Cortico-cortical feedback engages active dendrites in visual cortex.

Sensory processing in the neocortex requires both feedforward and feedback information flow between cortical areas1. In feedback processing, higher-level representations provide contextual information to lower levels, and facilitate perceptual functions such as contour integration and figure-ground segmentation2,3. However, we have limited understanding of the circuit and cellular mechanisms that mediate feedback influence. Here we use long-range all-optical connectivity mapping in mice to show that feedback influence from the lateromedial higher visual area (LM) to the primary visual cortex (V1) is spatially organized. When the source and target of feedback represent the same area of visual space, feedback is relatively suppressive. By contrast, when the source is offset from the target in visual space, feedback is relatively facilitating. Two-photon calcium imaging data show that this facilitating feedback is nonlinearly integrated in the apical tuft dendrites of V1 pyramidal neurons: retinotopically offset (surround) visual stimuli drive local dendritic calcium signals indicative of regenerative events, and two-photon optogenetic activation of LM neurons projecting to identified feedback-recipient spines in V1 can drive similar branch-specific local calcium signals. Our results show how neocortical feedback connectivity and nonlinear dendritic integration can together form a substrate to support both predictive and cooperative contextual interactions.

The Detection of Trace Metal Contaminants in Organic Products Using Ion Current Rectifying Quartz Nanopipettes.

While ion current rectification (ICR) in aprotic solvent has been fundamentally studied, its application in sensing devices lacks exploration. The development of sensors operable in these solvents is highly beneficial to the chemical industry, where polar aprotic solvents, such as acetonitrile, are widely used. Currently, this industry relies on the use of inductively coupled plasma mass spectrometry (ICP-MS) and optical emission spectroscopy (OES) for the detection of metal contamination in organic products. Herein, we present the detection of trace amounts of Pd2+ and Co2+ using ion current rectification, in cyclam-functionalized quartz nanopipettes, with tetraethylammonium tetrafluoroborate (TEATFB) in MeCN as supporting electrolyte. This methodology is employed to determine the concentration of Pd in organic products, before and after purification by Celite filtration and column chromatography, obtaining comparable results to ICP-MS within minutes and without complex sample preparation. Finite element simulations are used to support our experimental findings, which reveal that the formation of double-junction diodes in the nanopore enables trace detection of these metals, with a significant response from baseline even at picomolar concentrations.

Associations Between a General Factor and Group Factor from the Spanish-Language Eysenck Personality Questionnaire-Revised Short Form's Neuroticism Scale and the Revised NEO Personality Inventory Domains and Facets.

Prior studies used exploratory bifactor analyses to examine the structure of the Neuroticism scale from the Short-scale Eysenck Personality Questionnaire-Revised (EPQ-RS). These studies revealed a general factor and two group factors-Anxious-Tense and Worried-Vulnerable. These factors were related to poorer mental health, but their associations with physical health differed, as did their genetic and neurobiological underpinnings. A later study found that their associations with the Big Five Inventory-2 Short Form's factors and facets differed. We reanalyzed data on 1,006 Spanish students who completed Spanish-language versions of the EPQ-RS and the Revised NEO Personality Inventory (NEO PI-R). Using confirmatory factor analysis, we showed that a model comprising the general factor and a group factor-Anxious-Tense-fit well. In later correlations, a joint factor analysis, and simultaneous multiple regressions, we showed that the EPQ-RS's general factor and the group factor had different patterns of associations with the NEO PI-R domains and facets. These associations were consistent with the definition of the EPQ-RS Neuroticism scale's general factor and that of the group factor. Further investigation into the EPQ-RS Neuroticism scale's structure can improve our understanding of neuroticism's relationship with health and other outcomes.

Synthetic CTs for MRI-only brain RT treatment: integration of immobilization systems.

