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Previous studies suggest that subjective distress in children with functional neurological disorder (FND) is associated with stress-system dysregulation and modulates aberrant changes in neural networks. The current study documents illness-promoting psychological processes in 76 children with FND (60 girls and 16 boys, aged 10.00-17.08 years) admitted to the Mind-Body Program. The children completed a comprehensive family assessment and self-report measures, and they worked with the clinical team to identify psychological processes during their inpatient admission. A total of 47 healthy controls (35 girls and 12 boys, aged 8.58-17.92 years) also completed self-report measures, but were not assessed for illness-promoting psychological processes. Children with FND (vs. controls) reported higher levels of subjective distress (total DASS score, t(104.24) = 12.18; p ˂ 0.001) and more adverse childhood experiences across their lifespans (total ELSQ score, t(88.57) = 9.38; p ˂ 0.001). Illness-promoting psychological processes were identified in all children with FND. Most common were the following: chronic worries about schoolwork, friendships, or parental wellbeing (n = 64; 84.2%); attention to symptoms (n = 61; 80.3%); feeling sad (n = 58; 76.3%); experiencing a low sense of control (helplessness) in relation to symptoms (n = 44; 57.9%); pushing difficult thoughts out of mind (n = 44; 57.9%); self-critical rumination (n = 42; 55.3%); negative/catastrophic-symptom expectations (n = 40; 52.6%); avoidance of activities (n = 38; 50%); intrusive thoughts/feelings/memories associated with adverse events (n = 38, 50%); and pushing difficult feelings out of mind (n = 37; 48.7%). In children with FND-disabled enough to be admitted for inpatient treatment-illness-promoting psychological processes are part of the clinical presentation. They contribute to the child's ongoing sense of subjective distress, and if not addressed can maintain the illness process. A range of clinical interventions used to address illness-promoting psychological processes are discussed, along with illustrative vignettes.

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Density-dependent prey depletion around breeding colonies has long been considered an important factor controlling the population dynamics of colonial animals.1-4 Ashmole proposed that as seabird colony size increases, intraspecific competition leads to declines in reproductive success, as breeding adults must spend more time and energy to find prey farther from the colony.1 Seabird colony size often varies over several orders of magnitude within the same species and can include millions of individuals per colony.5,6 As such, colony size likely plays an important role in determining the individual behavior of its members and how the colony interacts with the surrounding environment.6 Using tracking data from murres (Uria spp.), the world's most densely breeding seabirds, we show that the distribution of foraging-trip distances scales to colony size0.33 during the chick-rearing stage, consistent with Ashmole's halo theory.1,2 This pattern occurred across colonies varying in size over three orders of magnitude and distributed throughout the North Atlantic region. The strong relationship between colony size and foraging range means that the foraging areas of some colonial species can be estimated from colony sizes, which is more practical to measure over a large geographic scale. Two-thirds of the North Atlantic murre population breed at the 16 largest colonies; by extrapolating the predicted foraging ranges to sites without tracking data, we show that only two of these large colonies have significant coverage as marine protected areas. Our results are an important example of how theoretical models, in this case, Ashmole's version of central-place-foraging theory, can be applied to inform conservation and management in colonial breeding species.

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Communities usually possess a multitude of interconnected trophic interactions within food webs. Their regulation generally depends on a balance between bottom-up and top-down effects. However, if sensitivity to temperature varies among species, rising temperatures may change trophic interactions via direct and indirect effects. We examined the critical thermal maximum (CTmax) of 19 species from temperate wetlands (insect predators, amphibian larvae, zooplankton and amphipods) and determined if they vary in their sensitivity to warming temperatures. CTmax differed between the groups, with predatory insects having higher CTmax than amphibians (both herbivorous larval anurans and predatory larval salamanders), amphipods and zooplankton. In a scenario of global warming, these differences in thermal tolerance may affect top-down and bottom-up processes, particularly considering that insect predators are more likely to maintain or improve their performance at higher temperatures, which could lead to increased predation rates on the herbivores in the food web. Further studies are needed to understand how the energy flows through communities, how species' energy budgets may change and whether other physiological and behavioral responses (such as phenotypic plasticity and thermoregulation) can buffer or increase these changes in the top-down regulation of wetland food webs.

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The study of the mechanisms controlling organ size during development and regeneration is critical to understanding how complex life arises from cooperating single cells. Long bones are powerful models in this regard, as their size depends on a scaffold made from another tissue (cartilage, composed of chondrocytes), and both tissues interact during the growth period. Investigating long bone growth offers a valuable window into the processes that integrate internal and external cues to yield finely controlled size of organs. Within the cellular and molecular pathways that control bone growth, the regulation of stem-cell renewal, along with amplification and differentiation of their progeny, are key to understanding normal and perturbed long-bone development. The phenomenon of "catch-up" growth-where cellular hyperproliferation occurs following injury to restore a normal growth trajectory-reveals key aspects of this regulation, such as the fact that bone growth is target-seeking. The control mechanisms that lead to this behavior are either bottom-up or top-down, and the interaction between these modes is likely critical to achieve a highly nuanced, yet flexible, degree of control. The role of cartilage-intrinsic mechanisms has been well studied, establishing a very solid groundwork for this field. However, addressing the unanswered questions of bone growth arguably requires new hypotheses and approaches. Future research could for example address to what extent extrinsic signals and cells, as well as communication with other tissues, modulate intra-limb and inter-organ growth coordination. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Vertebrate Organogenesis > Musculoskeletal and Vascular.

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This paper focuses on the ethical and regulatory issues raised by gene editing. In the introduction of this paper, authors provide the background where the ethical and regulatory issues by gene editing have been raised including the scientific dimension of gene-editing techniques. In the second part of the paper, the authors focus on ethical issues in human gene editing with the start of Huang Junjiu case and He Jiankui case. Here, the authors discuss the criteria for evaluating action, general ethical issues in gene editing, and try to answer two crucial questions: is it ethically justifiable to use human embryo in ex vivo genome editing study and is it ethically justifiable to perform heritable human genome editing? In answering the second question, the authors discuss the arguments against and for heritable human genome editing, methodological problem, and the building of an ethical framework for heritable human genome editing. In the third part of the paper, the authors focus on regulatory issues in gene editing including proactionary approach versus ethically thinking ahead approach, self-regulation versus top-down regulation, transparency versus confidentiality, and education versus punishment.

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OBJECTIVES: The study aims were 1) to investigate the direction of mutual inhibitory pathways on itch intensity by utilizing conditioned pain modulation paradigms for pain and itch attenuation and 2) to explore whether itch severity is affected by the individual pain sensitivity profile, as well as pain scores reported during the tests and the past week. DESIGN: Cross-sectional. SETTING: Testing was conducted at the Department of Dermatology, Rambam Health Care Campus. SUBJECTS: Forty patients suffering from chronic skin disorders associated with itch and treated in the Dermatology Clinic at Rambam Health Care Campus participated in the study. METHODS: Efficacy of descending inhibition was evaluated by two conditioned pain modulation (CPM) paradigms: by pruriception (CPMItch) induced by cold and heat as counterstimuli to inhibit itch intensity and by nociception (CPMPain). Severity and interference of clinical pain were assessed using the Brief Pain Inventory (BPI). RESULTS: Robust CPMItch responses were obtained following the various noxious stimulations. No associations were observed between CPMPain and CPMItch, itch severity, skin disease severity, and clinical pain symptoms. According to the linear regression model, itch severity was independently associated with less efficient CPMItch (B = -0.750, P < 0.001) and more efficient CPMPain (B = 0.031, P = 0.016), which affects itch in opposing manners. CONCLUSIONS: Findings indicate that the intrinsic capacity to inhibit pain and itch by exposure to exogenous noxious stimuli autonomously affects itch intensity in an opposing manner. These findings may shed new light on the mutual mechanistic similarity and dissimilarity between pain and itch and their hierarchy.

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The interaction between top-down and bottom-up forces determines the recovery trajectory of macroalgal forests exposed to multiple stressors. In an oligotrophic system, we experimentally investigated how nutrient inputs affected the recovery of Cystoseira brachycarpa following physical disturbance of varying intensities, both inside forested areas and at the boundary with sea urchin barrens. Unexpectedly, Cystoseira forests were highly resilient to disturbance, as they were able to recover from any partial damage. In general, the addition of nutrients sped up the recovery of Cystoseira. Thus, only the total canopy removal, in combination with either low nutrient availability or intense grazing pressure, promoted the expansion of mat-forming algae or urchin barrens, respectively. Our study suggests that the effects of enhanced nutrient levels may vary according to the trophic characteristics of the waterbody, and hence, are likely to vary among regions of the Mediterranean basin.

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The central executive system (CES) may be the most fundamental yet least understood component of working memory. There is an ongoing debate about which brain regions underlie the top-down regulation of CES during working memory tasks. The neural substrates and regulatory mechanisms of CES remain controversial partly because few previous studies have been focused on comprehensive activation and deactivation joint analysis on all systems involved in all working memory stages, which have shown increasing importance in depicting the neural configuration of working memory. To address these questions, we conducted a functional magnetic resonance imaging study using a comprehensive activation-deactivation-behavior joint analysis to examine the dynamics of a set of cortical systems in healthy subjects performing a modified Sternberg working memory task which was designed to push the subjects to their limit in working memory and to introduce strong demands for regulation by CES. We assessed brain activity during various working memory stages using general linear model and single trial-stage estimation, and examined the relationship between the single trial-stage activity and behavioral performance. We identified constant activation in the dorsal anterior cingulate cortexand anterior insula in all working memory stages and its relationship with performance, which indicate the CES's neural basis. We also identified dynamic configuration of multiple downstream systems in different working memory stages, which indicates the regulation mechanism of CES.

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The precise regulation of fluid and energy homeostasis is essential for survival. It is well appreciated that ingestive behaviors are tightly regulated by both peripheral sensory inputs and central appetite signals. With recent neurogenetic technologies, considerable progress has been made in our understanding of basic taste qualities, the molecular and/or cellular basis of taste sensing, and the central circuits for thirst and hunger. In this review, we first highlight the functional similarities and differences between mammalian and invertebrate taste processing. We then discuss how central thirst and hunger signals interact with peripheral sensory signals to regulate ingestive behaviors. We finally indicate some of the directions for future research.

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We hypothesize that the hexokinases of trypanosomes of the subgenus Trypanozoon match the blood glucose levels of hosts. We studied the kinetic properties of purified hexokinase in T. equiperdum (specific activity=302U/mg), and compare with other members of Trypanozoon. With ATP (Km=104.7µM) as phosphate donor, hexokinase catalyzes the phosphorylation of glucose (Km=24.9µM) and mannose (Km=8.8µM). With respect to glucose, mannose and inorganic pyrophosphate respectively are a competitive, and a mixed inhibitor of hexokinase. With respect to ATP, both are mixed inhibitors of this enzyme. In T. equiperdum, hexokinase shows a high affinity for glucose. Pleomorphism-transformation of trypanosomes from a multiplicative to a non-multiplicative form-results in a self-limited growth stabilizing glucose consumption. It delays the death of the host, thus prolonging its exposure to tsetse flies. When glucose levels descend, top-down regulation allows trypanosomes to survive through the expression of alternative metabolic pathways. It accelerates the death of the host, but helps trypanosome density to increase enough to ensure transmission without tsetse flies. Pleomorphism, and a hexokinase with a high affinity for glucose, are two main adaptive traits of T. b. brucei. The latter trait, and a strong top-down regulation, are two main adaptive traits of T. equiperdum. For trypanosomes living in glucose-rich blood, a hexokinase with a high affinity for glucose would unnecessarily harm hosts. This may explain why the human parasites, T. b. gambiense and T. b. rhodesiense, possess hexokinases with a low affinity for glucose.

