bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic models for PET displacement studies
Authors: Laurell Gjertrud Louise , Plavén-Sigray Pontus , Johansen Annette , Raval Nakul Ravi , Nasser Arafat , Madsen Clara Aabye , Madsen Jacob , Hansen Hanne Demant , Donovan Lene Lundgaard , Knudsen Gitte Moos , Lammertsma Adriaan A , Ogden R Todd , Svarer Claus , Schain Martin 
Published: November 2022

AbstractThe traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data.We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.
Beyond viral detection: multitrophic effects of covert infection with an RNA virus in medfly
Authors: Hernández-Pelegrín Luis , García-Martínez Ricardo , Llácer Elena , Nieves Lorena , Llopis-Giménez Ángel , Catalá-Oltra Marta , Dembilio Óscar , Pérez-Hedo Meritxell , Urbaneja Alberto , Ros Vera I.D. , Beitia Francisco , Herrero Salvador 
Published: November 2022

Summary/abstractBackgroundWith the advent of high-throughput sequencing, large sets of insect-infecting RNA viruses producing apparent asymptomatic infections are being discovered. In the Mediterranean fruit fly (medfly)Ceratitis capitata, an agricultural key pest of a wide range of fruits, up to 13 different RNA viruses have been described. Recent analysis demonstrated a wide distribution of these viruses in different medfly strains collected worldwide, but little is known about the interactions between those viruses and the medfly host. Previous studies suggested that a higher abundance of Ceratitis capitata nora virus (CcaNV) decreased medfly developmental time. Here, we investigated the effect of CcaNV on a broad range of parameters related to host fitness and its interaction with other trophic levels.ResultsCcaNV purified from a naturally infected medfly strain was used to infect CcaNV-free flies orally and subsequently monitor pupal weight, adult emergence, flying ability and longevity. Our results revealed detrimental effects associated with a CcaNV infection in the medfly, in terms of reduced pupal weight and reduced adult longevity. Moreover, we tested the influence of a CcaNV infection in medflies on the parasitism performance ofAganaspis daci, a medfly endoparasitoid used in biological control programs against medflies. Our results showed thatA. daciprogeny increased when parasitizing on CcaNV-infected larvae.ConclusionsOur results proved that covert RNA viruses can impact on the insect ecology, directly affecting its insect host biology and indirectly influencing multitrophic interactions.
Extracellular matrix protein anosmin-1 overexpression regulates dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in MPTP model of Parkinson’s disease
Authors: Villadiego Javier , García-Swinburn Roberto , García-González Diego , Lebrón-Galán Rafael , Murcia-Belmonte Verónica , García-Roldán Ernesto , Suárez-Luna Nela , Nombela Cristina , Marchena Miguel , de Castro Fernando , Toledo-Aral Juan José 
Published: November 2022

AbstractThe development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. Furthermore, overexpression of A1in vivogives rise to higher number of dopaminergic neurons in the olfactory bulb. Here, using A1 overexpressing mice (A1-mice), we studied the effects of A1 on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). A1 overexpression increases the number of dopaminergic SNpc neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice do not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, these analyses confirm A1 as a principal regulator of the FGF pathway in the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.
Virulence adaptation ofPseudomonas aeruginosaphospholipase mutant with altered membrane phospholipid composition
Authors: Caliskan Muttalip , Poschmann Gereon , Gudzuhn Mirja , Waldera-Lupa Daniel , Streit Wolfgang R. , Jaeger Karl-Erich , Stühler Kai , Kovacic Filip 
Published: November 2022

AbstractMembrane protein and phospholipid (PL) composition changes in response to environmental cues and during infections. Covalent modification and remodelling of the acyl chain length of PLs is an important bacterial adaptation mechanism. However, little is known about which bacterial pathways are regulated in response to altered PL composition. Here, we showed thatP. aeruginosaphospholipase A, PlaF, which modulates membrane PL composition, is important for biofilm biogenesis, and we performed whole-cell quantitative proteomics ofP. aeruginosawild-type and ΔplaFbiofilms to identify pathways regulated by PlaF. The results revealed profound alterations in the abundance of several two-component systems (TCSs), including accumulation of PprAB, which controls the transition to biofilm. Furthermore, a unique phosphorylation pattern of transcriptional regulators, transporters and metabolic enzymes, as well as differential production of seven proteases, in ΔplaF, indicate that PlaF-mediated virulence adaptation involves complex transcriptional and posttranscriptional regulation. Moreover, proteomics revealed the depletion of pyoverdine-mediated iron uptake pathway proteins in ΔplaF, which agrees with the decreased concentrations of extracellular pyoverdine and intracellular iron and is likely responsible for its prolonged lag growth phase, presumably due to reduced iron uptake. Conversely, the accumulation of proteins from alternative iron-uptake systems in ΔplaFsuggests that PlaF may function as a switch between different iron-acquisition pathways. The observation that ΔplaFaccumulates PL-acyl chain modifying and PL synthesis enzymes reveals novel insights into the role of PlaF for membrane PL homeostasis. Although the precise mechanism by which PlaF simultaneously affects multiple pathways remains to be elucidated, we suggest that PlaF-catalyses the degradation of PLs which then serve as a signal that is amplified by proteins of two-component, phosphorylation and proteolytic degradation systems to elicit the global adaptive response inP. aeruginosa.
A back-translational study of descending interactions with central mechanisms of hyperalgesia induced by high frequency stimulation in rat and human
Authors: Patel Ryan , Taylor Joseph L , Dickenson Anthony H , McMahon Stephen B , Bannister Kirsty 
Published: November 2022

