been confirmed by numerous studies including positive clinical trial data. Here, we investigated the potential role of another major regulator of renal cAMP, prostaglandin E2 (PGE2), in modifying disease progression in ADPKD models using selective receptor modulators to all four PGE2 receptor subtypes (EP1-4). In 3D-culture model systems utilizing dog (MDCK) and patient-derived (UCL93, OX161-C1) kidney cell lines, PGE2 strikingly promoted cystogenesis and inhibited tubulogenesis by stimulating proliferation while reducing apoptosis. The effect of PGE2 on tubulogenesis and cystogenesis in 3D-culture was mimicked or abolished by selective EP2 and EP4 agonists or antagonists but not those specific to EP1 or EP3. In a Pkd1 mouse model (Pkd1nl/nl), kidney PGE2 and COX-2 expression were increased by two-fold at the peak of disease (week four). However, Pkd1nl/nl mice treated with selective EP2 (PF-04418948) or EP4 (ONO-AE3-208) antagonists from birth for three weeks had more severe cystic disease and fibrosis associated with increased cell proliferation and macrophage infiltration. A similar effect was observed for the EP4 antagonist ONO-AE3-208 in a second Pkd1 model (Pax8rtTA-TetO-Cre-Pkd1f/f). Thus, despite the positive effects of slowing cyst growth in vitro, the more complex effects of inhibiting EP2 or EP4 in vivo resulted in a worse outcome, possibly related to unexpected pro-inflammatory effects

Fructan and hormone connections

Plants rely on “reserve” (stored) carbon (C) for growth and survival when newly synthesized C becomes limited. Besides a classic yet recalcitrant C reserve starch, fructans, a class of sucrose-derived soluble fructosyl-oligosaccharides, represent a major store of C in many temperate plant species including the economically important Asteraceae and Poaceae families (Hendry, 1993). Dicots typically accumulate inulin-type fructans as long-term storage (underground organs) whilst grasses and cereals accumulate fructans as short-term reserves in above-ground parts (Pollock and Cairns, 1991; Van Laere and Van den Ende, 2002). Unlike chloroplast-based water-insoluble starch, fructans are semi-soluble, possess flexible structures (Phelps, 1965; Valluru and Van den Ende, 2008), can be synthesized at low temperatures (Pollock and Cairns, 1991), and are degraded by a single type of fructan hydrolases, fructan exohydrolases (FEHs). Unlike starch that store in plastids, fructans store in vacuoles, which is physically less stressful to the active constituents of, and allows more C synthesis by, the photosynthetic cell, which may be different in dicots where fructans do not typically accumulate in green parts

Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for Autosomal Dominant Polycystic Kidney Disease

MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m2), nine with late disease (eGFR under 60ml/min/1.73m2), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194- 5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD

Transcriptional responses of winter barley to cold indicate nucleosome remodelling as a specific feature of crown tissues

We report a series of microarray-based comparisons of gene expression in the leaf and crown of the winter barley cultivar Luxor, following the exposure of young plants to various periods of low (above and below zero) temperatures. A transcriptomic analysis identified genes which were either expressed in both the leaf and crown, or specifically in one or the other. Among the former were genes responsible for calcium and abscisic acid signalling, polyamine synthesis, late embryogenesis abundant proteins and dehydrins. In the crown, the key organ for cereal overwintering, cold treatment induced transient changes in the transcription of nucleosome assembly genes, and especially H2A and HTA11, which have been implicated in cold sensing in Arabidopsis thaliana. In the leaf, various heat-shock proteins were induced. Differences in expression pattern between the crown and leaf were frequent for genes involved in certain pathways responsible for osmolyte production (sucrose and starch, raffinose, γ-aminobutyric acid metabolism), sugar signalling (trehalose metabolism) and secondary metabolism (lignin synthesis). The action of proteins with antifreeze activity, which were markedly induced during hardening, was demonstrated by a depression in the ice nucleation temperature

Phosphorous Efficiency and Tolerance Traits for Selection of Sorghum for Performance in Phosphorous-Limited Environments

Sorghum (Sorghum bicolor (L.) Moench) is widely cultivated in West Africa (WA) on soils with low phosphorus (P) availability. Large genetic variation for grain yield (GY) under low-P conditions was observed among WA sorghum genotypes, but information is lacking on the usefulness of P-tolerance ratios (relative performance in –P [no P fertilizer] vs. +P [with P fertilizer] conditions) and measures of P-acquisition and internal P-use efficiency as selection criteria for enhancing GY under low-P conditions. We evaluated 70 WA sorghum genotypes for GY performance under −P and +P conditions for 5 yr in two locations in Mali and assessed P acquisition (e.g., P content in biomass) and P-use efficiency (e.g., grain produced per unit P uptake) traits under −P and +P conditions in one site in 2010. Significant genetic variation existed for all P-tolerance ratios across multiple sites. Photoperiod-sensitive landrace genotypes showed significantly better P tolerance and less delay of heading under P-limited conditions compared with photoperiod-insensitive varieties. Genotypic correlations of P-tolerance ratios to GY under −P were moderate. Phosphorous acquisition and P-use efficiency traits independent of harvest index were of similar importance for GY under −P conditions in statistically independent trials. However grain-P and stover-P concentrations from one −P trial showed only weak correlations with GYs in statistically independent trials. Highest predicted gains for −P GY were obtained by theoretical index selection based on −P GY combined with P-use efficiency traits (e.g., low-grain P concentration). Such index selection is expected to achieve both increased sorghum productivity and P sustainability in the P-limited WA production systems

The Biochemistry, Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors

The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric ligand-gated ion channels that play crucial roles in synaptic transmission and plasticity. Our knowledge about the ultrastructure and subunit assembly mechanisms of intact AMPA-Rs was very limited. However, the new studies using single particle EM and X-ray crystallography are revealing important insights. For example, the tetrameric crystal structure of the GluA2cryst construct provided the atomic view of the intact receptor. In addition, the single particle EM structures of the subunit assembly intermediates revealed the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. These new data in the field provide new models and interpretations. In the brain, the native AMPA-R complexes contain auxiliary subunits that influence subunit assembly, gating, and trafficking of the AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become increasingly important to precisely describe the function of AMPA-Rs in the brain. The AMPA-R proteomics studies continuously reveal a previously unexpected degree of molecular heterogeneity of the complex. Because the AMPA-Rs are important drug targets for treating various neurological and psychiatric diseases, it is likely that these new native complexes will require detailed mechanistic analysis in the future. The current ultrastructural data on the receptors and the receptor-expressing stable cell lines that were developed during the course of these studies are useful resources for high throughput drug screening and further drug designing. Moreover, we are getting closer to understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity