Attention, predictive learning, and the inverse base-rate effect: Evidence from event-related potentials

We report the first electrophysiological investigation of the inverse base-rate effect (IBRE), a robust non-rational bias in predictive learning. In the IBRE, participants learn that one pair of symptoms (AB) predicts a frequently occurring disease, whilst an overlapping pair of symptoms (AC) predicts a rarely occurring disease. Participants subsequently infer that BC predicts the rare disease, a non-rational decision made in opposition to the underlying base rates of the two diseases. Error-driven attention theories of learning state that the IBRE occurs because C attracts more attention than B. On the basis of this account we predicted and observed the occurrence of brain potentials associated with visual attention: a posterior Selection Negativity, and a concurrent anterior Selection Positivity, for C vs. B in a post-training test phase. Error-driven attention theories further predict no Selection Negativity, Selection Positivity or IBRE, for control symptoms matched on frequency to B and C, but for which there was no shared symptom (A) during training. These predictions were also confirmed, and this confirmation discounts alternative explanations of the IBRE based on the relative novelty of B and C. Further, we observed higher response accuracy for B alone than for C alone; this dissociation of response accuracy (B>C) from attentional allocation (C>B) discounts the possibility that the observed attentional difference was caused by the difference in response accuracy

A Fluorescent Probe Identifies Active Site Ligands of Inositol Pentakisphosphate 2-Kinase

Inositol pentakisphosphate 2-kinase catalyzes the phosphorylation of the axial 2-OH of myo-inositol 1,3,4,5,6-pentakisphosphate for de novo synthesis of myo-inositol hexakisphosphate. Disruption of inositol pentakisphosphate 2-kinase profoundly influences cellular processes; from nuclear mRNA export and phosphate homeostasis in yeast and plants, to establishment of left-right asymmetry in zebra fish. We elaborate an active site fluorescent probe that allows high throughput screening of Arabidopsis inositol pentakisphosphate 2-kinase. We show that the probe has a binding constant comparable to the Km values of inositol phosphate substrates of this enzyme, and can be used to prospect for novel substrates and inhibitors of inositol phosphate kinases. We identify several micromolar Ki inhibitors and validate this approach by solving the crystal structure of protein in complex with purpurogallin. We additionally solve structures of protein in complexes with epimeric higher inositol phosphates. This probe may find utility in characterization of a wide family of inositol phosphate kinases

Prenatal hypoxia induces increased cardiac contractility on a background of decreased capillary density.

Background: Chronic hypoxia in utero (CHU) is one of the most common insults to fetal development and may be associated with poor cardiac recovery from ischaemia-reperfusion injury,yet the effects on normal cardiac mechanical performance are poorly understood. Methods: Pregnant female wistar rats were exposed to hypoxia (12% oxygen, balance nitrogen)for days 10–20 of pregnancy. Pups were born into normal room air and weaned normally. At 10 weeks of age, hearts were excised under anaesthesia and underwent retrograde 'Langendorff' perfusion. Mechanical performance was measured at constant filling pressure (100 cm H2O) with intraventricular balloon. Left ventricular free wall was dissected away and capillary density estimated following alkaline phosphatase staining. Expression of SERCA2a and Nitric Oxide Synthases (NOS) proteins were estimated by immunoblotting. Results: CHU significantly increased body mass (P < 0.001) compared with age-matched control rats but was without effect on relative cardiac mass. For incremental increases in left ventricular balloon volume, diastolic pressure was preserved. However, systolic pressure was significantly greater following CHU for balloon volume = 50 μl (P < 0.01) and up to 200 μl (P < 0.05). For higher balloon volumes systolic pressure was not significantly different from control. Developed pressures were correspondingly increased relative to controls for balloon volumes up to 250 μl (P < 0.05).Left ventricular free wall capillary density was significantly decreased in both epicardium (18%; P <0.05) and endocardium (11%; P < 0.05) despite preserved coronary flow. Western blot analysis revealed no change to the expression of SERCA2a or nNOS but immuno-detectable eNOS protein was significantly decreased (P < 0.001) in cardiac tissue following chronic hypoxia in utero. Conclusion: These data offer potential mechanisms for poor recovery following ischaemia, including decreased coronary flow reserve and impaired angiogenesis with subsequent detrimental effects of post-natal cardiac performance

Reducing Tick-Borne Disease in Alabama: Linking Health Risk Perception with Spatial Analysis Using the NASA Earth Observing System

