The avian vocal tract offers bioinspiration for the improvement of available vocal prosthetics, which do not currently capture the frequency of the patient’s natural voice. The avian vocal organ, the syrinx, is anatomically different from the human larynx, relying on vibratory membranes within the walls of the trachea, rather than vocal folds within the larynx. The avian system is capable of a much greater range of vocal diversity, suggesting unique ways in which birds produce and modify sounds. The objective of this fellowship is to directly observe and measure the anatomy, biomechanics, airflow, and acoustics of birdsong in vivo and understand how birds physically produce such vocal diversity. We will overcome previous methodological challenges by using a unique combination of cutting-edge methods. First, avian vocal tract anatomy will be described and quantified in 3D, using digital dissection techniques across three bird groups of vocal interest (songbirds, parrots, and doves). It will allow us to accurately determine which anatomical characteristics are linked to which sound characteristics. Next, interactions between the biomechanics of the vocal system (e.g., kinematics, volume changes), the airflow dynamics inside and outside the oral cavity, and the resulting sound production will be measured for the first time in vivo. We will use state-of-the-art biplanar x-ray video methods and 3D imaging of the resulting airflow, synchronized with acoustics, at the level of the individual. By combining in vivo results with the corresponding anatomy, we can directly observe and quantify structure-function relationships, and understand, rather than infer, how the components of the vocal tract work together to modulate sound. This project will be foundational for both the comprehension of the evolution of birdsong and the development of vocal prosthetics that will restore a natural-sounding voice to people who lost their voice.

Antibiotic-resistant microbes have become a serious health problem world-wide. Development of new antibiotics has been focused on killing pathogens. However, these antibiotics also kill other components of microbiome resulting in immune dysregulation. It is crucial to develop new strategies which can remove pathogens without damaging the homeostasis of the microbiome. Nanotechnology is one of the key enabling technologies identified in the European Union (EU) 2020 Strategy that may be promising in dealing with antibiotic-resistant microbe. My recent study showed that microbes' binding to nanomaterials (NMs) was dependent on NMs' characteristics. This finding inspired me to consider whether I can find functionalized NMs to recognize and remove specific pathogens from 100 trillion microbes in gut and pose no harm to the other microbes. The idea is novel and does not follow the conventional use of NMs killing microbes directly, but I believe this is possible because microbes have very different cell surfaces. This would enable the design of NMs that bind certain microbes but not others. I hypothesize that specific surface molecules of pathogens can be acted as the multiple targeted ligands for functionalized NMs to outcompete the binding sites of pathogens on the epithelium. To verify the hypothesis, I plan to use multiple ligand coated NMs, a new concept of personalized protein corona, and in vitro and in vivo gut microbiome models to study the mechanisms of functionalized nanomaterials binding to microbes in gut. My research experiences on nano-bio interactions combined with my host and collaborators’ expertise in nano-therapy (France), nano-protein corona (Germany) and nano-characterization (Denmark) will allow me to successfully execute this challenging program. The proposed study will result in a new strategy for using NMs to fight multi-resistant microbes without antibiotics.

SEPN1-related myopathy (SEPN1-RM) is a rare, untreatable debilitating congenital myopathy in which SEPN1 mutations impair the antioxidant system, ER stress protection and mitochondrial oxidative function. These altered cellular processes ultimately lead to a significant loss of bioenergetic production and abrogate muscle cellular functions. SEPN1-RM patients experience potentially-lethal respiratory failure and major life burden due to loss of mobility. Currently, there are no high-throughput or appropriate preclinical models to facilitate identification of disease-modifying drugs; this has hampered efforts in devising therapeutic strategies. To overcome these bottlenecks, I aim to use patient-derived cells to establish (1) high-throughput measureable readouts of metabolism, facilitating repurposed drug screen for SEPN1-RM; (2) an original treatment strategy by exploiting potential biased signalings, which bypass SEPN1 defects to restore cellular bioenergetics. I will capitalize on (1) the availability of SEPN1-RM biopsies, (2) host lab expertise for handling and culturing primary SEPN1-RM cells and (3) my experience in muscle biology and innovative tools for analysing metabolic/signalling pathways. I aim to implement transcriptomic analyses by using next-generation RNA-seq, optogenetic based sensors to quantify metabolic activity, real-time clonal analysis of cell fate with dynamic fluorescent time-lapse microscopy and multi-dimensional assessment of intracellular activities at single-cell level via CYTOF technology. This study will not only facilitate the establishment of SEPN1-RM biomarkers and novel therapeutic studies, it will also provide a model paradigm for analysing and treating other inherited or acquired myopathies sharing an underlying bioenergetic deficiency, including sarcopenia and cancer cachexia.

Studying the brain mechanisms behind consciousness is a major challenge for neuroscience and medicine. Accumulating evidence shows that the structural, histological, functional, genetic, and neurochemical inhomogeneities of the mammalian cortex do not follow a modular distribution; instead, these properties change following gradients, understood as axes of variance along which cortical features are ordered continuously. The gradient describing the axis of largest variance (principal gradient) obtained for an ample range of cortical features follows a unimodal-transmodal organization, ranging from externally-oriented sensory and motor regions to multimodal association regions, culminating in regions linked with internally oriented higher-order cognitive functions. In this project we propose a novel approach, constructing, validating and exploring whole-brain computational models combining empirical information including anatomical connectivity, spatial maps of local neuroanatomical features, to reproduce the configuration of human functional gradients, as determined using manifold learning techniques applied to functional magnetic resonance imaging (fMRI) data. This will allow us to investigate the process by which functional gradients emerge from the spatial distribution of cortical anatomical inhomogeneities. The models will also provide the possibility to investigate how different global brain states behave under perturbations. In order to achieve our goals, we propose a highly interdisciplinary project that combines state-of-the-art principal gradient expertise with whole-brain computational modelling proposing a synergy between two groups with large expertise in each area to address a common question: do realistic functional gradients emerge from the dynamical equations when coupled by realistic long-range structural connections, and modulated locally by empirical maps encoding relevant neurochemical data?

This proposal develops in the framework of applications of set theory to C*-algebras and it is organized into three main themes: (1) the set-theoretic study of the Calkin algebra, (2) Naimark's problem, (3) the Stone-Weierstrass problem for noncommutative C*-algebras. The first part of the project consists of a systematic analysis of the class of the C*-algebras which embed into the Calkin algebra and of how set-theoretic principles influence such class. This study will be achieved by means of forcing techniques and through the adaptation of methods coming from the framework of boolean algebras. The main objectives are to reach a deeper understanding of the structure of the Calkin algebra, and to provide a benchmark for future applications of forcing methods in a more abstract C*-algebraic context. The second part of the proposal is in continuity with the line of research opened by Akemann and Weaver in the study of Naimark's problem, and it involves a series of applications of set-theoretic combinatorial statements in the construction of nonseparable C*-algebras with peculiar properties, specifically for what concerns their representation theory. With these investigations we aim to extend, by means of set theory, the current knowledge on the discrepancies between the nonseparable and the separable framework in operator algebras. The last part of the project regards the Stone-Weierstrass problem for noncommutative C*-algebras, an old open question which asks whether the classical Stone-Weierstrass theorem can be generalized to all C*-algebras. We plan to study this topic using set-theoretic methods, with the objective to find new consistency results, and extend to the nonseparable setting the known theorems holding for separable C*-algebras.