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MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3' untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
We carry out an in-depth analysis of the prompt-collapse behaviour of binary neutron star (BNS) mergers. To this end, we perform more than 80 general relativistic BNS merger simulations using a family of realistic Equations of State (EOS) with different stiffness, which feature a first order deconfinement phase transition between hadronic and quark matter. From these simulations we infer the critical binary mass Mcrit that separates the prompt from the non-prompt collapse regime. We show that the critical mass increases with the stiffness of the EOS and obeys a tight quasi-universal relation, Mcrit/MTOV ≈ 1.41 ± 0.06, which links it to the maximum mass MTOV of static neutron stars, and therefore provides a straightforward estimate for the total binary mass beyond which prompt collapse becomes inevitable. In addition, we introduce a novel gauge independent definition for a one-parameter family of threshold masses in terms of curvature invariants of the Riemann tensor which characterizes the development toward a more rapid collapse with increasing binary mass. Using these diagnostics, we find that the amount of matter remaining outside the black hole sharply drops in supercritical mass mergers compared to subcritical ones and is further reduced in mergers where the black hole collapse is induced by the formation of a quark matter core. This implies that Mcrit, particularly for merger remnants featuring quark matter cores, imposes a strict upper limit on the emission of any detectable electromagnetic counterpart in BNS mergers.
In this special issue of Matrix Biology centered on proteoglycan biology we have assembled a blend of articles focused on the state-of-the-art of proteoglycanology. The field has greatly expanded in the past three decades and now encompasses all the areas of biology. This special issue is divided into five chapters describing hyaluronan metabolism, biosynthetic and catabolic pathways of proteoglycans and their roles in inflammation, cancer, repair and development. We hope that the new original work and the reviews from recognized leaders will stimulate investigations in this exciting and fertile field of research.
Post-merger gravitational-wave signal from neutron-star binaries: a new look at an old problem
(2023)
The spectral properties of the post-merger gravitational-wave signal from a binary of neutron stars encodes a variety of information about the features of the system and of the equation of state describing matter around and above nuclear saturation density. Characterising the properties of such a signal is an “old” problem, which first emerged when a number of frequencies were shown to be related to the properties of the binary through “quasi-universal” relations. Here we take a new look at this old problem by computing the properties of the signal in terms of the Weyl scalar ψ4. In this way, and using a database of more than 100 simulations, we provide the first evidence for a new instantaneous frequency, f ψ4 0, associated with the instant of quasi timesymmetry in the postmerger dynamics, and which also follows a quasi-universal relation. We also derive a new quasi-universal relation for the merger frequency f h mer, which provides a description of the data that is four times more accurate than previous expressions while requiring fewer fitting coefficients. Finally, consistently with the findings of numerous studies before ours, and using an enlarged ensamble of binary systems we point out that the ℓ = 2, m = 1 gravitational-wave mode could become comparable with the traditional ℓ = 2, m = 2 mode on sufficiently long timescales, with strain amplitudes in a ratio |h 21|/|h 22| ∼ 0.1 − 1 under generic orientations of the binary, which could be measured by present detectors for signals with large signal-to-noise ratio or by third-generation detectors for generic signals should no collapse occur.
A considerable effort has been dedicated recently to the construction of generic equations of state (EOSs) for matter in neutron stars. The advantage of these approaches is that they can provide model-independent information on the interior structure and global properties of neutron stars. Making use of more than 106 generic EOSs, we asses the validity of quasi-universal relations of neutron star properties for a broad range of rotation rates, from slow-rotation up to the mass-shedding limit. In this way, we are able to determine with unprecedented accuracy the quasi-universal maximum-mass ratio between rotating and nonrotating stars and reveal the existence of a new relation for the surface oblateness, i.e., the ratio between the polar and equatorial proper radii. We discuss the impact that our findings have on the imminent detection of new binary neutron-star mergers and how they can be used to set new and more stringent limits on the maximum mass of nonrotating neutron stars, as well as to improve the modelling of the X-ray emission from the surface of rotating stars.
We have investigated the systematic differences introduced when performing a Bayesian-inference analysis of the equation of state of neutron stars employing either variable- or constant-likelihood functions. The former have the advantage that it retains the full information on the distributions of the measurements, making an exhaustive usage of the data. The latter, on the other hand, have the advantage of a much simpler implementation and reduced computational costs. In both approaches, the EOSs have identical priors and have been built using the sound-speed parameterization method so as to satisfy the constraints from X-ray and gravitationalwaves observations, as well as those from Chiral Effective Theory and perturbative QCD. In all cases, the two approaches lead to very similar results and the 90%-confidence levels are essentially overlapping. Some differences do appear, but in regions where the probability density is extremely small and are mostly due to the sharp cutoff set on the binary tidal deformability Λ˜ ≤ 720 employed in the constant-likelihood analysis. Our analysis has also produced two additional results. First, a clear inverse correlation between the normalized central number density of a maximally massive star, nc,TOV/ns, and the radius of a maximally massive star, RTOV. Second, and most importantly, it has confirmed the relation between the chirp mass Mchirp and the binary tidal deformability Λ˜. The importance of this result is that it relates a quantity that is measured very accurately, Mchirp, with a quantity that contains important information on the micro-physics, Λ˜. Hence, once Mchirp is measured in future detections, our relation has the potential of setting tight constraints on Λ˜.
Using full 3+1 dimensional general-relativistic hydrodynamic simulations of equal- and unequal-mass neutron-star binaries with properties that are consistent with those inferred from the inspiral of GW170817, we perform a detailed study of the quark-formation processes that could take place after merger. We use three equations of state consistent with current pulsar observations derived from a novel finite-temperature framework based on V-QCD, a non-perturbative gauge/gravity model for Quantum Chromodynamics. In this way, we identify three different post-merger stages at which mixed baryonic and quark matter, as well as pure quark matter, are generated. A phase transition triggered collapse already ≲10ms after the merger reveals that the softest version of our equations of state is actually inconsistent with the expected second-long post-merger lifetime of GW170817. Our results underline the impact that multi-messenger observations of binary neutron-star mergers can have in constraining the equation of state of nuclear matter, especially in its most extreme regimes.
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.