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Food web studies provide a useful tool to assess the organization and complexity of natural communities. Nevertheless, the seasonal dynamics of food web properties, their environmental correlates, and potential association with community diversity and stability remain poorly studied. Here, we condensed an incomplete 6-year community dataset of a subtropical coastal lake to examine how monthly variation in diversity impacts food web structure over an idealized time series for an averaged year. Phytoplankton, zooplankton, macroinvertebrates, and fish were mostly resolved to species level (n = 120 trophospecies). Our results showed that the seasonal organization of the food web could be aggregated into two clusters of months grouped here as 'summer' and 'winter'. During 'winter', the food web decreases in size and complexity, with the number of trophospecies dropping from 106 to 82 (a 22.6% decrease in the number of nodes) and the trophic interactions from 1,049 to 637 between month extremes (a 39.3% drop in the number of links). The observed simplification in food web structure during 'winter' suggests that community stability is more vulnerable to the impact of any change during this period.

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Most demonstrated trophic cascades originate with predators, but infectious agents can also cause top-down indirect effects in ecosystems. Here we synthesize the literature on trophic cascades initiated by infectious agents including parasitoids, pathogens, parasitic castrators, macroparasites, and trophically transmitted parasites. Like predators, infectious agents can cause density-mediated and trait-mediated indirect effects through their direct consumptive and nonconsumptive effects respectively. Unlike most predators, however, infectious agents are not fully and immediately lethal to their victims, so their consumptive effects can also trigger trait-mediated indirect effects. We find that the frequency of trophic cascades reported for different consumer types scales with consumer lethality. Furthermore, we emphasize the value of uniting predator-prey and parasite-host theory under a general consumer-resource framework.

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Herbivore effects on diversity and succession were often studied in plants, but not in cryptogams. Besides direct herbivore effects on cryptogams, we expected indirect effects by changes in competitive interactions among cryptogams. Therefore, we conducted a long-term gastropod exclusion experiment testing for grazing effects on epiphytic cryptogam communities. We estimated the grazing damage, cover and diversity of cryptogams before gastropods were excluded and three and six years thereafter. Gastropod herbivory pronouncedly affected cryptogams, except for bryophytes, strongly depending on host tree species and duration of gastropod exclusion. On control trees, gastropod grazing regulated the growth of algae and non-lichenized fungi and thereby maintained a high lichen diversity and cover. On European beech, the release from gastropod grazing temporarily increased lichen vitality, cover, and species richness, but later caused rapid succession where algae and fungi overgrew lichens and thereby reduced their cover and diversity compared with the control. On Norway spruce, without gastropods lichen richness decreased and lichen cover increased compared with the control. Our findings highlight the importance of long-term exclusion experiments to disentangle short-term, direct effects from longer-term, indirect effects via changes in competitive relationships between taxa. We further demonstrated that gastropod feeding maintains the diversity of cryptogam communities.

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Deficient cognitive top-down executive control has long been hypothesized to underlie inattention and impulsivity in attention-deficit/hyperactivity disorder (ADHD). However, top-down cognitive dysfunction explains a modest proportion of the ADHD phenotype whereas the salience of emotional dysregulation is being noted increasingly. Together, these two types of dysfunction have the potential to account for more of the phenotypic variance in patients diagnosed with ADHD. We develop this idea and suggest that top-down dysregulation constitutes a gradient extending from mostly non-emotional top-down control processes (i.e., "cool" executive functions) to mainly emotional regulatory processes (including "hot" executive functions). While ADHD has been classically linked primarily to the former, conditions involving emotional instability such as borderline and antisocial personality disorder are closer to the other. In this model, emotional subtypes of ADHD are located at intermediate levels of this gradient. Neuroanatomically, gradations in "cool" processing appear to be related to prefrontal dysfunction involving dorsolateral prefrontal cortex (dlPFC) and caudal anterior cingulate cortex (cACC), while "hot" processing entails orbitofrontal cortex and rostral anterior cingulate cortex (rACC). A similar distinction between systems related to non-emotional and emotional processing appears to hold for the basal ganglia (BG) and the neuromodulatory effects of the dopamine system. Overall we suggest that these two systems could be divided according to whether they process non-emotional information related to the exteroceptive environment (associated with "cool" regulatory circuits) or emotional information related to the interoceptive environment (associated with "hot" regulatory circuits). We propose that this framework can integrate ADHD, emotional traits in ADHD, borderline and antisocial personality disorder into a related cluster of mental conditions.

