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Functional Profiling of Olfactory Sensory Neurons: Electrophysiological Characterization of Human Olfactory Epithelium and Maturation-Dependent Changes in Mouse Neuronal Excitability
No full textThe olfactory system is crucial for the detection of chemical cues from the environment, allowing species survival. Olfactory sensory neurons (OSNs) within the olfactory epithelium (OE) are responsible for odorant detection and signal transmission to the brain. To investigate olfaction, rodents, along with other species such as amphibians and fishes, have been extensively used as laboratory models. In the first part of this thesis, we provided the first electrophysiological characterization of human OSNs. Current knowledge about human OE is primarily confined to its morphology and molecular profile. However, little is known about the functional properties of human OSNs and supporting cells. We obtained acute slices of human OE from nasal biopsies and demonstrated their viability for whole-cell patch-clamp recordings. We measured voltage-gated currents from both OSNs and supporting cells in voltage-clamp configuration. Current-clamp protocols allowed us to assess the excitability of OSNs, which exhibited diverse firing patterns. Moreover, we demonstrated that these acute slices are also feasible for studying olfactory transduction, as we obtained the first electrophysiological responses of human OSNs upon odorant stimulation.
Stimulation with a phosphodiesterase inhibitor elicited neuronal inward currents and action potentials, providing evidence that cyclic adenosine monophosphate (cAMP) is involved in the transduction pathway of human olfaction.
In the second part of the thesis, we investigated immature OSNs from the mouse OE. The OE has the capability to continuously regenerate throughout life. To better characterize epithelial regeneration, a deeper knowledge of immature OSNs is required. While gene remodelling and morphological rearrangements are well established, changes in electrophysiological properties across maturation, remain largely unexplored. Using an electrophysiological approach, we explored the intrinsic properties of immature OSNs. Through loose-patch recordings, we demonstrated that immature OSNs are already endowed with a spontaneous activity. Currentclamp experiments showed that these neurons are excitable, although displaying lower excitability and slower action potential kinetics compared to mature OSNs. Both electrophysiological and transcriptomic analyses revealed differences in voltage-gated currents
along development. Focusing on voltage-gated Na+ and K+ channels, we found the emergence of tetrodotoxin-resistant Na+ currents and transient A-type K+ currents when neurons become mature, likely influencing changes in firing behaviour. Altogether, these findings provide a comprehensive electrophysiological characterization of human OSNs, contributing to a deeper understanding of olfactory mechanisms in humans, and expand the current knowledge of OSN functional maturation through the functional description of immature OSNs in a mouse model
Neural Empirical Interpolation Method for Nonlinear Model Reduction
No full textIn this paper, we introduce the neural empirical interpolation method (NEIM), a neural network-based alternative to the discrete empirical interpolation method for reducing the time complexity of computing the nonlinear term in a reduced-order model (ROM) for a parameterized nonlinear partial differential equation. NEIM is a greedy algorithm which accomplishes this reduction by approximating an affine decomposition of the nonlinear term of the ROM, where the vector terms of the expansion are given by neural networks depending on the ROM solution, and the coefficients are given by an interpolation of some “optimal” coefficients. Because NEIM is based on a greedy strategy, we are able to provide a basic error analysis to investigate its performance. NEIM has the advantages of being easy to implement in models with automatic differentiation, of being a nonlinear projection of the ROM nonlinearity, of being efficient for both nonlocal and local nonlinearities, and of relying solely on data and not the explicit form of the ROM nonlinearity. We demonstrate the effectiveness of the methodology on solution-dependent and solution-independent nonlinearities, a nonlinear elliptic problem, and a nonlinear parabolic model of liquid crystals. Code availability: https://github.com/maxhirsch/NEIM. © 2025 Society for Industrial and Applied Mathematic
Exotic surfaces in 4-manifolds, stabilizations, and framings.
No full textWe show that many explicit examples of exotic pairs of surfaces in a smooth 4-manifold become
smoothly isotopic after one external stabilization with S^2×S^2 or CP^2#-CP^2. Our results cover
surfaces produced by rim-surgery, twist-rim-surgery, annulus rim-surgery, as well as infinite families
of nullhomologous surfaces and examples with non-cyclic fundamental group of the complement. A
special attention is given to the identification of the stabilizing manifold and its dependence on the
choices in the construction of the surface. The main idea of this thesis is given by relating internal
and external stabilization, and most of the results, but not all, are proved using this relation.
