Biology subjects

Cellini, B.

Publications and source records attributed to Cellini, B..

8 recordsLinked to original sources

bioRxiv2025

A compact multisensory representation of self-motion is sufficient for computing an external world variable

External forces such as gravity and wind fundamentally shape how an animal navigates through the world, but force magnitude and direction cannot be directly measured by an animal in motion. How the brain integrates multiple sensory cues to determine the direction of such external forces remains unclear. In the fruit fly (Drosophila melanogaster) columnar inputs to the navigation center, known as PFNs, have been shown to represent both visual and mechano-sensory cues about self-motion in a similar vector format, but the dynamics and integration of these cues, particularly during complex natural movements, are not known. Here we used 2-photon imaging to investigate the dynamic representation and integration of multi-sensory self-motion cues - optic flow and airflow - across PFNs. We find that one type, called PFNd, linearly integrates optic flow and airflow direction signals with distinct dynamics. We next reveal airflow speed as well as direction encoding by PFNp_c neurons. Imaging from available genetic lines suggests that many PFN types likely encode functions of airflow speed and direction. Based on these data, we construct and validate computational models of how visual and mechano-sensory dynamics are integrated and represented across PFN populations. We then use these models to estimate neural responses during real and simulated flight maneuvers. Applying a nonlinear empirical observability analysis to these responses, we show that active turning and deceleration maneuvers combined with PFN representations can decode the direction of an ambient external cue (wind) during free flight, and identify the theoretical contribution of different PFNs to this ability. Finally, we show that an anatomically-inspired artificial neural network can successfully decode wind direction from PFN representations and identify components of the algorithm used by both the network and real flies to orient upwind during olfactory navigation in flight. Our work provides evidence that active sensation, combined with multi-sensory encoding, can allow a compact system like the fly navigation center to infer a property of the external world that cannot be directly measured by a single sensory system.

neuroscience↗

bioRxiv2025

Nanobodies as therapies for loss-of-function misfolding diseases.

Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by mutations in the alanine:glyoxylate aminotransferase 1 (AGT) enzyme. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (enhanced aggregation and mitochondrial mistargeting). The main therapeutic approach to increase patients lifespan and quality of life is a double kidney and liver transplantation. Alternative treatments such as gene and enzyme replacement and pharmacological chaperones are currently being introduced, but other alternatives are necessary. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics for PH1 misfolding. We show that NB-AGTs are very stable proteins and bind to pathogenic and non-pathogenic variants of AGT with extreme affinities (with Kd values from low nM to low pM). Structural studies showed that NB-AGTs bind to different epitopes of AGT with selectivity for different AGT variants. Experiments in cellular PH1 models showed that internalization of engineered NB-AGT-3 enhanced the specific activity of disease-associated variants. Overall, we show that NBs are a novel and promising approach to treat PH1 and other loss-of-function misfolding diseases.

biophysics↗

bioRxiv2025

RNA condensates as platforms for prebiotic chemistry

The RNA world hypothesis posits the existence of life-like assemblies that consisted mostly of RNA. However, questions remain regarding the emergence of RNA catalysis, stability, reactant availability, and compartmentalization of genetic material. At acidic pH, short RNAs (average {approx} 20 nt) readily phase-separate into a condensed phase en-riched with long RNA. These RNA condensates stably compartmentalize RNA as well as DNA and maintain stable identities even in the absence of membranes. Additionally, the RNA condensates concentrate ions, small molecules, phospholipids, peptides, ri-bozymes, and proteins. Beyond enriching such diverse components, RNA condensates function as microreactors with two catalytic capabilities: they physically enhance reac-tion rates by concentrating reactants within a confined space and simultaneously act as inherent catalysts that directly facilitate chemical transformations. RNA condensates can also support ribozyme and enzymatic activity. Together, these findings suggest that RNA phase separation may have played a crucial role in lifes origins by providing compartmentalization, inherent catalytic activity, and molecular enrichment of long, potentially catalytic biopolymers.

biochemistry↗

bioRxiv2024

Discovering and exploiting active sensing motifs forestimation with empirical observability

Organisms and machines must use measured sensory cues to estimate unknown information about themselves or their environment. Cleverly applied sensor motion can be exploited to enrich the quality of sensory data and improve estimation. However, a major barrier to modeling such active sensing problems is the lack of empirical, yet rigorous, tools for quantifying the relationship between movement and estimation performance. Here, we introduce "BOUNDS: Bounding Observability for Uncertain Nonlinear Dynamic Systems". BOUNDS can discover patterns of sensor motion that increase information and reduce uncertainty in either real or simulated data. Crucially, it is suitable for high dimensional and partially observable nonlinear systems with sensor noise. We demonstrate BOUNDS through a case study on how flying insects estimate wind properties, showing that specific active sensing motifs improve estimation. Additionally, we present a framework to refine sporadic estimates from active sensing. When combined with an artificial neural network, we show that the information gained via active sensing in real Drosophila flight trajectories is suitable for precise wind direction estimation. Collectively, our work will help decode active sensing in organisms and inform the design of estimation algorithms for machines.

