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Developmental trajectory of social influence integration into perceptual decisions in children.
The opinions of others have a profound influence on decision making in adults. The impact of social influence appears to change during childhood, but the underlying mechanisms and their development remain unclear. We tested 125 neurotypical children between the ages of 6 and 14 years on a perceptual decision task about 3D-motion figures under informational social influence. In these children, a systematic bias in favor of the response of another person emerged at around 12 years of age, regardless of whether the other person was an age-matched peer or an adult. Drift diffusion modeling indicated that this social influence effect in neurotypical children was due to changes in the integration of sensory information, rather than solely a change in decision behavior. When we tested a smaller cohort of 30 age- and IQ-matched autistic children on the same task, we found some early decision bias to social influence, but no evidence for the development of systematic integration of social influence into sensory processing for any age group. Our results suggest that by the early teens, typical neurodevelopment allows social influence to systematically bias perceptual processes in a visual task previously linked to the dorsal visual stream. That the same bias did not appear to emerge in autistic adolescents in this study may explain some of their difficulties in social interactions.
A simple educational programme substantially reduces unnecessary use of coagulation screening testing in an acute medical department.
A review suggested that coagulation screening tests (CST) were frequently performed unnecessarily in our Acute Medical Department. We reviewed the records of all patients for whom CST was ordered in one week (n141) before designing and delivering an e-mail, poster and presentation based educational programme to clinicians. We repeated the review of records three weeks after this programme (n79). The proportion of patients in whom CST was ordered was significantly lower (22% versus 32%, p0.0014) and proportion of CSTs sent with a valid indication was significantly higher (87% versus 49%, p 0.0001) in the second review period. This study demonstrates that a simple educational programme substantially reduces unnecessary use of CST in an acute medical department with significant potential efficiency savings.
An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28.
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Myocardial perfusion and oxygenation are impaired during stress in severe aortic stenosis and correlate with impaired energetics and subclinical left ventricular dysfunction.
BACKGROUND: Left ventricular (LV) hypertrophy in aortic stenosis (AS) is characterized by reduced myocardial perfusion reserve due to coronary microvascular dysfunction. However, whether this hypoperfusion leads to tissue deoxygenation is unknown. We aimed to assess myocardial oxygenation in severe AS without obstructive coronary artery disease, and to investigate its association with myocardial energetics and function. METHODS: Twenty-eight patients with isolated severe AS and 15 controls underwent cardiovascular magnetic resonance (CMR) for assessment of perfusion (myocardial perfusion reserve index-MPRI) and oxygenation (blood-oxygen level dependent-BOLD signal intensity-SI change) during adenosine stress. LV circumferential strain and phosphocreatine/adenosine triphosphate (PCr/ATP) ratios were assessed using tagging CMR and 31P MR spectroscopy, respectively. RESULTS: AS patients had reduced MPRI (1.1 ± 0.3 vs. controls 1.7 ± 0.3, p < 0.001) and BOLD SI change during stress (5.1 ± 8.9% vs. controls 18.2 ± 10.1%, p = 0.001), as well as reduced PCr/ATP (1.45 ± 0.21 vs. 2.00 ± 0.25, p < 0.001) and LV strain (-16.4 ± 2.7% vs. controls -21.3 ± 1.9%, p < 0.001). Both perfusion reserve and oxygenation showed positive correlations with energetics and LV strain. Furthermore, impaired energetics correlated with reduced strain. Eight months post aortic valve replacement (AVR) (n = 14), perfusion (MPRI 1.6 ± 0.5), oxygenation (BOLD SI change 15.6 ± 7.0%), energetics (PCr/ATP 1.86 ± 0.48) and circumferential strain (-19.4 ± 2.5%) improved significantly. CONCLUSIONS: Severe AS is characterized by impaired perfusion reserve and oxygenation which are related to the degree of derangement in energetics and associated LV dysfunction. These changes are reversible on relief of pressure overload and hypertrophy regression. Strategies aimed at improving oxygen demand-supply balance to preserve myocardial energetics and LV function are promising future therapies.
Obese subjects show sex-specific differences in right ventricular hypertrophy.
BACKGROUND: As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. METHODS AND RESULTS: Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001). CONCLUSIONS: A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling.
CagA-ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids.
The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA-ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway-identified by a high-content imaging screen-or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.
Cross-species cortical alignment identifies different types of anatomical reorganization in the primate temporal lobe.
Evolutionary adaptations of temporo-parietal cortex are considered to be a critical specialization of the human brain. Cortical adaptations, however, can affect different aspects of brain architecture, including local expansion of the cortical sheet or changes in connectivity between cortical areas. We distinguish different types of changes in brain architecture using a computational neuroanatomy approach. We investigate the extent to which between-species alignment, based on cortical myelin, can predict changes in connectivity patterns across macaque, chimpanzee, and human. We show that expansion and relocation of brain areas can predict terminations of several white matter tracts in temporo-parietal cortex, including the middle and superior longitudinal fasciculus, but not the arcuate fasciculus. This demonstrates that the arcuate fasciculus underwent additional evolutionary modifications affecting the temporal lobe connectivity pattern. This approach can flexibly be extended to include other features of cortical organization and other species, allowing direct tests of comparative hypotheses of brain organization.
