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EphrinB2 and GRIP1 stabilize mushroom spines during denervation-induced homeostatic plasticity
(2021)
Highlights
• Denervation induces mushroom spine loss and AMPAR redistribution to the surface
• GRIP1 and ephrinB2 mediate homeostatic mechanisms after lesion
• Stimulation with the ephrinB2 receptor EphB4 promotes a surface shift of AMPARs
• AMPARs surface shift restores impaired spine recovery after lesion in GRIP1 mutants
Summary
Despite decades of work, much remains elusive about molecular events at the interplay between physiological and structural changes underlying neuronal plasticity. Here, we combined repetitive live imaging and expansion microscopy in organotypic brain slice cultures to quantitatively characterize the dynamic changes of the intracellular versus surface pools of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) across the different dendritic spine types and the shaft during hippocampal homeostatic plasticity. Mechanistically, we identify ephrinB2 and glutamate receptor interacting protein (GRIP) 1 as mediating AMPAR relocation to the mushroom spine surface following lesion-induced denervation. Moreover, stimulation with the ephrinB2 specific receptor EphB4 not only prevents the lesion-induced disappearance of mushroom spines but is also sufficient to shift AMPARs to the surface and rescue spine recovery in a GRIP1 dominant-negative background. Thus, our results unravel a crucial role for ephrinB2 during homeostatic plasticity and identify a potential pharmacological target to improve dendritic spine plasticity upon injury.
Background/Objective: Evidence-based clinical pathways can be a useful tool for guideline implementation. However, there seem to be barriers to the use of clinical pathways. The aim of the present questionnaire survey was to assess the perceived usability of the clinical pathway “Overweight/obesity in children and adolescents at primary care level” and to identify factors promoting and hindering the use of the clinical pathway.
Methods: In January 2020, an online questionnaire survey was sent out to 3,916 general practitioners and 470 pediatricians in Austria. The data collected were analysed descriptively.
Results: A total of 148 people took part in the questionnaire survey (response rate 3.7 %). The majority of respondents indicated that they, in general, perceive evidence-based clinical pathways as helpful (90 %) and also make use of them (57 %). Few respondents (9 %) felt well-informed about new clinical pathways developed in Austria. Most of the respondents considered the clinical pathway “Overweight/obesity in children and adolescents at primary care level” as a useful support (60 %), as a reference work (72 %) or as a facilitator for justifying their approach to their patients (68 %). However, a large proportion of the respondents stated that the clinical pathway is not easily applicable in everyday practice. The three most frequently cited barriers to using the clinical pathway were lack of time resources, lack of structures and lack of financial incentives. Other display and access options (e. g., individualisation, integration into practice software) were most frequently cited as factors that might promote the use of the pathway.
Conclusion: Although the majority of the respondents had positive expectations regarding the use of the clinical pathway “Overweight/obesity in children and adolescents at primary care level”, many of them still perceived its usability in everyday clinical practice as difficult. The necessary next steps to improve the use of evidence-based clinical pathways seem to be: an economic and practicable design, easy accessibility of clinical pathways and the creation of framework conditions that facilitate their use in everyday practice.
In the past two decades, an increasing body of studies has been published on the intersex phenomenon in separate-sexed crustaceans from marine and freshwater ecosystems. Various causes are being considered that could have an influence on the occurrence of intersex. Besides genetic factors, environmental conditions such as photoperiodicity, temperature, salinity and parasitism, but also environmental pollution with endocrine disrupting chemicals (EDCs) are discussed. As part of a long-term monitoring (2012 – 2020) in north-west Brittany, we recorded the occurrence of intersex in the marine amphipod Echinogammarus marinus. We quantified the intersex incidence at marine and estuarine sites and analyzed the incidence in relation to the endocrine potential of the sediments. Intersex occurred with mean frequencies between 0.87% and 12%. It was striking that the incidence of intersex increased with increasing distance from the sea. Since the highest incidence was observed at the range boundary of this stenohaline species, we assume that intersex is triggered by endocrine potential and increasing stress due to increasing freshwater content − and thus an interplay of different environmental factors.
Recombinant DNA technology is an essential area of life engineering. The main aim of research in this field is to experimentally explore the possibilities of repairing damaged human DNA, healing or enhancing future human bodies. Based on ethnographic research in a Czech biochemical laboratory, the article explores biotechnological corporealities and their specific ontology through dealings with bio-objects, the bodywork of scientists. Using the complementary concepts of utopia and heterotopia, the text addresses the situation of bodies and bio-objects in a laboratory. Embodied utopias are analyzed as material semiotic phenomena that are embodied by scientists in their visions and emotions and that are related to potential bodies and to future, not-yet-actualized embodiments. As a counterpart to this, the text explores embodied heterotopias, which are always the other spaces, like biotechnological bio-objects that are simulated in computers or stored in special solutions.