Moreover, we show that the 2-links in the exotic family constructed by the author of this thesis, in
a joint work with Bais, Benyahia and Torres, are brunnian, i.e., they become smoothly unlinked if
any of the components is removed
One-Back Perceptual Memory Task: Psychophysics, Computational Model, and EEG Correlates
No full textTo yield generalizable insights, models of cognitive function must explain behavioral and brain data across diverse experimental paradigms. In the domain of sensory-perceptual memory, however, most models are tailored to specific tasks, raising the question: are perceptual memories governed by paradigm-specific mechanisms, or can broader, unified principles be
identified? A general framework in which different forms of perceptual memory arise from the interaction of multiple memory buffers with distinct dynamics has been proposed in our research group (Hachen et al. , Giana et al.). In this model, the “short-term buffer” (STB) retains recent sensory input for comparison, while the “long-term buffer” (LTB) stores stable contextual
information such as categorization boundaries. Critically, the STB and LTB interact via mutual attraction. This dynamic can explain both contraction bias in working memory tasks (where short-term traces shift toward the recency-weighted longer-term prior) and repulsion effects in reference memory tasks (where judgments are biased away from the stimuli of recent-past
trials).
To challenge this theory with new data, in this thesis we develop a novel paradigm—the one-back memory task—which integrates delayed comparison and binary categorization. Two sequential trials can be referred to as n-1 and n. In each trial, the participant receives one vibrotactile stimulus and is tasked with judging whether that stimulus (trial n) is stronger or weaker than that of the previous trial (n-1 ). Each stimulus thus serves a dual role: as a comparison target in relation to the preceding trial and as a reference for the next trial. We
hypothesize that the memory of trial n–1, held in the STB, is attracted toward the LTB across the intertrial interval between n-1 and n. In parallel, the LTB is “updated” via an attraction towards n-1 across this same interval. Although the LTB is not explicitly read out, it biases perception by acting upon the STB.
Stimuli follow a deterministic Markov sequence spanning nine intensity levels. The stimuli are organized into high- and low-intensity “clouds,” with sequences of stimuli tending to occupy one cloud before jumping to the other. For reasons that will be expanded in the thesis main body, this structure allows us to investigate whether, and how, the STB and LTB jointly shape
perception. To formalize these interactions, we implement a computational model in which the STB and LTB influence each other with distinct time constants (τ STB and τ LTB). Both symmetric dynamics (τ STB equal to τ LTB) and asymmetric dynamics (τ STB not constrained to be equal to τ LTB) are evaluated to determine which best accounts for behavioral findings.
Finally, to identify the neuronal mechanisms underpinning these interactions, we record EEG while participants perform the task. Multivariate pattern analysis reveals dynamic activation patterns in prefrontal and posterior cortices during encoding, maintenance, and decision-making.
