Biology subjects

Grimaldi, A.

Publications and source records attributed to Grimaldi, A..

8 recordsLinked to original sources

bioRxiv2026

Information Flow and Traveling Waves show distinct cortical trajectories

Traveling waves (TWs) are a hallmark of cortical dynamics, proposed to organize neuronal activity across space and time. Yet their propagation can oppose the causal flow of information, challenging their functional interpretation. We demonstrate this using computational simulations and validate our predictions in electrophysiological recordings. We introduce the Directional Information Flow Field (DIFF), which adapts Granger causality to two-dimensional neural recordings to map directed interactions across cortical networks. In computational models, DIFF recovers the direction and sources of information flow, whereas delays and inhibition can cause TWs to propagate in opposing or orthogonal directions. We validate these findings in human and non-human primate electrophysiological recordings, revealing reversed or orthogonal flow axes, distinct spatial origins, and frequency-dependent differences in feedforward and feedback dynamics. These findings challenge the functional interpretation of TWs and establish DIFF as a complementary framework for revealing directed neural communication underlying cortical dynamics.

neuroscience↗

bioRxiv2026

OKN4395, a first-in-class EP2/EP4/DP1 triple antagonist reprograms prostanoid-driven immunosuppression to restore antitumor immunity

Immune checkpoint inhibitors, particularly T cell targeting anti-PD(L)1 therapies, have revolutionized the treatment landscape for solid malignancies, but challenges related to non-responsiveness and the development of treatment resistance continue to be observed. An additional immunosuppressive axis relates to prostaglandin signaling downstream of cyclooxygenase-2 (COX2), where COX2 inhibitors have shown clinical promise in re-engaging both T and non-T cell immune compartments, yet have suffered from toxicity concerns. We report here the preclinical characterization of OKN4395, a highly potent and specific first-in-class triple antagonist of EP2, EP4, and DP1, major tumor immunosuppressive receptors downstream of COX2. OKN4395 restores immune function on both T cells and NK cells in vitro. Additionally, OKN4395 acts synergistically with anti-PD1 to increase speed and depth of antitumor activity. Overall, these findings robustly support the clinical investigation of OKN4395 in an ongoing Phase 1 trial (NCT06789172) as an innovative cancer immunotherapy for solid tumors, as a single agent and in combination with anti-PD1 therapy. Statement of significanceOKN4395, a first-in-class oral EP2/EP4/DP1 antagonist, reverses prostanoid-driven immunosuppression to restore antitumor immunity. Integrated pharmacology defines mechanism, translational biomarkers as well as both monotherapy and anti-PD1 combination strategies. These data position prostanoid tri-receptor antagonism as a translatable strategy in solid tumors. A global Phase 1 study is underway (NCT06789172).

pharmacology and toxicology↗

bioRxiv2025

Method to estimate amide base-catalyzed back exchange rates in H2O/D2O mixtures

Hydrogen-deuterium exchange (HDX) measurements are widely used to probe protein structural dynamics. Quantitative interpretation of HDX data relies on the concept of an intrinsic exchange rate, which is well characterized in isotopically pure H2O or D2O but does not explicitly account for the back exchange that necessarily occurs in H2O/D2O mixtures: in this case, both the approach-to-equilibrium rate and the equilibrium deuterium enrichment of amides depend nontrivially on solvent composition and acidity. A practical method is presented to predict intrinsic forward and reverse amide exchange rates in H2O/D2O mixtures. The approach combines known second-order reference rates measured in pure solvents with established empirical descriptions of H2O/D2O mixtures. The resulting framework yields explicit expressions for forward and back exchange rates as functions of solvent composition and acidity, and correctly recovers the known limits in pure H2O and pure D2O. The model predicts composition-dependent kinetic isotope effects and an equilibrium amide fractionation factor of{phi} = 1.20 for unstructured peptides in base-catalyzed conditions, in close agreement with the experimental value 1.22 reported for poly-D,L-alanine. By providing a physically motivated description of exchange in mixed solvents, this method offers a practical starting point for quantitatively correcting back exchange in HDX-MS and HDX-NMR experiments.

biochemistry↗

bioRxiv2025

What do neural travelling waves tell us about information flow?