systems biology↗

bioRxiv2024

Engineered Oxalate decarboxylase boosts activity and stability for biological applications

Oxalate decarboxylase (OxDC) from Bacillus subtilis is a Mn-dependent hexameric enzyme which converts oxalate to carbon dioxide and formate. Recently, OxDC has attracted the interest of the scientific community, due to its biotechnological and medical applications for the treatment of hyperoxalurias, a group of pathologic conditions associated with excessive oxalate urinary excretion due to either increased endogenous production or increased exogenous absorption. The fact that OxDC displays optimum pH in the acidic range, represents a big limitation for most biotechnological applications involving processes occurring at neutral pH, where the activity and stability of the enzyme are remarkably reduced. Here, through bioinformatics-guided protein engineering, followed by combinatorial mutagenesis and analyses of activity and thermodynamic stability, we identified a double mutant of OxDC endowed with enhanced catalytic efficiency and stability under physiological conditions. The obtained engineered form of OxDC offers a potential tool for improved intestinal oxalate degradation in hyperoxaluria patients.

biochemistry↗

bioRxiv2022

Flies adaptively control flight to compensate for added inertia

Animal locomotion is highly adaptive, displaying a large degree of flexibility, yet how this flexibility arises from the integration of mechanics, sensing and neural control remains elusive. For instance, animals require flexible strategies to maintain performance as changes in mass or inertia impact stability. Compensatory strategies to mechanical loading are especially critical for animals that rely on flight for survival. To shed light on the capacity and flexibility of flight neuromechanics to mechanical loading, we pushed the performance of fruit flies (Drosophila) near its limit and implemented a control theoretic framework to quantify how flies compensated for added inertia. Flies with added inertia were placed inside a virtual reality arena which enabled free rotation about the vertical (yaw) axis. Adding inertia increased the flys response time yet had little influence on overall gaze performance. Flies maintained stability following the addition of inertia by adaptively modulating both visuomotor gain and damping. In contrast, mathematical modeling predicted a significant decrease in flight stability and performance. Adding inertia altered saccades, however flies compensated for the added inertia by increasing yaw torque production, indicating that flies sense that they are mechanically loaded. Taken together, in response to added inertia flies trade off reaction time to maintain flight performance through adaptive neural modulation. Our work highlights the flexibility and capacity of motor control in flight.

biophysics↗

bioRxiv2021

Cryptic genetic variations of alanine:glyoxylate aminotransferase shape its fitness and dynamics

Genetic variations expand the conformational landscape of proteins and may underlie cryptic properties that promote environmental adaptability. However, they can also represent modifying factors for disease susceptibility, by changing frustrated regions that in turn affect protein overall intracellular fitness. In this dichotomy between conservation and innovation, understanding at structural level how genetic variations keep the balance to maintain protein fitness represents an unmet need. Herein, we took advantage of known genetic variations of human alanine:glyoxylate aminotransferase (AGT1), which is present as a common major allelic form (AGT-Ma) and a minor polymorphic form (AGT-Mi) expressed in 20% of Caucasian population. By crystallographic studies and molecular dynamics simulations we showed that the polymorphic amino acid substitutions shape the conformational flexibility of AGT1 so that three surface regions that are structured in AGT-Ma become disordered in AGT-Mi, thanks to plasticity effects propagated from the mutation site(s) to the whole structure. In-depth biochemical characterisation of variants from a library encompassing the three regions correlate this plasticity to a fitness window between AGT-Ma and AGT-Mi, and suggest the existence of cryptic functions related to protein-protein interactions. These results establish that naturally-occurring genetic variations tip the balance between stability and frustration to expand the potential innovability of the protein.

biochemistry↗

bioRxiv2020

Mechanisms of punctuated vision in fly flight

To guide locomotion, animals control their gaze via movements of their eyes, head, and/or body, but how the nervous system controls gaze during complex motor tasks remains elusive. Notably, eye movements are constrained by anatomical limits, which requires resetting eye position. By studying tethered, flying flies (Drosophila) in a virtual reality flight simulator, we show that ballistic head movements (saccades) reset eye position, are stereotyped and leverage elastic recoil of the neck joint, enabling mechanically assisted redirection of gaze. Head reset saccades were of proprioceptive origin and interrupted smooth movements for as little as 50 ms, enabling punctuated, near-continuous gaze stabilization. Wing saccades were modulated by head orientation, establishing a causal link between neck signals and execution of body saccades. Furthermore, we demonstrate that head movements are gated by behavioral state. We propose a control architecture for biological and bio-inspired active vision systems with limits in sensor range of motion.

neuroscience↗