We consider a linear ill-posed equation in the Hilbert space setting. Multiple independent unbiased measurements of the right-hand side are available. A natural approach is to take the average of the measurements as an approximation of the right-hand side and to estimate the data error as the inverse of the square root of the number of measurements. We calculate the optimal convergence rate (as the number of measurements tends to infinity) under classical source conditions and introduce a modified discrepancy principle, which asymptotically attains this rate.
A single wavelength heterodyne interferometer has been set up to investigate the free electron density integrated axially along the line of sight (line density) in a theta-pinch plasma to determine its applicability as a plasma target for ion beam stripping. The maximal line density reached in this experiment was (3.57 ± 0.28) × 1018 cm−2 at 80 Pa and 20 kV. The findings demonstrate the pulsed character of the line density and its increase by raising the load voltage and the working gas pressure. Additionally, the results were compared with spectroscopic free electron density estimations, which were carried out by Hβ -line broadening and peak separation. The time behavior of the line density indicates that its peak value is delayed by about 10 μs compared to the spectroscopic results. This effect is due to the formation of an extended, magnetically compressed plasma column in the vicinity of the current maximum, although the highest volumetric free electron density is reached near the current zero crossing. Since the line density is an essential parameter in describing the stripping capabilities of the plasma target, the interferometric diagnostic is superior to a spectroscopic diagnostic, because it directly provides integrated values along the line of sight. Furthermore, the measurements of the line density in this experiment partially show nonphysical negative values, which is due to gaseous effects and residual shot vibrations.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium.
Dealing with potential stress in species that have high husbandry requirements, such as elephants, is a challenge for zoos. The objective of the present study was to determine whether positive reinforcement training (PRT) and exposure to a novel object (NOV) for enrichment induced a salivary cortisol response indicative of activation of the hypothalamic–pituitary–adrenal (HPA) axis and which factors determine individual variation in this regard in captive African elephants. We repeatedly sampled the saliva of ten animals (three zoos) for the analysis of cortisol (SACort) before and up to 60 min (in 10–15 min intervals) after the onset of PRT (three repeats) or NOV (nine repeats), which lasted 10 min. There was considerable individual variation in SACort in response to PRT or NOV. Using mixed models, we were able to control these and to reveal that PRT was associated with high SACort before and relatively low SACort after PRT, while NOV induced a moderate SACort increase. The individual differences in SACort were related to age and sex (NOV), while the effects of zoo, handling method (free vs. protected contact) and reproductive and social status were variable. We conclude that positive affective states, such as anticipation or arousal, should be taken into account when interpreting the differences in the SACort responses between PRT and NOV. In addition, understanding the individuality of stress will support management decisions aimed at promoting captive elephant welfare.
In recent decades, mass spectrometry has moved more than ever before into the front line of protein-centered research. After being established at the qualitative level, the more challenging question of quantification of proteins and peptides using mass spectrometry has become a focus for further development. In this chapter, we discuss and review actual strategies and problems of the methods for the quantitative analysis of peptides, proteins, and finally proteomes by mass spectrometry. The common themes, the differences, and the potential pitfalls of the main approaches are presented in order to provide a survey of the emerging field of quantitative, mass spectrometry-based proteomics.
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
Efficient processing of visual environment necessitates the integration of incoming sensory evidence with concurrent contextual inputs and mnemonic content from our past experiences. To delineate how this integration takes place in the brain, we studied modulations of feedback neural patterns in non-stimulated areas of the early visual cortex in humans (i.e., V1 and V2). Using functional magnetic resonance imaging and multivariate pattern analysis, we show that both, concurrent contextual and time-distant mnemonic information, coexist in V1/V2 as feedback signals. The extent to which mnemonic information is reinstated in V1/V2 depends on whether the information is retrieved episodically or semantically. These results demonstrate that our stream of visual experience contains not just information from the visual surrounding, but also memory-based predictions internally generated in the brain.
We use holography to study the dynamics of a strongly-coupled gauge theory in four-dimensional de Sitter space with Hubble rate H. The gauge theory is non-conformal with a characteristic mass scale M. We solve Einstein’s equations numerically and determine the time evolution of homogeneous gauge theory states. If their initial energy density is high compared with H4 then the early-time evolution is well described by viscous hydrodynamics with a non-zero bulk viscosity. At late times the dynamics is always far from equilibrium. The asymptotic late-time state preserves the full de Sitter symmetry group and its dual geometry is a domain-wall in AdS5. The approach to this state is characterised by an emergent relation of the form P = w ℰ that is different from the equilibrium equation of state in flat space. The constant w does not depend on the initial conditions but only on H/M and is negative if the ratio H/M is close to unity. The event and the apparent horizons of the late-time solution do not coincide with one another, reflecting its non-equilibrium nature. In between them lies an “entanglement horizon” that cannot be penetrated by extremal surfaces anchored at the boundary, which we use to compute the entanglement entropy of boundary regions. If the entangling region equals the observable universe then the extremal surface coincides with a bulk cosmological horizon that just touches the event horizon, while for larger regions the extremal surface probes behind the event horizon.