AbstractIn humans and animals, high frequency electrocutaneous stimulation (HFS) may produce an ‘early long-term potentiation-like’ sensitisation. Peripheral and central modulatory processes are proposed to play a role. To explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we concurrently applied HFS with i) a conditioned pain modulation (CPM) paradigm during psychophysical testing in humans, or ii) a diffuse noxious inhibitory controls (DNIC) paradigm duringin vivoelectrophysiological recording of spinal neurones in anaesthetised animals in parallel studies that utilised identical stimuli. HFS induced enhanced perceptual responses to pin-prick stimuli in cutaneous areas secondary to the area of stimulation in humans and heightened the excitability of spinal neurones in rats (which exhibited stimulus intensity dependent coded responses to pin-prick stimulation in a manner that tracked with human psychophysics), where we also observed indicators of increased central neuronal hyperexcitability. In humans, a HFS(+CPM) paradigm did not alter primary or secondary hyperalgesia, and the area and pain intensity of secondary hyperalgesia did not correlate with temporal summation of pain or CPM magnitude, while in rats application of a DNIC paradigm concurrent to HFS did not impact the development of neuronal hyperexcitability. Concordance between human and rat data supports their translational validity. Our finding that excitatory signalling exceeds inhibitory controls suggests that dampening facilitatory mechanisms may be a preferable strategy for certain chronic pain states. If facilitatory mechanisms dominate, our data could explain why enhancing activity in descending inhibitory controls is not sufficient to induce pain relief in vulnerable patients.
Self-Regulation of Visual Word Form Area activation with real-time fMRI neurofeedback
Authors: Haugg Amelie , Frei Nada , Menghini Milena , Stutz Felizia , Steinegger Sara , Röthlisberger Martina , Brem Silvia 
Published: November 2022

AbstractThe Visual Word Form Area (VWFA) is a key region of the brain’s reading network and its activation has been shown to be strongly associated with reading skills. Here, for the first time, we investigated whether voluntary regulation of VWFA activity is feasible using real-time fMRI neurofeedback. 40 adults with typical reading skills were instructed to either upregulate (UP group) or downregulate (DOWN group) their own VWFA activity during six neurofeedback training runs. The VWFA target region was individually defined based on a functional localizer task. Before and after training, also regulation runs without feedback (“no-feedback runs”) were performed.When comparing the two groups, we found stronger activity across the whole reading network, including the VWFA, for the UP than the DOWN group. Crucially, we observed a significant interaction of group and time (pre, post) for the no-feedback runs: The two groups did not differ in their VWFA activity before neurofeedback training, but the UP group showed significantly stronger activity than the DOWN group after neurofeedback training. Our results indicate that self-regulation of the VWFA activity is feasible and that, once learned, successful self-regulation can even be performed in the absence of feedback. These results are a crucial step toward to development of a potential clinical intervention to improve reading skills in individuals with reading impairments.
Flux analysis reveals specific regulatory modalities of gene expression
Authors: Martin Benjamin , Suter David Michael 
Published: November 2022

AbstractThe level of a given protein is determined by rates of mRNA and protein synthesis and degradation. The reliable quantification of these rates is thus essential to understand how protein levels are regulated. While several studies have quantified the contribution of different steps of gene expression in regulating protein levels, these are limited by the use of equilibrium approximations when studying out-of-equilibrium biological systems. Here we introduce flux analysis to quantify the contribution of gene expression steps to regulate the dynamics of the expression level for specific proteins. We use flux analysis to analyze a published RNA-seq and proteomics dataset of mouse bone marrow-derived DCs stimulated with LPS. Our analysis revealed six regulatory modalities shared by sets of genes with clear functional signatures. We also find that protein degradation plays a stronger role than expected in the adaptation of protein levels to LPS stimulation. These findings suggest that shared regulatory strategies can lead to versatile responses at the protein level and highlight the importance of going beyond steady-state approximations to uncover the dynamic contribution of different steps of gene expression to protein levels.
PTHrP buffers Wnt/β-catenin activity through a negative feedback loop to maintain articular cartilage homeostasis
Authors: Tong Wenxue , Xu Jiankun , Qi Qiuli , Chen Hongjiang , Huang Tao , Chen Chunxia , Liu Weiyang , Huang Zhonglian , Chen Youbin , Ma Zebin , Zhao Di , Hu Jun 
Published: November 2022

AbstractOsteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/β-catenin cascade is essential in articular cartilage development and homeostasis. It has proved that both overexpression and loss of β-catenin lead to cartilage degeneration and OA symptoms. However, the mechanism of Wnt/β-catenin balance in healthy cartilage remains unclear. In the present work, we confirmed that the Wnt/β-catenin activation and PTHrP suppression in cartilage during the post-traumatic OA process. Then, we demonstrated that Wnt/β-catenin upregulated PTHrP expression through binding to its promoter (P2), and induce mRNA (AT6) transcript expression, while PTHrP repressed Wnt/β-catenin activity, and formed a Wnt/β-catenin-PTHrP negative feedback loop in the very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1β treated very primary chondrocytes. We further found that miR-106b-5p was increased in these “aberrant” chondrocytes and directly targeted PTHrP mRNA to abolish the feedback loop. PKC-ζ was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced β-catenin phosphorylation and ubiquitination. Finally, we disclosed that exogenous PTHrP attenuated OA progression exogenous PTHrP attenuated OA progression. Together, these findings reveal that PTHrP is a vital mediator to keep Wnt/β-catenin activity homeostasis in healthy cartilage through a negative feedback loop, and PTHrP might be a therapeutic target for OA and cartilage regeneration.
Dendritic modulation enables multitask representation learning in hierarchical sensory processing pathways
Authors: Wybo Willem A.M. , Tsai Matthias C. , Khoa Tran Viet Anh , Illing Bernd , Jordan Jakob , Morrison Abigail , Senn Walter 
Published: November 2022

AbstractWhile sensory representations in the brain depend on context, it remains unclear how such modulations are implemented at the biophysical level, and how processing layers further in the hierarchy can extract useful features for each possible contextual state. Here, we first demonstrate that thin dendritic branches are well suited to implementing contextual modulation of feedforward processing. Such neuron-specific modulations exploit prior knowledge, encoded in stable feedforward weights, to achieve transfer learning across contexts. In a network of biophysically realistic neuron models with context-independent feedforward weights, we show that modulatory inputs to thin dendrites can solve linearly non-separable learning problems with a Hebbian, error-modulated learning rule. Finally, we demonstrate that local prediction of whether representations originate either from different inputs, or from different contextual modulations of the same input, results in representation learning of hierarchical feedforward weights across processing layers that accommodate a multitude of contexts.
Intraspecific diversity in the mechanisms underlying abamectin resistance in a cosmopolitan pest
Authors: Villacis-Perez Ernesto , Xue Wenxin , Vandenhole Marilou , De Beer Berdien , Dermauw Wannes , Van Leeuwen Thomas 
Published: November 2022

AbstractPesticide resistance relies on a myriad of mechanisms, ranging from single mutations to a complex and polygenic architecture, and it involves mechanisms such as target-site insensitivity, metabolic detoxification, or a combination of these, with either additive or synergistic effects. Several resistance mechanisms against abamectin, a macrocyclic lactone widely used in crop protection, have been reported in the cosmopolitan pestTetranychus urticae. However, it has been shown that a single mechanism cannot account for the high levels of abamectin resistance found across different mite populations. Here, we used experimental evolution combined with bulked segregant analyses to map quantitative trait loci (QTL) associated with abamectin resistance in two genetically unrelated strains ofT. urticae. In these two independent QTL mapping experiments, three and four QTLs were identified, of which three were shared between experiments. Shared QTLs contained genes encoding subunits of the glutamate-gated chloride channel (GluCl) and harboured previously reported mutations, including G314D inGluCl1and G326E inGluCl3, but also novel resistance candidate loci, including DNA helicases and chemosensory receptors. Surprisingly, the fourth QTL, present only in only one of the experiments and thus unique for one parental resistant strain, revealed a non-functional variant ofGluCl2, suggesting gene knock-out as resistance mechanism. Our study uncovers the complex basis of abamectin resistance, and it highlights the intraspecific diversity of genetic mechanisms underlying resistance in a cosmopolitan pest.
An ultra-fast, proteome-wide response to the plant hormone auxin
Authors: Roosjen Mark , Kuhn Andre , Mutte Sumanth K. , Boeren Sjef , Krupar Pavel , Koehorst Jasper , Fendrych Matyáš , Friml Jiří , Weijers Dolf 
Published: November 2022

