Visual Attention and the Neuroimage Bias

Several highly-cited experiments have presented evidence suggesting that neuroimages may unduly bias laypeople’s judgments of scientific research. This finding has been especially worrisome to the legal community in which neuroimage techniques may be used to produce evidence of a person’s mental state. However, a more recent body of work that has looked directly at the independent impact of neuroimages on layperson decision-making (both in legal and more general arenas), and has failed to find evidence of bias. To help resolve these conflicting findings, this research uses eye tracking technology to provide a measure of attention to different visual representations of neuroscientific data. Finding an effect of neuroimages on the distribution of attention would provide a potential mechanism for the influence of neuroimages on higher-level decisions. In the present experiment, a sample of laypeople viewed a vignette that briefly described a court case in which the defendant’s actions might have been explained by a neurological defect. Accompanying these vignettes was either an MRI image of the defendant’s brain, or a bar graph depicting levels of brain activity–two competing visualizations that have been the focus of much of the previous research on the neuroimage bias. We found that, while laypeople differentially attended to neuroimagery relative to the bar graph, this did not translate into differential judgments in a way that would support the idea of a neuroimage bias

Acid mine drainage biogeochemistry at Iron Mountain, California

The Richmond Mine at Iron Mountain, Shasta County, California, USA provides an excellent opportunity to study the chemical and biological controls on acid mine drainage (AMD) generation in situ, and to identify key factors controlling solution chemistry. Here we integrate four years of field-based geochemical data with 16S rRNA gene clone libraries and rRNA probe-based studies of microbial population structure, cultivation-based metabolic experiments, arsenopyrite surface colonization experiments, and results of intermediate sulfur species kinetics experiments to describe the Richmond Mine AMD system. Extremely acidic effluent (pH between 0.5 and 0.9) resulting from oxidation of approximately 1 × 10(5 )to 2 × 10(5 )moles pyrite/day contains up to 24 g/1 Fe, several g/1 Zn and hundreds of mg/l Cu. Geochemical conditions change markedly over time, and are reflected in changes in microbial populations. Molecular analyses of 232 small subunit ribosomal RNA (16S rRNA) gene sequences from six sites during a sampling time when lower temperature (<32°C), higher pH (>0.8) conditions predominated show the dominance of Fe-oxidizing prokaryotes such as Ferroplasma and Leptospirillum in the primary drainage communities. Leptospirillum group III accounts for the majority of Leptospirillum sequences, which we attribute to anomalous physical and geochemical regimes at that time. A couple of sites peripheral to the main drainage, "Red Pool" and a pyrite "Slump," were even higher in pH (>1) and the community compositions reflected this change in geochemical conditions. Several novel lineages were identified within the archaeal Thermoplasmatales order associated with the pyrite slump, and the Red Pool (pH 1.4) contained the only population of Acidithiobacillus. Relatively small populations of Sulfobacillus spp. and Acidithiobacillus caldus may metabolize elemental sulfur as an intermediate species in the oxidation of pyritic sulfide to sulfate. Experiments show that elemental sulfur which forms on pyrite surfaces is resistant to most oxidants; its solublization by unattached cells may indicate involvement of a microbially derived electron shuttle. The detachment of thiosulfate ([Image: see text]) as a leaving group in pyrite oxidation should result in the formation and persistence of tetrathionate in low pH ferric iron-rich AMD solutions. However, tetrathionate is not observed. Although a [Image: see text]-like species may form as a surface-bound intermediate, data suggest that Fe(3+ )oxidizes the majority of sulfur to sulfate on the surface of pyrite. This may explain why microorganisms that can utilize intermediate sulfur species are scarce compared to Fe-oxidizing taxa at the Richmond Mine site

Period-1 Encodes an ATP-Dependent RNA Helicase that Influences Nutritional Compensation of the Neurospora Circadian Clock

Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 [DEAD (Asp-Glu-Ala-Asp) Box Helicase 5] and DDX17 in humans and DBP2 (Dead Box Protein 2) in yeast, are implicated in various processes, including transcriptional regulation, elongation, and termination, ribosome biogenesis, and mRNA decay. Although prd-1 mutants display a long period (∼25 h) circadian developmental cycle, they interestingly display a WT period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator in the prd-1 mutant strain runs with a long period under glucose-sufficient conditions. Thus, PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein, and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose, PRD-1 is in the nucleus until glucose runs out, which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd-1 may be formally viewed as a clock mutant with defective nutritional compensation of circadian period length

Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy

G protein-coupled receptors exist in a whole spectrum of conformations which are stabilised by the binding of ligands with different efficacy or intracellular effector proteins. Here, we investigate whether three-dimensional structures of receptor conformations in different states of activation can be utilised to enrich ligands with agonist behaviour in prospective docking calculations. We focused on the β2-adrenergic receptor, as it currently is the receptor with the highest number of active-state crystal structures. Comparative docking calculations to distinct conformations of the receptor were used for the in silico prediction of ligands with agonist efficacy. The pharmacology of molecules selected based on these predictions was characterised experimentally, resulting in a hit rate of 37% ligands, all of which were agonists. The ligands furthermore contain a pyrazole moiety which has previously not been described for β2 -adrenergic receptor ligands and one of them shows an intrinsic efficacy comparable to salbutamol

Negative cooperativity across 1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 1-adrenoceptor binding conformation

At the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 of the β1-adrenoceptor as key for this low-affinity conformation. Others suggested that TM4 has a role in β1-adrenoceptor oligomerization. Here, assessment of the dissociation rate of a fluorescent analog of CGP 12177 [bordifluoropyrromethane-tetramethylrhodamine-(±)CGP 12177 (BODIPY-TMR-CGP)] at the human β1-adrenoceptor expressed in Chinese hamster ovary cells revealed negative cooperative interactions between 2 distinct β1-adrenoceptor conformations. The dissociation rate of 3 nM BODIPY-TMR-CGP was 0.09 ± 0.01 min−1 in the absence of competitor ligands, and this was enhanced 2.2- and 2.1-fold in the presence of 1 µM CGP 12177 and 1 µM propranolol, respectively. These effects on the BODIPY-TMR-CGP dissociation rate were markedly enhanced in β1-adrenoceptor homodimers constrained by bimolecular fluorescence complementation (9.8- and 9.9-fold for 1 µM CGP 12177 and 1 µM propranolol, respectively) and abolished in β1-adrenoceptors containing TM4 mutations vital for the second conformation pharmacology. This study suggests that negative cooperativity across a β1-adrenoceptor homodimer may be responsible for generating the low-affinity pharmacology of the secondary β1-adrenoceptor conformatio

Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor

The orexin receptors are peptide-sensing G protein-coupled receptors that are intimately linked with regulation of the sleep/wake cycle. We used a recently solved X-ray structure of the orexin receptor subtype 2 in computational docking calculations with the aim to identify additional ligands with unprecedented chemotypes. We found validated ligands with a high hit rate of 29% out of those tested, none of them showing selectivity with respect to the orexin receptor subtype 1. Furthermore, of the higher-affinity compounds examined, none showed any agonist activity. While novel chemical structures can thus be found, selectivity is a challenge owing to the largely identical binding pockets

A Full Pharmacological Analysis of the Three Turkey β-Adrenoceptors and Comparison with the Human β-Adrenoceptors

There are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Stable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.There are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation

Self-Reported Cognitive Function and Mental Health Diagnoses among Former Professional American-Style Football Players

Clinical practice strongly relies on patients' self-report. Former professional American-style football players are hesitant to seek help for mental health problems, but may be more willing to report cognitive symptoms. We sought to assess the association between cognitive symptoms and diagnosed mental health problems and quality of life among a cohort of former professional players. In a cross-sectional design, we assessed self-reported cognitive function using items from the Quality of Life in Neurological Disorders (Neuro-QOL) Item Bank. We then compared mental health diagnoses and quality of life, assessed by items from the Patient-Reported Outcome Measurement Information System (PROMIS ®), between former professional players reporting daily problems in cognitive function and former players not reporting daily cognitive problems. Of the 3758 former professional players included in the analysis, 40.0% reported daily problems due to cognitive dysfunction. Former players who reported daily cognitive problems were more likely to also report depression (18.0% vs. 3.3%, odds ratio [OR] = 6.42, 95% confidence interval [CI] [4.90-8.40]) and anxiety (19.1% vs. 4.3%, OR = 5.29, 95% CI [4.14-6.75]) than those without daily cognitive problems. Further, former players reporting daily cognitive problems were more likely to report memory loss and attention deficit(/hyperactivity) disorder and poorer general mental health, lower quality of life, less satisfaction with social activities and relationships, and more emotional problems. These findings highlight the potential of an assessment of cognitive symptoms for identifying former players with mental health, social, and emotional problems