PURPOSE: Auxiliary devices such as immobilization systems should be considered in synthetic CT (sCT)-based treatment planning (TP) for MRI-only brain radiotherapy (RT). A method for auxiliary device definition in the sCT is introduced, and its dosimetric impact on the sCT-based TP is addressed. METHODS: T1-VIBE DIXON was acquired in an RT setup. Ten datasets were retrospectively used for sCT generation. Silicone markers were used to determine the auxiliary devices' relative position. An auxiliary structure template (AST) was created in the TP system and placed manually on the MRI. Various RT mask characteristics were simulated in the sCT and investigated by recalculating the CT-based clinical plan on the sCT. The influence of auxiliary devices was investigated by creating static fields aimed at artificial planning target volumes (PTVs) in the CT and recalculated in the sCT. The dose covering 50% of the PTV (D50) deviation percentage between CT-based/recalculated plan (∆D50[%]) was evaluated. RESULTS: Defining an optimal RT mask yielded a ∆D50[%] of 0.2 ± 1.03% for the PTV and between -1.6 ± 3.4% and 1.1 ± 2.0% for OARs. Evaluating each static field, the largest ∆D50[%] was delivered by AST positioning inaccuracy (max: 3.5 ± 2.4%), followed by the RT table (max: 3.6 ± 1.2%) and the RT mask (max: 3.0 ± 0.8% [anterior], 1.6 ± 0.4% [rest]). No correlation between ∆D50[%] and beam depth was found for the sum of opposing beams, except for (45°â€¯+ 315°). CONCLUSION: This study evaluated the integration of auxiliary devices and their dosimetric influence on sCT-based TP. The AST can be easily integrated into the sCT-based TP. Further, we found that the dosimetric impact was within an acceptable range for an MRI-only workflow.

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming.

Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we performed a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identified components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we showed in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that, upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed-forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming.

From vibrational spectroscopy and quantum tunnelling to periodic band structures - a self-supervised, all-purpose neural network approach to general quantum problems.

In this work, a feed-forward artificial neural network (FF-ANN) design capable of locating eigensolutions to Schrödinger's equation via self-supervised learning is outlined. Based on the input potential determining the nature of the quantum problem, the presented FF-ANN strategy identifies valid solutions solely by minimizing Schrödinger's equation encoded in a suitably designed global loss function. In addition to benchmark calculations of prototype systems with known analytical solutions, the outlined methodology was also applied to experimentally accessible quantum systems, such as the vibrational states of molecular hydrogen H2 and its isotopologues HD and D2 as well as the torsional tunnel splitting in the phenol molecule. It is shown that in conjunction with the use of SIREN activation functions a high accuracy in the energy eigenvalues and wavefunctions is achieved without the requirement to adjust the implementation to the vastly different range of input potentials, thereby even considering problems under periodic boundary conditions.

Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life.

Higher scores on the personality trait of neuroticism, the tendency to experience negative emotions, are associated with worse mental and physical health. Studies examining links between neuroticism and health typically operationalize neuroticism by summing the items from a neuroticism scale. However, neuroticism is made up of multiple heterogeneous facets, each contributing to the effect of neuroticism as a whole. A recent study showed that a 12-item neuroticism scale described one broad trait of general neuroticism and two special factors, one characterizing the extent to which people worry and feel vulnerable, and the other characterizing the extent to which people are anxious and tense. This study also found that, although individuals who were higher on general neuroticism lived shorter lives, individuals whose neuroticism was characterized by worry and vulnerability lived longer lives. Here, we examine the genetic contributions to the two special factors of neuroticism-anxiety/tension and worry/vulnerability-and how they contrast with that of general neuroticism. First, we show that, whereas the polygenic load for neuroticism is associated with the genetic risk of coronary artery disease, lower intelligence, lower socioeconomic status (SES), and poorer self-rated health, the genetic variants associated with high levels of anxiety/tension, and high levels of worry/vulnerability are associated with genetic variants linked to higher SES, higher intelligence, better self-rated health, and longer life. Second, we identify genetic variants that are uniquely associated with these protective aspects of neuroticism. Finally, we show that different neurological pathways are linked to each of these neuroticism phenotypes.