Lyme disease (LD) accounts for most vector-borne disease reports in the U.S., and although its existence in Alabama remains controversial, other tick-borne illnesses (TBI) such as Southern Tick-Associated Rash Illness (STARI) pose a health concern in the state. Phase One of the Marshall Space Flight Center-UAB DEVELOP study of TBI identified the presence of the chain of infection for LD (Ixodes scapularis ticks carrying Borrelia burgdorferi bacteria) and STARI (Amblyomma americanum ticks and an as-yet-unconfirmed agent) in Alabama. Both LD and STARI are associated with the development of erythema migrans rashes around an infected tick bite, and while treatable with oral antibiotics, a review of educational resources available to state residents revealed low levels of prevention information. To improve prevention, recognition, and treatment of TBI in Alabama, Phase Two builds a health communication campaign based on vector habitat mapping and risk perception assessment. NASA Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) satellite imagery identified likely tick habitats using remotely sensed measurements of vegetation vigor (Normalized Difference Vegetation Index) and soil moisture. Likely tick habitats, identified as those containing both high vegetation density and soil moisture, included Oak Mountain State Park, Bankhead National Forest, and Talladega National Forest. To target a high-risk group -- outdoor recreation program participants at Alabama universities -- the study developed a behavior survey instrument based on existing studies of LD risk factors and theoretical constructs from the Social Ecological Model and Health Belief Model. The survey instrument was amended to include geographic variables in the assessment of TBI knowledge, attitudes, and prevention behaviors, and the vector habitat model will be expanded to incorporate additional environmental variables and in situ data. Remotely sensed environmental data combined with risk perception assessments inform an ongoing outreach campaign consisting of stakeholder meetings and educational seminars

Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3

Mutations in CCM1, CCM2, or CCM3 lead to cerebral cavernous malformations, one of the most common hereditary vascular diseases of the brain. Endothelial cells within these lesions are the main disease compartments. Here, we show that adenoviral CCM3 expression inhibits endothelial cell migration, proliferation, and tube formation while downregulation of endogenous CCM3 results in increased formation of tube-like structures. Adenoviral CCM3 expression does not induce apoptosis under normal endothelial cell culture conditions but protects endothelial cells from staurosporine-induced cell death. Tyrosine kinase activity profiling suggests that CCM3 supports PDPK-1/Akt-mediated endothelial cell quiescence and survival

The future is now: Model-based clinical trial design for Alzheimer's disease

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease.1 CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)

Priming by Chemokines Restricts Lateral Mobility of the Adhesion Receptor LFA-1 and Restores Adhesion to ICAM-1 Nano-Aggregates on Human Mature Dendritic Cells

LFA-1 is a leukocyte specific β2 integrin that plays a major role in regulating adhesion and migration of different immune cells. Recent data suggest that LFA-1 on mature dendritic cells (mDCs) may function as a chemokine-inducible anchor during homing of DCs through the afferent lymphatics into the lymph nodes, by transiently switching its molecular conformational state. However, the role of LFA-1 mobility in this process is not yet known, despite that the importance of lateral organization and dynamics for LFA-1-mediated adhesion regulation is broadly recognized. Using single particle tracking approaches we here show that LFA-1 exhibits higher mobility on resting mDCs compared to monocytes. Lymphoid chemokine CCL21 stimulation of the LFA-1 high affinity state on mDCs, led to a significant reduction of mobility and an increase on the fraction of stationary receptors, consistent with re-activation of the receptor. Addition of soluble monomeric ICAM-1 in the presence of CCL21 did not alter the diffusion profile of LFA-1 while soluble ICAM-1 nano-aggregates in the presence of CCL21 further reduced LFA-1 mobility and readily bound to the receptor. Overall, our results emphasize the importance of LFA-1 lateral mobility across the membrane on the regulation of integrin activation and its function as adhesion receptor. Importantly, our data show that chemokines alone are not sufficient to trigger the high affinity state of the integrin based on the strict definition that affinity refers to the adhesion capacity of a single receptor to its ligand in solution. Instead our data indicate that nanoclustering of the receptor, induced by multi-ligand binding, is required to maintain stable cell adhesion once LFA-1 high affinity state is transiently triggered by inside-out signals.Peer ReviewedPostprint (published version

Nursing heroism in the 21st Century'

Abstract Background The Vivian Bullwinkel Oration honours the life and work of an extraordinary nurse. Given her story and that of her World War II colleagues, the topic of nursing heroism in the 21st century could not be more germane. Discussion Is heroism a legitimate part of nursing, or are nurses simply 'just doing their job' even when facing extreme personal danger? In this paper I explore the place and relevance of heroism in contemporary nursing. I propose that nursing heroism deserves a broader appreciation and that within the term lie many hidden, 'unsung' or 'unrecorded' heroisms. I also challenge the critiques of heroism that would condemn it as part of a 'militarisation' of nursing. Finally, I argue that nursing needs to be more open in celebrating our heroes and the transformative power of nursing achievements. Summary The language of heroism may sound quaint by 21st Century standards but nursing heroism is alive and well in the best of our contemporary nursing ethos and practice.</p

Professionalism, Golf Coaching and a Master of Science Degree: A commentary

As a point of reference I congratulate Simon Jenkins on tackling the issue of professionalism in coaching. As he points out coaching is not a profession, but this does not mean that coaching would not benefit from going through a professionalization process. As things stand I find that the stimulus article unpacks some critically important issues of professionalism, broadly within the context of golf coaching. However, I am not sure enough is made of understanding what professional (golf) coaching actually is nor how the development of a professional golf coach can be facilitated by a Master of Science Degree (M.Sc.). I will focus my commentary on these two issues

GSK3β Regulates Differentiation and Growth Arrest in Glioblastoma

Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3β), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3β. Interference with GSK3β activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3β. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status