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

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

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

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

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

: 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

Ultraviolet aspects of Peccei--Quinn Inflation

The possibility of observing a value of the tensor-to-scalar ratio $r$ of the order $r\sim 10^{-3}$ 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 $10^{12}-10^{13} \rm{GeV}$. 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 $r \sim 10^{-3 }$ 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

The brain cytokine orchestra in multiple sclerosis: from neuroinflammation to synaptopathology

: The central nervous system (CNS) is finely protected by the blood-brain barrier (BBB). Immune soluble factors such as cytokines (CKs) are normally produced in the CNS, contributing to physiological immunosurveillance and homeostatic synaptic scaling. CKs are peptide, pleiotropic molecules involved in a broad range of cellular functions, with a pivotal role in resolving the inflammation and promoting tissue healing. However, pro-inflammatory CKs can exert a detrimental effect in pathological conditions, spreading the damage. In the inflamed CNS, CKs recruit immune cells, stimulate the local production of other inflammatory mediators, and promote synaptic dysfunction. Our understanding of neuroinflammation in humans owes much to the study of multiple sclerosis (MS), the most common autoimmune and demyelinating disease, in which autoreactive T cells migrate from the periphery to the CNS after the encounter with a still unknown antigen. CNS-infiltrating T cells produce pro-inflammatory CKs that aggravate local demyelination and neurodegeneration. This review aims to recapitulate the state of the art about CKs role in the healthy and inflamed CNS, with focus on recent advances bridging the study of adaptive immune system and neurophysiology

On improving the efficiency of ADER methods

The (modern) arbitrary derivative (ADER) approach is a popular technique for the numerical solution of differential problems based on iteratively solving an implicit discretization of their weak formulation. In this work, focusing on an ODE context, we investigate several strategies to improve this approach. Our initial emphasis is on the order of accuracy of the method in connection with the polynomial discretization of the weak formulation. We demonstrate that precise choices lead to higher-order convergences in comparison to the existing literature. Then, we put ADER methods into a Deferred Correction (DeC) formalism. This allows to determine the optimal number of iterations, which is equal to the formal order of accuracy of the method, and to introduce efficient p-adaptive modifications. These are defined by matching the order of accuracy achieved and the degree of the polynomial reconstruction at each iteration. We provide analytical and numerical results, including the stability analysis of the new modified methods, the investigation of the computational efficiency, an application to adaptivity and an application to hyperbolic PDEs with a Spectral Difference (SD) space discretization

A comparison of data-driven reduced order models for the simulation of mesoscale atmospheric flow

The simulation of atmospheric flows by means of traditional discretization methods remains computationally intensive, hindering the achievement of high forecasting accuracy in short time frames. In this paper, we apply three reduced order models that have successfully reduced the computational time for different applications in computational fluid dynamics while preserving accuracy: Dynamic Mode Decomposition (DMD), Hankel Dynamic Mode Decomposition (HDMD), and Proper Orthogonal Decomposition with Interpolation (PODI). The three methods are compared in terms of computational time and accuracy in the simulation of two well-known 2D benchmarks for mesoscale flow. The accuracy of the DMD and HDMD solutions deteriorates rather quickly as the forecast time window expands, although these methods are designed to predict the dynamics of a system. The reason is likely the strong nonlinearity in the benchmark flows. The PODI solution is accurate for the entire duration of the time interval of interest thanks to the use of interpolation with radial basis functions. This holds true also when the model features a physical parameter expected to vary in a given range, as is typically the case in weather prediction, and for preliminary results in 3D