AtFAHD1a: A New Player Influencing Seed Longevity and Dormancy in Arabidopsis?

Fumarylacetoacetate hydrolase (FAH) proteins form a superfamily found in Archaea, Bacteria, and Eukaryota. However, few fumarylacetoacetate hydrolase domain (FAHD)-containing proteins have been studied in Metazoa and their role in plants remains elusive. Sequence alignments revealed high homology between two Arabidopsis thaliana FAHD-containing proteins and human FAHD1 (hFAHD1) implicated in mitochondrial dysfunction-associated senescence. Transcripts of the closest hFAHD1 orthologue in Arabidopsis (AtFAHD1a) peak during seed maturation drying, which influences seed longevity and dormancy. Here, a homology study was conducted to assess if AtFAHD1a contributes to seed longevity and vigour. We found that an A. thaliana T-DNA insertional line (Atfahd1a-1) had extended seed longevity and shallower thermo-dormancy. Compared to the wild type, metabolite profiling of dry Atfahd1a-1 seeds showed that the concentrations of several amino acids, some reducing monosaccharides, and δ-tocopherol dropped, whereas the concentrations of dehydroascorbate, its catabolic intermediate threonic acid, and ascorbate accumulated. Furthermore, the redox state of the glutathione disulphide/glutathione couple shifted towards a more reducing state in dry mature Atfahd1a-1 seeds, suggesting that AtFAHD1a affects antioxidant redox poise during seed development. In summary, AtFAHD1a appears to be involved in seed redox regulation and to affect seed quality traits such as seed thermo-dormancy and longevity.

Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1).

FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC50 range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1.

Postoperative pain therapy with hydromorphone; comparison of patient-controlled analgesia with target-controlled infusion and standard patient-controlled analgesia: A randomised controlled trial.

BACKGROUND: The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative. OBJECTIVE: To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone. DESIGN: Single-blinded, randomised trial. SETTING: University Hospital, Germany from December 2013 to April 2015. PARTICIPANTS: Fifty adults undergoing cardiac surgery. INTERVENTIONS: Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study. MAIN OUTCOME MEASURES: NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects. RESULTS: NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ±â€Š6 min during TCI-PCA, compared with 19 ±â€Š4 min during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46). CONCLUSION: TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice. TRIAL REGISTRATION: EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.

Structural basis for the bi-functionality of human oxaloacetate decarboxylase FAHD1.

Whereas enzymes in the fumarylacetoacetate hydrolase (FAH) superfamily catalyze several distinct chemical reactions, the structural basis for their multi-functionality remains elusive. As a well-studied example, human FAH domain-containing protein 1 (FAHD1) is a mitochondrial protein displaying both acylpyruvate hydrolase (ApH) and oxaloacetate decarboxylase (ODx) activity. As mitochondrial ODx, FAHD1 acts antagonistically to pyruvate carboxylase, a key metabolic enzyme. Despite its importance for mitochondrial function, very little is known about the catalytic mechanisms underlying FAHD1 enzymatic activities, and the architecture of its ligated active site is currently ill defined. We present crystallographic data of human FAHD1 that provide new insights into the structure of the catalytic center at high resolution, featuring a flexible 'lid'-like helical region which folds into a helical structure upon binding of the ODx inhibitor oxalate. The oxalate-driven structural transition results in the generation of a potential catalytic triad consisting of E33, H30 and an associated water molecule. In silico docking studies indicate that the substrate is further stabilized by a complex hydrogen-bond network, involving amino acids Q109 and K123, identified herein as potential key residues for FAHD1 catalytic activity. Mutation of amino acids H30, E33 and K123 each had discernible influence on the ApH and/or ODx activity of FAHD1, suggesting distinct catalytic mechanisms for both activities. The structural analysis presented here provides a defined structural map of the active site of FAHD1 and contributes to a better understanding of the FAH superfamily of enzymes.

