The rubber hand illusion (RHI) has been widely used to investigate the bodily self in healthy individuals. The aim of the present study was to extend the use of the RHI to examine the bodily self in ...eating disorders (EDs).
The RHI and self-report measures of ED psychopathology the Eating Disorder Inventory - 3 (EDI-3) subscales of Drive for Thinness, Bulimia, Body Dissatisfaction, Interoceptive Deficits, and Emotional Dysregulation; the 21-item Depression, Anxiety and Stress Scale (DASS-21); and the Self-Objectification Questionnaire (SOQ) were administered to 78 individuals with an ED and 61 healthy controls.
Individuals with an ED experienced the RHI significantly more strongly than healthy controls on both perceptual (i.e. proprioceptive drift) and subjective (i.e. self-report questionnaire) measures. Furthermore, both the subjective experience of the RHI and associated proprioceptive biases were correlated with ED psychopathology. Approximately 23% of the variance for embodiment of the fake hand was accounted for by ED psychopathology, with interoceptive deficits and self-objectification significant predictors of embodiment.
These results indicate that the bodily self is more plastic in people with an ED. These findings may shed light on both aetiological and maintenance factors involved in EDs, particularly visual processing of the body, interoceptive deficits, and self-objectification.
Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an ...RNA-DNA hybrid with a displaced non-template DNA strand. We developed RNA-DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA-DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.
Microbiome and Allergic Diseases Pascal, Mariona; Perez-Gordo, Marina; Caballero, Teresa ...
Frontiers in immunology,
07/2018, Letnik:
9
Journal Article
Recenzirano
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Allergic diseases, such as respiratory, cutaneous, and food allergy, have dramatically increased in prevalence over the last few decades. Recent research points to a central role of the microbiome, ...which is highly influenced by multiple environmental and dietary factors. It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. It has been described at some extent changes in environment and nutrition produce dysbiosis in the gut but also in the skin, and lung microbiome, inducing qualitative and quantitative changes in composition and metabolic activity. Here, we review the potential role of the skin, respiratory, and gastrointestinal tract (GIT) microbiomes in allergic diseases. In the GIT, the microbiome has been proven to be important in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells. In the lung, the microbiome may play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis and psoriasis. Thus, the microbiome can be considered a therapeutical target for treating inflammatory diseases, such as allergy. Despite some limitations, interventions with probiotics, prebiotics, and/or synbiotics seem promising for the development of a preventive therapy by restoring altered microbiome functionality, or as an adjuvant in specific immunotherapy.
Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have ...potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity ...contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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•Methotrexate (MTX) causes a microglia-dependent reduction in Bdnf expression•Activity-regulated myelination requires Bdnf-TrkB signaling and fails after MTX•Conditional, inducible TrkB loss in OPCs impairs cognitive behavioral performance•TrkB agonism rescues cognitive performance after MTX only if OPCs express TrkB
Methotrexate chemotherapy results in a microglial-dependent reduction of Bdnf expression and loss of activity-regulated myelination, which requires Bdnf to TrkB signaling. OPC-specific loss of TrkB results in cognitive impairment. Stimulating OPC TrkB signaling restores myelination and rescues cognition after MTX.
This study focuses on the application of Electro-Fenton technique for the remediation of wastewater contaminated with synthetic dyes. A bubble reactor was designed to develop this treatment operating ...in continuous mode. In order to increase the efficiency of Electro-Fenton treatment, the effect of key parameters (iron dosage and pH) that play an important role in this process was investigated for Lissamine Green B decoloration in batch mode. Operating at the optimal conditions, determined for Lissamine Green B, several dyes (Methyl Orange, Reactive Black 5 and Fuchsin Acid) were decolorized by using Electro-Fenton process. A first-order kinetic model was used to simulate the experimental results operating at different pH, and iron concentration of 150
mg
L
−1. This kinetic model for Lissamine Green, Methyl Orange and Reactive Black 5 was successfully used in the progression of the process from batch to continuous mode. About 80% color removal was achieved for Lissamine Green and Methyl Orange with a residence time of 21
h. The decoloration for Reactive Black 5 was lower, reached a value around 60% at the same residence time. Nevertheless in all assays a good agreement between experimental results and proposed model in a continuous bubble reactor was detected. In addition a continuous treatment with a mixture of dyes was carried out. Operating with a residence time of 21
h the obtained decoloration was close to 43% which is squared with a TOC reduction around 46%. Therefore, the results provide fundamental knowledge for the treatment of a real wastewater stream.
Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic ...function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.
Enzymes catalyze a vast range of reactions. Their catalytic performances, mechanisms, global folds, and active-site architectures are also highly diverse, suggesting that enzymes are shaped by an ...entire range of physiological demands and evolutionary constraints, as well as by chemical and physicochemical constraints. We have attempted to identify signatures of these shaping demands and constraints. To this end, we describe a bird’s-eye view of the enzyme space from two angles: evolution and chemistry. We examine various chemical reaction parameters that may have shaped the catalytic performances and active-site architectures of enzymes. We test and weigh these considerations against physiological and evolutionary factors. Although the catalytic properties of the “average” enzyme correlate with cellular metabolic demands and enzyme expression levels, at the level of individual enzymes, a multitude of physiological demands and constraints, combined with the coincidental nature of evolutionary processes, result in a complex picture. Indeed, neither reaction type (a chemical constraint) nor evolutionary origin alone can explain enzyme rates. Nevertheless, chemical constraints are apparent in the convergence of active-site architectures in independently evolved enzymes, although significant variations within an architecture are common.
Nat/Ivy is a diverse and ubiquitous CoA‐binding evolutionary lineage that catalyzes acyltransferase reactions, primarily converting thioesters into amides. At the heart of the Nat/Ivy fold is a ...phosphate‐binding loop that bears a striking resemblance to that of P‐loop NTPases—both are extended, glycine‐rich loops situated between a β‐strand and an α‐helix. Nat/Ivy, therefore, represents an intriguing intersection between thioester chemistry, a putative primitive energy currency, and an ancient mode of phospho‐ligand binding. Current evidence suggests that Nat/Ivy emerged independently of other cofactor‐utilizing enzymes, and that the observed structural similarity—particularly of the cofactor binding site—is the product of shared constraints instead of shared ancestry. The reliance of Nat/Ivy on a β‐α‐β motif for CoA‐binding highlights the extent to which this simple structural motif may have been a fundamental evolutionary “nucleus” around which modern cofactor‐binding domains condensed, as has been suggested for HUP domains, Rossmanns, and P‐loop NTPases. Finally, by dissecting the patterns of conserved interactions between Nat/Ivy families and CoA, the coevolution of the enzyme and the cofactor was analyzed. As with the Rossmann, it appears that the pyrophosphate moiety at the center of the cofactor predates the enzyme, suggesting that Nat/Ivy emerged sometime after the metabolite dephospho‐CoA.
Smoking Rain Clouds over the Amazon Andreae, M. O.; Rosenfeld, D.; Artaxo, P. ...
Science (American Association for the Advancement of Science),
02/2004, Letnik:
303, Številka:
5662
Journal Article
Recenzirano
Odprti dostop
Heavy smoke from forest fires in the Amazon was observed to reduce cloud droplet size and so delay the onset of precipitation from 1.5 kilometers above cloud base in pristine clouds to more than 5 ...kilometers in polluted clouds and more than 7 kilometers in pyro-clouds. Suppression of low-level rainout and aerosol washout allows transport of water and smoke to upper levels, where the clouds appear "smoking" as they detrain much of the pollution. Elevating the onset of precipitation allows invigoration of the updrafts, causing intense thunderstorms, large hail, and greater likelihood for overshooting cloud tops into the stratosphere. There, detrained pollutants and water vapor would have profound radiative impacts on the climate system. The invigorated storms release the latent heat higher in the atmosphere. This should substantially affect the regional and global circulation systems. Together, these processes affect the water cycle, the pollution burden of the atmosphere, and the dynamics of atmospheric circulation.
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