SUMMARYThe plant signaling molecule auxin controls growth and development through a simple nuclear pathway that regulates gene expresion. There are however several cellular and physiological responses to auxin that occur within seconds, far too rapid to be mediated by transcriptional changes, for which no molecular mechanism has yet been identified. Using a phosphoproteomic strategy inArabidopsis thalianaroots, we identify an ultra-rapid auxin response system that targets over 1700 proteins, many within 30 seconds. Auxin response is chemically specific, requires known auxin-binding proteins, and targets various pathways. Through exploring its temporal dynamics, we infer auxin-triggered kinase-substrate networks and identify apoplastic pH changes as a target of signaling and as part of a relay mechanism. By generating a variety of phosphoproteomic datasets, integrated with structural information in a web-app, and by demonstrating analysis and inference strategies, we offer a resource to explore rapid and dynamic signaling in plants.
A serine-folate metabolic unit controls resistance and tolerance of infection
Authors: Grimes Krista , Beckwith Esteban J. , Pearson William H. , Jacobson Jake , Chaudhari Surabhi , Aughey Gabriel N. , Larrouy-Maumus Gerald , Southall Tony D. , Dionne Marc S. 
Published: November 2022

AbstractImmune activation drives metabolic change in most animals. Immune-induced metabolic change is most conspicuous as a driver of pathology in serious or prolonged infection, but it is normally expected to be important to support immune function and recovery. Many of the signalling mechanisms linking immune detection with metabolic regulation, and their specific consequences, are unknown. Here, we show thatDrosophila melanogasterrespond to many bacterial infections by altering expression of genes of the folate cycle and associated enzymes of amino acid metabolism. The net result of these changes is increased flow of carbon from glycolysis into serine and glycine synthesis and a shift of folate cycle activity from the cytosol into the mitochondrion. Immune-induced transcriptional induction ofastrayandNmdmc, the two most-induced of these enzymes, depends onDifandfoxo. Loss ofastrayorNmdmcresults in infection-specific immune defects. Our work thus shows a key mechanism that connects immune-induced changes in metabolic signalling with the serine-folate metabolic unit to result in changed immune function.
3D Analysis of the Force Generated by a Honeybee During Flight
Authors: Mahadeeswara Mandiyam Y. , Srinivasan Mandyam V. 
Published: November 2022

AbstractTo better understand the turning flight characteristics of the bees, we developed a procedure for estimating the instantaneous total force generated by the bee, along with its centrifugal force component, at each instant of time. We calculated the magnitude and direction of the total force vector (TFV) with respect to the three body axes of the bee and examined its variation with time during turning flights. The results of this study revealed that turns in the cloud are executed by (a) holding the magnitude of the TFV vector constant and (b) by redirecting the body (and therefore the turning force) appropriately to execute a coordinated turn. We also calculated and analysed the TFVs of bees flying in a curved tunnel. The characteristics of these TFVs (magnitude and direction) are very similar to those for bees flying in the cloud. This is a novel finding as there are no studies which have estimated the instantaneous flight force magnitude and direction of a turning bee (these are not saccadic or evasive turns) in an outdoor or indoor setup. However, similar results have been reported for pigeons and cockatiels while executing smooth turns in the horizontal plane.
GSK3 inhibition reverts mesenchymal transition in human primary corneal endothelial cells
Authors: Maurizi Eleonora , Merra Alessia , Macaluso Claudio , Schiroli Davide , Pellegrini Graziella 
Published: November 2022

AbstractHuman corneal endothelial cells are organized in a tight mosaic of hexagonal cells and serve a critical function in maintaining corneal hydration and clear vision. Regeneration of the corneal endothelial tissue is hampered by its poor proliferative capacity, which is partially retrievedin vitro, albeit only for a limited number of passages before the cells undergo mesenchymal transition (EnMT). Although different culture conditions have been proposed in order to delay this process and prolong the number of cell passages, EnMT has still not been fully understood and successfully counteracted. In this perspective, we identified herein a single GSK3 inhibitor, CHIR99021, able to revert and avoid EnMT in primary human corneal endothelial cells (HCEnCs) from old donors until late passagesin vitro(P8), as shown from cell morphology analysis (circularity). In accordance, CHIR99021 reduced expression of α-SMA, an EnMT marker, while restored endothelial markers such as ZO-1, Na+/K+ATPase and N-cadherin, without increasing cell proliferation. A further analysis on RNA expression confirmed CHIR99021 induced downregulation of EnMT markers (αSMA and CD44), upregulation of the proliferation repressor p21 and revealed novel insights into the β-catenin and TGFβ pathways intersections in HCEnCs. The use of CHIR99021 sheds light on the mechanisms involved in EnMT and brings a substantial advantage in maintaining primary HCEnCs in culture until late passages, while preserving the correct morphology and phenotype. Altogether, these results bring crucial advancements towards the improvement of the corneal endothelial cells based therapy.