The fumarylacetoacetate hydrolase (FAH) superfamily of enzymes: multifunctional enzymes from microbes to mitochondria.

Prokaryotic and eukaryotic fumarylacetoacetate hydrolase (FAH) superfamily members, sharing conserved regions that form the so-called FAH-domain, catalyze a remarkable variety of reactions. These enzymes are essential in the metabolic pathways to degrade aromatic compounds in prokaryotes and eukaryotes. It appears that prokaryotic FAH superfamily members evolved mainly to allow microbes to generate energy and useful metabolites from complex carbon sources. We review recent findings, indicating that both prokaryotic and eukaryotic members of the FAH superfamily also display oxaloacetate decarboxylase (ODx) activity. The identification of human FAH domain-containing protein 1 as mitochondrial ODx regulating mitochondrial function supports the new concept that, during evolution, eukaryotic FAH superfamily members have acquired important regulatory functions beyond catabolism of complex carbon sources. Molecular studies on the evolution and function of FAH superfamily members are expected to provide new mechanistic insights in their physiological roles.

The interaction between individualism and wellbeing in predicting mortality: Survey of Health Ageing and Retirement in Europe.

The link between greater wellbeing and longevity is well documented. The aim of the current study was to test whether this association is consistent across individualistic and collectivistic cultures. The sample consisted of 13,596 participants from 11 European countries, each of which was assigned an individualism score according to Hofstede et al.'s (Cultures and organizations: software of the mind, McGraw Hill, New York, 2010) cultural dimension of individualism. We tested whether individualism moderated the cross-sectional association between wellbeing and self-rated health or the longitudinal association between wellbeing and mortality risk. Our analysis revealed a significant interaction between individualism and wellbeing such that the association between wellbeing and self-rated health or risk of mortality from cardiovascular disease was stronger in more individualistic countries. However, the interaction between wellbeing and individualism was not significant in analysis predicting all-cause mortality. Further prospective studies are needed to confirm our finding and to explore the factors responsible for this culturally dependent effect.

Rhesus macaque personality, dominance, behavior, and health.

Previous studies of nonhuman primates have found relationships between health and individual differences in personality, behavior, and social status. However, despite knowing these factors are intercorrelated, many studies focus only on a single measure, for example, rank. Consequently, it is difficult to determine the degree to which these individual differences are independently associated with health. The present study sought to untangle the associations between health and these individual differences in rhesus macaques (Macaca mulatta). We studied 85 socially housed macaques at the Oregon and California National Primate Research Centers, and used veterinary records to determine the number of injuries and illnesses for each macaque. We measured personality using 12 items from a well-established primate personality questionnaire, performed focal observations of behaviors, and calculated dominance status from directional supplant data. All twelve personality questionnaire items were reliable and were used to represent five of the six personality dimensions identified in rhesus macaques-Dominance, Confidence, Openness, Anxiety, and Friendliness (also known as Sociability). Following this, we fit generalized linear mixed effects models to understand how these factors were associated with an animal's history of injury and history of illness. In the models, age was an offset, facility was a random effect, and the five personality dimensions, behavior, sex, and dominance status were fixed effects. Number of injuries and illnesses were each best represented by a negative binomial distribution. For the injury models, including the effects did improve model fit. This model revealed that more confident and more anxious macaques experienced fewer injuries. For the illness models, including the fixed effects did not significantly improve model fit over a model without the fixed effects. Future studies may seek to assess mechanisms underlying these associations.

Personality Traits: A View From the Animal Kingdom.

