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    Microglial Refinement of A-Fiber Projections in the Postnatal Spinal Cord Dorsal Horn Is Required for Normal Maturation of Dynamic Touch

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    Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganisation, including the refinement of primary afferent A-fibre terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fibre terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fibre refinement and elimination, resulting in altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioural hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fibre projections remain in the dorsal horn and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch.Significance statement Dynamic touch is the sensation of movement across the skin, transmitted by mechanosensory A-fibres, the myelinated primary afferents that respond to innocuous mechanical stimulation. The central terminals of these fibres are located in the deep laminae of the sensory spinal cord dorsal horn in the adult. However, in early life they are widespread and retract from the superficial laminae of the dorsal horn during normal postnatal development. The underlying mechanisms remain unknown. We found that microglia phagocytose superfluous A-fibres and furthermore, disruption of this process leads to long-term aberrant dynamic touch processing and behaviour. Microglia mediated refinement of A-fibres during the early postnatal period is therefore critical to both normal dorsal horn development and appropriate spatial encoding of dynamic touch

    Weyl's law for singular Riemannian manifolds

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    Obscuration beyond the nucleus: infrared quasars can be buried in extreme compact starbursts

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    In the standard quasar model, the accretion disc obscuration is due to the canonical dusty torus. Here, we argue that a substantial part of the quasar obscuration can come from the interstellar medium (ISM) when the quasars are embedded in compact starbursts. We use an obscuration-unbiased sample of 578 infrared (IR) quasars at z ≈1–3 and archi v al Atacama Large Millimetre/submillimetre Array submillimetre host galaxy sizes to investigate the ISM contribution to the quasar obscuration. We calculate star formation rates (SFR) and ISM column densities for the IR quasars and a control sample of submillimetre galaxies (SMGs) not hosting quasar activity and show that: (1) the quasar obscured fraction is constant up to SFR ≈300 M yr −1 , and then increases towards higher SFR, suggesting that the ISM obscuration plays a significant role in starburst host galaxies, and (2) at SFR 300 M yr −1 , the SMGs and IR quasars have similarly compact submillimetre sizes ( R e ≈0 . 5 –3 kpc ) and consequently, the ISM can heavily obscure the quasar, even reaching Compton-thick ( N H > 10 24 cm −2 ) levels in extreme cases. Based on our results, we infer that ≈10 –30 per cent of the IR quasars with SFR 300 M yr −1 are obscured solely by the ISM

    Structural heterogeneity of the ion and lipid channel TMEM16F

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    Transmembrane protein 16 F (TMEM16F) is a Ca2+-activated homodimer which functions as an ion channel and a phospholipid scramblase. Despite the availability of several TMEM16F cryogenic electron microscopy (cryo-EM) structures, the mechanism of activation and substrate translocation remains controversial, possibly due to restrictions in the accessible protein conformational space. In this study, we use atomic force microscopy under physiological conditions to reveal a range of structurally and mechanically diverse TMEM16F assemblies, characterized by variable inter-subunit dimerization interfaces and protomer orientations, which have escaped prior cryo-EM studies. Furthermore, we find that Ca2+-induced activation is associated to stepwise changes in the pore region that affect the mechanical properties of transmembrane helices TM3, TM4 and TM6. Our direct observation of membrane remodelling in response to Ca2+ binding along with additional electrophysiological analysis, relate this structural multiplicity of TMEM16F to lipid and ion permeation processes. These results thus demonstrate how conformational heterogeneity of TMEM16F directly contributes to its diverse physiological functions

    Boosting Ensemble Refinement with Transferable Force-Field Corrections: Synergistic Optimization for Molecular Simulations

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    : A novel method combining the force-field fitting approach and ensemble refinement by the maximum entropy principle is presented. Its formulation allows us to continuously interpolate between these two methods, which can thus be interpreted as two limiting cases. A cross-validation procedure enables us to correctly assess the relative weight of both of them, distinguishing scenarios in which the combined approach is meaningful from those in which either ensemble refinement or force-field fitting separately prevails. The efficacy of their combination is examined for a realistic case study of RNA oligomers. Within the new scheme, molecular dynamics simulations are integrated with experimental data provided by nuclear magnetic resonance measures. We show that force-field corrections are in general superior when applied to the appropriate force-field terms but are automatically discarded by the method when applied to inappropriate force-field terms

    Investigating neural representations in rat visual cortex and deep neural networks

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    lifex-cfd: an open-source computational fluid dynamics solver for cardiovascular applications

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    Computational fluid dynamics (CFD) is an important tool for the simulation of the cardiovascular function and dysfunction. Due to the complexity of the anatomy, the transitional regime of blood flow in the heart, and the strong mutual influence between the flow and the physical processes involved in the heart function, the development of accurate and efficient CFD solvers for cardiovascular flows is still a challenging task. In this paper we present lifeImage 1-cfd, an open-source CFD solver for cardiovascular simulations based on the lifeImage 1 finite element library, written in modern C++ and exploiting distributed memory parallelism. We model blood flow in both physiological and pathological conditions via the incompressible Navier-Stokes equations, accounting for moving cardiac valves, moving domains, and transition-to-turbulence regimes. In this paper, we provide an overview of the underlying mathematical formulation, numerical discretization, implementation details and examples on how to use lifeImage 1-cfd. We verify the code through rigorous convergence analyses, and we show its almost ideal parallel speedup. We demonstrate the accuracy and reliability of the numerical methods implemented through a series of idealized and patient-specific vascular and cardiac simulations, in different physiological flow regimes. The lifeImage 1-cfd source code is available under the LGPLv3 license, to ensure its accessibility and transparency to the scientific community, and to facilitate collaboration and further developments

    A sign that used to annoy me, and still does

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    Ultraviolet aspects of Peccei--Quinn Inflation

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    The possibility of observing a value of the tensor-to-scalar ratio rr of the order r103r\sim 10^{-3} would project us into a new era for the cosmology of the early Universe. Such an observation would lead to confirmation of inflation and a measurement of the energy scale at which this phase occurred, revolutionizing the idea of the early stages of the evolution of the Universe. This scale would be beyond the reach of any possible terrestrial experiment, exploring a region of energies of the order of 10121013GeV10^{12}-10^{13} \rm{GeV} . Since a theory of quantum gravity is missing, this relegates inflation models to effective models that are reliable only within a certain range of energies. Hence, the question of whether the predictions of these models are reliable is crucial. In other words, is it always possible to ignore the tower of higher-dimensional operators present? This thesis aims to answer this question by focusing on the model called Peccei-Quinn inflation. This model offers the possibility of explaining inflation, dark matter and providing a solution to the strong CP problem. It also predicts a value of r103r \sim 10^{-3 } and makes this model falsifiable in the future. In addition, this thesis addresses a crucial aspect related to the production of dark matter through axions. It involves modeling the evolution after inflation, which is a crucial point. The findings significantly alter what was previously known about the Peccei-Quinn model. In the thesis we prove that Peccei–Quinn inflation is extremely sensitive to higher-dimensional operators, undermining its validity as an effective field theory. Further combined with the discussion on the axion quality required for solving the strong CP problem, we examine the validity of this scenario. We also show that after Peccei–Quinn inflation, resonant amplifications of the field fluctuations are inevitably triggered, casting serious doubts on the typical assumption of a homogeneous evolution. In conclusion, this thesis asks and tries to answer some profound questions regarding theoretical models that are in the sights of future groundbreaking observations in cosmology that will potentially provide a deeper understanding of the fundamental properties of our Universe


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