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Novel assemblages of native and introduced species characterize a growing proportion of ecosystems worldwide. Some introduced species have contributed to extinctions, even extinction waves, spurring widespread efforts to eradicate or control them. We propose that trophic cascade theory offers insights into why introduced species sometimes become harmful, but in other cases stably coexist with natives and offer net benefits. Large predators commonly limit populations of potentially irruptive prey and mesopredators, both native and introduced. This top-down force influences a wide range of ecosystem processes that often enhance biodiversity. We argue that many species, regardless of their origin or priors, are allies for the retention and restoration of biodiversity in top-down regulated ecosystems.

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Lytic bacteriophages and protozoan predators are the major causes of bacterial mortality in natural microbial communities, which also makes them potential candidates for biological control of bacterial pathogens. However, little is known about the relative impact of bacteriophages and protozoa on the dynamics of bacterial biomass in aqueous and biofilm phases. Here, we studied the temporal and spatial dynamics of bacterial biomass in a microcosm experiment where opportunistic pathogenic bacteria Serratia marcescens was exposed to particle-feeding ciliates, surface-feeding amoebas, and lytic bacteriophages for 8 weeks, ca. 1300 generations. We found that ciliates were the most efficient enemy type in reducing bacterial biomass in the open water, but least efficient in reducing the biofilm biomass. Biofilm was rather resistant against bacterivores, but amoebae had a significant long-term negative effect on bacterial biomass both in the open-water phase and biofilm. Bacteriophages had only a minor long-term effect on bacterial biomass in open-water and biofilm phases. However, separate short-term experiments with the ancestral bacteriophages and bacteria revealed that bacteriophages crash the bacterial biomass dramatically in the open-water phase within the first 24 h. Thereafter, the bacteria evolve phage-resistance that largely prevents top-down effects. The combination of all three enemy types was most effective in reducing biofilm biomass, whereas in the open-water phase the ciliates dominated the trophic effects. Our results highlight the importance of enemy feeding mode on determining the spatial distribution and abundance of bacterial biomass. Moreover, the enemy type can be crucially important predictor of whether the rapid defense evolution can significantly affect top-down regulation of bacteria.

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1. Studies demonstrating trophic cascades through the loss of top-down regulatory processes in productive and biologically diverse terrestrial ecosystems are limited. 2. Elk Island National Park, Alberta and surrounding protected areas have a wide range of ungulate density due to the functional loss of top predators, management for high ungulate numbers and variable hunting pressure. This provides an ideal setting for studying the effects of hyper-abundant ungulates on vegetation and shrub-dependent bird and butterfly species. 3. To examine the cascading effects of high ungulate density, we quantified vegetation characteristics and abundances of yellow warbler Dendroica petechia and Canadian tiger swallowtail Papilio canadensis under different ungulate density in and around Elk Island National Park. 4. Using Structural Equation Models we found that ungulate density was inversely related to shrub cover, whereas shrub cover was positively related to yellow warbler abundance. In addition, chokecherry Prunus virginiana abundance was inversely related to browse impact but positively related to P. canadensis abundance. 5. These results demonstrate a cascade resulting from hyper-abundant ungulates on yellow warblers and Canadian tiger swallowtails through reductions in shrub cover and larval host plant density. The combined effect of the functional loss of top predators and management strategies that maintain high ungulate numbers can decouple top-down regulation of productive temperate ecosystems.

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The medial prefrontal cortex (MFC) is critical for our ability to learn from previous mistakes. Here we provide evidence that neurophysiological oscillatory long-range synchrony is a mechanism of post-error adaptation that occurs even without conscious awareness of the error. During a visually signaled Go/No-Go task in which half of the No-Go cues were masked and thus not consciously perceived, response errors enhanced tonic (i.e., over 1-2 s) oscillatory synchrony between MFC and occipital cortex (OCC) leading up to and during the subsequent trial. Spectral Granger causality analyses demonstrated that MFC --> OCC directional synchrony was enhanced during trials following both conscious and unconscious errors, whereas transient stimulus-induced occipital --> MFC directional synchrony was independent of errors in the previous trial. Further, the strength of pre-trial MFC-occipital synchrony predicted individual differences in task performance. Together, these findings suggest that synchronous neurophysiological oscillations are a plausible mechanism of MFC-driven cognitive control that is independent of conscious awareness.