Cluster-based analyses further uncovered context-sensitive neural signatures modulated by cloud identity, string position, and statistical transitions, indicating dynamic tracking of higher-order temporal structure. Time-frequency analyses further hints toward large-scale network dynamics
spanning the somatosensory, prefrontal, and parietal cortices. These results provide new insight into how past and present sensory information are integrated by interacting memory systems to guide perceptual decisions
Full-Length Cryptochrome 1 in the Outer Segments of the Retinal Blue Cone Photoreceptors in Humans and Great Apes Suggests a Role Beyond Transcriptional Repression
No full textMammalian cryptochrome 1 (CRY1) is a central player in the circadian transcription-translation feedback loop, crucial for maintaining a roughly 24-h rhythm. CRY1 was suggested to also function as a blue-light photoreceptor in humans and has been found to be expressed at the mRNA level in various cell types of the inner retina. However, attempts to detect CRY1 at the protein level in the human retina have remained unsuccessful so far. Using various C-terminal specific antibodies recognizing full-length CRY1 protein, we consistently detected selective labeling in the outer segments of short wavelength-sensitive (SWS1, "blue") cone photoreceptor cells across human, bonobo, and gorilla retinae. No other retinal cell types were stained, which is in contrast to what would be expected of a ubiquitous clock protein. Subcellular fractionation experiments in transfected HEK cells using a C-terminal specific antibody located full-length CRY1 in the cytosol and membrane fractions. Our findings indicate that human CRY1 has several different functions including at least one nonclock function. Our results also raise the likely possibility that several different versions of CRY1 exist in humans. We suggest that truncation of the C-terminal tail, maybe to different degrees, may affect the localization and function of human CRY1
From Numerical Discretization to Real-Time Simulation: Reduced Order Models in Cardiovascular Hemodynamics
No full textThe increasing demand for accurate and efficient cardiovascular simulations in
clinical practice highlights the need for the development of efficient computational
tools. Although high-fidelity simulations can achieve excellent accuracy, the large
cost associated with full order models, especially in complex patient-specific geometries and under varying physical and geometrical parameters, motivates the development of Reduced Order Models (ROMs). This thesis investigates several ROM strategies, including data-driven, equation-based and hybrid approaches, for incompressible
fluid dynamics problems in realistic cardiovascular applications and biomedical benchmarks. Moreover, preliminary investigations of ongoing projects start to explore the
use of surrogate modeling approaches combined with machine learning techniques for
haemodynamics and cardiac electrophysiology.
We first introduce a data-driven ROM framework that integrates linear reduction
techniques with interpolation strategies, applied to blood flow in coronary arteries.
This approach enables efficient parametrization of both physical and geometrical features and its effectiveness is demonstrated in the context of forward and optimal
control problems. Next, we extend our investigation to a more challenging vascular
domain, the left atrium, where we estimate the time of blood residence starting from
forward haemodynamic simulations.
Furthermore, we propose a hybrid reduced order modeling approach for blood flow
in large vessels, specifically applied to the aortic arch. The method combines classical
projection-based ROM techniques with a lifting strategy to incorporate nonhomogeneous, time-dependent pressure boundary conditions at the outlets, often simplified
as homogeneous in many existing models. This enhancement allows for a more physiologically accurate representation of the system. In addition, we integrate machine
learning techniques into the ROM framework to improve the ability of the model to
generalize across different time values.
Concerning biomedical benchmarks, we address challenges associated with transitional and turbulent flows in the food and drug administration benchmark nozzle, an
idealized medical device that exhibits flow features similar to those of the cardiovascular system. Due to the convection-dominated nature of the problem, we evaluate and
compare different stabilization strategies within the classical projection-based ROM,
highlighting their strengths and limitations in accurately reproducing time-averaged
flow quantities.
Finally, we outline several early-stage investigations and exploratory works, including physics-informed modeling and strategies to decompose complex domains for
cardiac electrophysiology and time-dependent optimal control formulations for drug
delivery and non-Newtonian fluid flow.
Overall, this thesis provides a comprehensive and critical perspective on reduced
order modeling for cardiovascular applications, highlighting both the mathematical
modeling challenges and the practical implications of different ROM techniques across
various biomedical context
De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome
No full textDDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harboring de novo missense variants in DDX39B, and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients. 3D molecular modeling predicts these variants would alter protein structure. In vitro studies using overexpression of HA-tagged human DDX39B protein in 293FT cells revealed variants p.(Gly92Asp) and c.433-1G>T impaired interaction with DDX39B and other TREX complex members, while variants p.(Gly37Cys), p.(Ser44Arg), and p.(Arg123Gln) did not affect TREX complex assembly. Blood transcriptomics studies demonstrated significantly elevated aberrant splicing events in individuals carrying the p.(Gly37Cys), p.(Arg123Gln), and c.433-1G>T variant, compared to controls, suggesting a mRNA signature of disrupted mRNA splicing and export. To understand variant effects in vivo, we generated Drosophila transgenic DDX39B-reference and variant flies. Human reference DDX39B when overexpressed ubiquitously led to lethality but the patient variants did not, suggesting that the mutants are loss-of-function alleles. Zebrafish anti-sense morpholino knockdown of DDX39B led to reduced head size and body length consistent with the patient phenotypes, and these effects were mitigated by synthesized mRNA, indicating a loss-of-function effect of DDX39B. Collectively, our human genetic data, coupled with in silico, in vitro, and in vivo data supports that DDX39B is a novel candidate gene in a potential group of disorders called TREX-complex-related neurodevelopmental syndrome
Cosmography via stellar archaeology of low-redshift early-type galaxies from SDSS
No full textContext. Cosmic chronometers offer a model-independent way to trace the expansion history of the Universe via the dating of passively evolving objects. This enables testing the validity of cosmological models without concrete assumptions about their energy content. Aims. The main goal of this work is to derive model-independent constraints on the Hubble parameter up to z ∼ 0.4 using stellar ages from the fitting of Lick index absorption lines in passively evolving galaxies. Contrary to recent, related studies that rely on finite differences to obtain a discrete measurement of the expansion of the Universe at an average redshift, our goal is to perform a cosmographic fit of H(z) in terms of the Hubble constant (H0) and the deceleration (q0) and jerk (j0) parameters. Methods. We carefully selected spectra of massive and passively evolving galaxies from the SDSS Legacy Survey. After applying a stacking procedure to ensure a high S/N, the strength of Lick indices was fitted using two stellar population models (TMJ and Knowles) to derive stellar population parameters. A cosmographic fit to the stellar ages was performed, which in turn enabled the sampling of the Hubble parameter within the considered redshift range. Results. The baseline result comes from using the TMJ-modelled ages, and it yields a value of H0 = 70.0+4.17.6 km s1 Mpc1 for the Hubble constant, where uncertainties refer only to the statistical treatment of the data. The sampling of the Hubble parameter at 0.05< 0.35 is competitive with discrete model-independent measurements from the literature. As a by-product of the Lick index fitting procedure, we provide scaling and dispersion relations of stellar population parameters with respect to velocity dispersion using the low-redshift end of our sample. We finally draw attention to an unexpected oscillating pattern in a number of critical indices with respect to redshift, which translates into a similar behaviour in the t-z relations. These features have never been discussed before, although they are present in previous measurements. We show that they do not originate from our methodology, suggesting a possible origin in the data reduction process
Renormalization and running couplings in higher derivative theories
No full textThe renormalization group has a crucial role in modern physics, however some of its
features have not been completely understood yet. While its perturbative realization in 2-derivative theories in d = 4 spacetime has been widely studied, other classes of theories can still hide some subtleties.
Higher derivative theories, and in particular quadratic gravity, could furnish a UV
completion to general relativity within the framework of quantum field theory. For this reason, a detailed study of the renormalization group of this class of theories is of great importance and is the main object of this thesis.
Higher derivative theories suffer from the Ostrogradskij instability at the classical level, which translates into ghost particles in the spectrum at the quantum level, with related problems with unitarity and negative norm states. In recent years many solutions to this pathology have been suggested in order to obtain a well-defined quantum theory and we review some of them.
Then, we study the nonperturbative renormalization group of a higher derivative shift-invariant scalar model. In the theory space, we find an interesting region where the renormalization group trajectories flow between the two free Gaussian fixed points corresponding respectively to the 2- and 4-derivative kinetic term.
From the perturbative point of view, the fourth power of transferred momentum in the propagator reduces the degree of UV divergence of Feynman diagrams, but at the same time it introduces new off-shell IR divergences. We notice that not all renormalization prescriptions are sensible to this type of infrared effects, potentially leading to running couplings that do not resum all the large logarithms of momenta in scattering amplitudes.
We define a “physical” prescription using a momentum subtraction renormalization scheme and we apply it to various higher derivative theories.
In particular, we focus on the higher derivative scalar toy model already studied non-
perturbatively and on some quantum field theories in curved spacetime. We find that shift invariance seems to protect the universality of one-loop beta functions from IR effects and that quadratic gravity, according to its physical running, has an asymptotically free sector without tachyonic particles, in contradiction with older results which predict asymptotic freedom only in the presence of a scalar tachyon.
Finally, we observe that the same type of IR effects can also emerge in 2-derivative
theories in d = 2 spacetime. For this reason, we study the renormalization group of the CP (1) non-linear sigma model (NLSM). We observe that in this case the symmetries of the theory seem to protect the running of couplings from IR effects, preserving one-loop universality