In many behavioral conditions, neural activity manifests itself within and across brain regions as traveling waves, revealing the importance of analyzing spatiotemporal dynamics in electrophysiological data. Most methods detect traveling waves by measuring spatial phase gradients, i.e., monotonic and ordered phase changes through space. It is unclear, however, how these traveling waves relate to the causal directionality of information flow. Here, we analyze systems of coupled nodes with an external input to one node. We demonstrate that the phase ordering in traveling waves does not always correspond to the direction of effective information flow. We show that discrepancies can emerge in the case of systems with delays and inhibitory influences. As a methodological solution, we show that Granger causality analysis can, in linear systems, recover the directionality of the information flow. We propose a new measure called DIFF, the Directional Information Flow Field. DIFF is constructed by analyzing directed causal influences in space and time between neighbours, yielding a vector field. As a proof of principle, we show that, in a 2D field where a connected network is perturbed by an external input, the Divergence of DIFF can identify the spatial source of the perturbations. We propose that causal inference methods provide complementary information to phase-based traveling wave methods in analyzing system dynamics and information flow.

neuroscience↗

bioRxiv2023

Extraocular muscle stem cells exhibit distinct cellular properties associated with non-muscle molecular signatures

The muscle stem cell (MuSC) population is recognized as functionally heterogeneous. Cranial muscle stem cells, which originate from head mesoderm, can have greater proliferative capacity in culture and higher regenerative potential in transplantation assays when compared to those in the limb. The existence of such functional differences in phenotypic outputs remain unresolved as a comprehensive understanding of the underlying mechanisms is lacking. We addressed this issue using a combination of clonal analysis, live imaging, and scRNA-seq, identifying critical biological features that distinguish extraocular (EOM) and limb (Tibialis anterior, TA) MuSC populations. Time-lapse studies using a MyogenintdTomatoreporter showed that the increased proliferation capacity of EOM MuSCs is accompanied by a differentiation delay in vitro. Unexpectedly, in vitro activated EOM MuSCs expressed a large array of distinct extracellular matrix (ECM) components, growth factors, and signaling molecules that are typically associated with mesenchymal non-muscle cells. These unique features are regulated by a specific set of transcription factors that constitute a coregulating module. This transcription factor network, which includes Foxc1 as one of the major players, appears to be hardwired to EOM identity as it is present in quiescent adult MuSCs, in the activated counterparts during growth and retained upon passages in vitro. These findings provide insights into how high-performing MuSCs regulate myogenic commitment by active remodeling of their local environment.

developmental biology↗

bioRxiv2021

Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse

How distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types within a field of cells is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissues cells provides a model for examining how muscle functional units are established. Most craniofacial structures originate from the vertebrate-specific neural crest cells except in the dorsal portion of the head, where they arise from cranial mesoderm. Here, using multiple lineage-traced single cell RNAseq, advanced computational methods and in situ analyses, we identify Myf5+ bipotent progenitors that give rise to both muscle and juxtaposed connective tissue. Following this bifurcation, muscle and connective tissue cells retain complementary signalling features and maintain spatial proximity. Interruption of upstream myogenic identity shifts muscle progenitors to a connective tissue fate. Interestingly, Myf5-derived connective tissue cells, which adopt a novel regulatory signature, were not observed in ventral craniofacial structures that are colonised by neural crest cells. Therefore, we propose that an ancestral program gives rise to bifated muscle and connective tissue cells in skeletal muscles that are deprived of neural crest.

developmental biology↗

bioRxiv2021

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

neuroscience↗

bioRxiv2018

Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues

In vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis of Tbx1- and Pax3-null mice reveal a unique genetic program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies.

developmental biology↗