Given their backgrounds in classical ethology and in comparative psychology, researchers who study animal personality in biology and psychology, respectively, differ in how they measure personality, what questions they see as important, and how they address these questions. Despite these differences, both comparative psychologists and biologists embrace personality traits. By doing so, they have solved empirical and conceptual problems in animal behavior. Studies of animal personality have provided answers to questions about the evolution of human personality and have presented conceptual and empirical anomalies for sociocognitive theories. Animal personality research does not break from trait theories of personality. Instead, it enriches trait theories by conceiving of traits as not belonging to a species, but as expressed, with some modifications, across species. Broadening trait theory in this way has the potential to further enhance its ability to answer questions related to animal and human personality.

A human model for primate personality.

In this article, I review the literature to determine how successful the latent trait theory model of personality from differential psychology has been for studying personality in non-human primates. The evidence for the success of this model is quite good, and offers insights and directions for personality research in primates and other animals. This, I conclude, stems from (i) the human trait model's simplicity, and (ii) the fact that the human differential model of personality developed in the face of harsh criticism, which led researchers to test and refine their models.

Well-Being and Arthritis Incidence: The Role of Inflammatory Mechanisms. Findings From the English Longitudinal Study of Ageing.

OBJECTIVE: Higher levels of well-being are associated with lower levels of inflammatory markers in healthy populations; however, it is unclear whether this association translates into a reduced risk of disease. In the current study, we tested whether the association between well-being and inflammation results in a lower risk of arthritis. METHODS: The sample consisted of 5266 participants 50 years or older from the English Longitudinal Study of Ageing and included six waves of data collection. We used a structural equation modeling approach to test whether inflammatory markers (C-reactive protein [CRP] or fibrinogen) mediated the association between well-being and arthritis risk for a 10-year follow-up period. RESULTS: Higher levels of well-being were associated with a decrease in arthritis risk (hazard ratio = 0.97 per unit, 95% confidence interval = 0.96 to 0.98, p < .001). Of the two inflammatory markers, only CRP was associated with arthritis risk. Mediation analysis revealed that the indirect effect of well-being (at wave 1) on arthritis risk via CRP (at wave 2) was significant (hazard ratio = 0.996, 95% confidence interval = 0.995 to 0.998, p < .001). This effect remained significant after adjustment for demographic and health behavior variables and depressive symptoms. CONCLUSIONS: CRP accounts for a small proportion of the association between well-being and a reduced risk of arthritis.

Automation of radiation treatment planning : Evaluation of head and neck cancer patient plans created by the Pinnacle3 scripting and Auto-Planning functions.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) techniques are now standard practice. IMRT or volumetric-modulated arc therapy (VMAT) allow treatment of the tumor while simultaneously sparing organs at risk. Nevertheless, treatment plan quality still depends on the physicist's individual skills, experiences, and personal preferences. It would therefore be advantageous to automate the planning process. This possibility is offered by the Pinnacle3 treatment planning system (Philips Healthcare, Hamburg, Germany) via its scripting language or Auto-Planning (AP) module. MATERIALS AND METHODS: AP module results were compared to in-house scripts and manually optimized treatment plans for standard head and neck cancer plans. Multiple treatment parameters were scored to judge plan quality (100 points = optimum plan). Patients were initially planned manually by different physicists and re-planned using scripts or AP. RESULTS AND DISCUSSION: Script-based head and neck plans achieved a mean of 67.0 points and were, on average, superior to manually created (59.1 points) and AP plans (62.3 points). Moreover, they are characterized by reproducibility and lower standard deviation of treatment parameters. Even less experienced staff are able to create at least a good starting point for further optimization in a short time. However, for particular plans, experienced planners perform even better than scripts or AP. Experienced-user input is needed when setting up scripts or AP templates for the first time. Moreover, some minor drawbacks exist, such as the increase of monitor units (+35.5% for scripted plans). CONCLUSION: On average, automatically created plans are superior to manually created treatment plans. For particular plans, experienced physicists were able to perform better than scripts or AP; thus, the benefit is greatest when time is short or staff inexperienced.