As cryo-EM approaches the physical resolution limits imposed by electron optics and radiation damage, it becomes increasingly urgent to address the issues that impede high-resolution structure determination of biological specimens. One of the persistent problems has been beam-induced movement, which occurs when the specimen is irradiated with high-energy electrons. Beam-induced movement results in image blurring and loss of high-resolution information. It is particularly severe for biological samples in unsupported thin films of vitreous water. By controlled devitrification of conventionally plunge-frozen samples, the suspended film of vitrified water was converted into cubic ice, a polycrystalline, mechanically stable solid. It is shown that compared with vitrified samples, devitrification reduces beam-induced movement in the first 5 e Å−2 of an exposure by a factor of ∼4, substantially enhancing the contribution of the initial, minimally damaged frames to a structure. A 3D apoferritin map reconstructed from the first frames of 20 000 particle images of devitrified samples resolved undamaged side chains. Devitrification of frozen-hydrated specimens helps to overcome beam-induced specimen motion in single-particle cryo-EM, as a further step towards realizing the full potential of cryo-EM for high-resolution structure determination.
We use the quantum null energy condition in strongly coupled two-dimensional field theories (QNEC2) as diagnostic tool to study a variety of phase structures, including crossover, second and first order phase transitions. We find a universal QNEC2 constraint for first order phase transitions with kinked entanglement entropy and discuss in general the relation between the QNEC2-inequality and monotonicity of the Casini-Huerta c-function. We then focus on a specific example, the holographic dual of which is modelled by three-dimensional Einstein gravity plus a massive scalar field with one free parameter in the self-interaction potential. We study translation invariant stationary states dual to domain walls and black branes. Depending on the value of the free parameter we find crossover, second and first order phase transitions between such states, and the c-function either flows to zero or to a finite value in the infrared. We present evidence that evaluating QNEC2 for ground state solutions allows to predict the existence of phase transitions at finite temperature.
Holography has provided valuable insights into the time evolution of strongly coupled gauge theories in a fixed spacetime. However, this framework is insufficient if this spacetime is dynamical. We present a novel scheme to evolve a four-dimensional, strongly interacting gauge theory coupled to four-dimensional dynamical gravity in the semiclassical regime. We use holography to evolve the quantum gauge theory stress tensor. The four-dimensional metric evolves according to the four-dimensional Einstein equations coupled to the expectation value of the stress tensor. We focus on Friedmann-Lemaître-Robertson-Walker geometries and evolve far-from-equilibrium initial states that lead to asymptotically expanding, flat or collapsing Universes.
We use the quantum null energy condition in strongly coupled two-dimensional field theories (QNEC2) as diagnostic tool to study a variety of phase structures, including crossover, second and first order phase transitions. We find a universal QNEC2 constraint for first order phase transitions with kinked entanglement entropy and discuss in general the relation between the QNEC2-inequality and monotonicity of the Casini-Huerta c-function. We then focus on a specific example, the holographic dual of which is modelled by three-dimensional Einstein gravity plus a massive scalar field with one free parameter in the self-interaction potential. We study translation invariant stationary states dual to domain walls and black branes. Depending on the value of the free parameter we find crossover, second and first order phase transitions between such states, and the c-function either flows to zero or to a finite value in the infrared. Strikingly, evaluating QNEC2 for ground state solutions allows to predict the existence of phase transitions at finite temperature.
We present a novel framework for the equation of state of dense and hot Quantum Chromodynamics (QCD), which focuses on the region of the phase diagram relevant for neutron star mergers and core-collapse supernovae. The model combines predictions from the gauge/gravity duality with input from lattice field theory, QCD perturbation theory, chiral effective theory and statistical modeling. It is therefore, by construction, in good agreement with theoretical constraints both at low and high densities and temperatures. The main ingredients of our setup are the non-perturbative V-QCD model based on the gauge/gravity duality, a van der Waals model for nucleon liquid, and the DD2 version of the Hempel-Schaffner-Bielich statistical model of nuclear matter. By consistently combining these models, we also obtain a description for the nuclear to quark matter phase transition and its critical endpoint. The parameter dependence of the model is represented by three (soft, intermediate and stiff) variants of the equation of state, all of which agree with observational constraints from neutron stars and their mergers. We discuss resulting constraints for the equation of state, predictions for neutron stars and the location of the critical point.