Sensorimotor control
© 2017 Elsevier Inc. All rights reserved. Later in development many marine tunicates that start life as mobile larvae fix themselves onto a rock and never move thereafter; they then proceed to autolyze their own nervous systems because they no longer need to waste precious resources on servicing such an energy-hungry organ as the brain. This highlights that the main reason for having a brain at all is to control movement and to plan and execute appropriate actions in any given situation by representing in the brain, the whole panoply of current sensory inputs plus stored memories of previous sensory contexts, of the actions then selected and how successful they were, in order to predict which behavior will now best meet current requirements. Hence this sensorimotor section of the Reference Module in Neuroscience will include not only articles on muscle, proprioception, and spinal, subcortical, and cortical control of muscle contractions, but also articles on how decisions to embark on a particular course of action are made and how these movements are planned in relation to past experience and current predictions of their likely outcomes in order to optimize their adaptation to the needs of the moment.
Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
The ability to prevent blood loss in response to injury is a conserved function of all vertebrates. Complete deficiency of the central clotting enzyme prothrombin has never been observed in humans and is incompatible with postnatal life in mice, thus limiting the ability to study its role in vivo. Zebrafish are able to tolerate severe hemostatic deficiencies that are lethal in mammals. We have generated a targeted genetic deletion in the kringle 1 domain of zebrafish prothrombin. Homozygous mutant embryos develop normally into the mid-juvenile stage but demonstrate complete mortality by 2 months of age primarily due to internal hemorrhage. Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants. Human prothrombin engineered with the equivalent mutation exhibits a severe reduction in secretion, thrombin generation, and fibrinogen cleavage. Together, these data demonstrate the conserved function of thrombin in zebrafish and provide insight into the role of kringle 1 in prothrombin maturation and activity. Understanding how zebrafish are able to develop normally and survive into early adulthood without thrombin activity will provide important insight into its pleiotropic functions as well as the management of patients with bleeding disorders.
MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles.
Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood-brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.
Against the microfoundation hegemony: cooperation in biology, business and economics.
We use recent insights from evolutionary biology and the principle of biological relativity to reveal the remarkable parallels between forms of cooperation in biology, business and economics. The principle of biological relativity states that there is no privileged level of causation. The creation of higher levels of organisation and regulation constrains the components of co-operation in a form of downward causation. The upward and downward forms of causation are not equivalent. Downward causation is an organising principle arising from the ordered creation of the 'initial' and 'boundary' conditions experienced by the lower level components. But the existence of the lower level components is also the necessary condition for the creation of the higher-level constraints. Very similar processes are at work in corporations. The restrictions imposed by the legal form of the corporation bind investors to the provision of permanent capital in a similar way to that of fusion of organisms in biological processes, creating a form of symbiogenesis. The higher order conditions imposed on the agents of the firm provide an organising principle and the existence of the lower level agents is a necessary condition for the creation of the higher-level constraints. Furthermore, the process of entry into new business environments resembles that of symbiosis or symbiogenesis in that the interaction is asymmetric; the subsequent process is dynamic, resulting in super-additivity. The dynamic processes can create higher levels of organisation, such as new business models involving cooperation between businesses, corporations, regulators and governments. These in turn constrain the entities forming the new process.
Corrigendum: Ion Channel Targeted Mechanisms of Anti-arrhythmic Chinese Herbal Medicine Xin Su Ning.
[This corrects the article DOI: 10.3389/fphar.2019.00070.].
Sleep homeostasis reflects temporally integrated local cortical neuronal activity
<jats:title>Abstract</jats:title><jats:p>The homeostatic regulation of sleep manifests as a relative constancy of its daily amount and intensity. Theoretical descriptions of this phenomenon define “Process S”, a variable with dynamics dependent only on sleep-wake history, whose levels are reflected in electroencephalogram (EEG) slow wave activity (0.5 – 4 Hz) during sleep. Here we developed novel mathematical models of Process S in mice, assuming that its dynamics are a function of the deviation of cortical neuronal firing rates from a locally defined set-point, crucially without explicit knowledge of sleep-wake state. Our results suggest that Process S tracks global sleep-wake history through an integration of local cortical neuronal activity levels over time. We posit that, instead of reflecting sleep-wake-dependent changes in specific variables and serving their homeostatic regulation, Process S may be a time-keeping mechanism which enables individuals to obtain a species-specific and ecologically-relevant quantity of sleep, even in the absence of external temporal information.</jats:p>
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism.
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.