Biology subjects

Coscia, A.

Publications and source records attributed to Coscia, A..

5 recordsLinked to original sources

bioRxiv2026

Structure-affinity correlations and separable optical activity in carbon nanotube protein coronas

Biomolecular corona on nanoparticle surfaces enriches low-abundance proteins and compresses the dynamic range of the plasma proteome. Single-walled carbon nanotubes are particularly attractive because their surface chemistry is highly tunable, and their near-infrared fluorescence directly reports corona modulation. However, how surface chemistry shapes the corona and how the corona relates to the fluorescence response remain unclear. We profiled protein enrichment patterns and the resulting fluorescence in a library of 25 chemically modified carbon nanotubes by quantitative proteomics and near-infrared fluorescence spectroscopy. We found that polymer and quantum-defect chemistry orthogonally modulate corona composition and dispersion forces are the dominant, universal driver of protein-nanotube binding. Proteomics and fluorescence correlation analyses indicate that enrichment and fluorescence response are partially decoupled. A subset of corona proteins stays optically silent, but where responses occur, enriched proteins respond at lower, physiologically relevant ranges than depleted ones. Our findings inform design principles for carbon nanomaterial-based sensors and biomarker discovery platforms.

biochemistry↗

bioRxiv2024

Electrophysiological responses reveal a dedicated learning mechanism to process salient consonant sounds in human newborns

Isolating relevant sounds in the auditory stream is a crucial feature accomplished by human infants and a pivotal ability for language acquisition. Therefore, it is reasonable to postulate the existence of early mechanisms reorienting attention toward salient acoustic stimuli. Previous studies suggest that infants consider consonant sounds as more salient than dissonant ones, because the former resemble human vocalizations. However, systematic evidence investigating the neural processes underlying consonance tuning in newborns is still scarce. Here, we investigate newborns ability to recognize and learn salient auditory stimuli by collecting Mismatch Responses (MMRs) to consonant and dissonant sounds and by computing the trial-by-trial correlation of the neural signal with Bayesian Surprise (a theoretical measure of learning). We present 22 healthy newborns (40.4 {+/-} 15.8 hours) with a pseudo-random sequence of deviant and standard auditory events, while we record their electroencephalogram. Our results show that newborns exhibit a neural encoding of auditory regularities for all sound types (consonant and dissonant), as demonstrated by the presence of MMRs and significant correlation of the neural signal with Bayesian Surprise. Furthermore, consonant and dissonant sounds elicited MMRs and correlations with Bayesian Surprise of opposite polarities, with consonant auditory stimulation evoking negative responses, reminiscent of an adult-like MMR. Overall, our findings suggest that newborns display a dedicated perceptual learning mechanism for salient consonant sounds. We speculate that this mechanism might represent an evolutionary-achieved neural tuning to detect and learn salient auditory stimuli with acoustic features resembling human vocalizations. SIGNIFICANCE STATEMENTDiscriminating salient sounds in noisy sensory streams is a fundamental ability displayed by human infants, pivotal for acquiring crucial skills including language. Our study shed light on this ability by: (1) investigating perceptual learning mechanisms in newborns with a neurocomputational approach; (2) exploring the role of salient consonant sounds in modulating such mechanisms. Since human vocalizations are often consonant, the presence of a mechanism dedicated to enhance the processing of consonant sounds in newborns would confer evolutionary advantages. Our findings, indicating that newborns possess a dedicated and more refined perceptual learning mechanism to process consonance, corroborates this hypothesis. We speculate that this neural mechanism might facilitate the identification of salient acoustic input and support language acquisition in early infancy.

neuroscience↗

bioRxiv2023

Structural basis for VLDLR recognition by eastern equine encephalitis virus

Alphaviruses are arthropod-borne enveloped RNA viruses that include several important human pathogens with outbreak potential. Among them, eastern equine encephalitis virus (EEEV) is the most virulent, and many survivors develop neurological sequelae, including paralysis and intellectual disability. The spike proteins of alphaviruses comprise trimers of heterodimers of their envelope glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), two closely related proteins that are expressed in the brain, as cellular receptors for EEEV and a distantly related alphavirus, Semliki forest virus (SFV)1. The EEEV and SFV spike glycoproteins have low sequence homology, and how they have evolved to bind the same cellular receptors is unknown. Here, we used single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain. The structures reveal that EEEV and SFV use distinct surfaces to bind VLDLR; EEEV uses a cluster of basic residues on the E2 subunit of its spike glycoprotein, while SFV uses two basic residues at a remote site on its E1 glycoprotein. Our studies reveal that different alphaviruses interact with the same cellular receptor through divergent binding modes. They further suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses.

microbiology↗

bioRxiv2020

Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2

The SARS-CoV-2 viral spike (S) protein mediates attachment and entry into host cells and is a major target of vaccine and drug design. Potent SARS-CoV-2 neutralizing antibodies derived from closely related antibody heavy chain genes (IGHV3-53 or 3-66) have been isolated from multiple COVID-19 convalescent individuals. These usually contain minimal somatic mutations and bind the S receptor-binding domain (RBD) to interfere with attachment to the cellular receptor angiotensin-converting enzyme 2 (ACE2). We used antigen-specific single B cell sorting to isolate S-reactive monoclonal antibodies from the blood of a COVID-19 convalescent individual. The seven most potent neutralizing antibodies were somatic variants of the same IGHV3-53-derived antibody and bind the RBD with varying affinity. We report X-ray crystal structures of four Fab variants bound to the RBD and use the structures to explain the basis for changes in RBD affinity. We show that a germline revertant antibody binds tightly to the SARS-CoV-2 RBD and neutralizes virus, and that gains in affinity for the RBD do not necessarily correlate with increased neutralization potency, suggesting that somatic mutation is not required to exert robust antiviral effect. Our studies clarify the molecular basis for a heavily germline-biased human antibody response to SARS-CoV-2.

microbiology↗

bioRxiv2019

Molecular Mechanism of Action of Mitochondrial Therapeutic SS-31 (Elamipretide): Membrane Interactions and Effects on Surface Electrostatics

Mitochondrial dysfunction includes heritable diseases, acquired pathologies, and age-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that have demonstrated efficacy in treating a wide array of mitochondrial disorders, and are believed to target mitochondrial membranes due to their enrichment in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, we have analyzed the interactions of the lead compound SS-31 (Elamipretide) with model and mitochondrial membranes using biophysical and computational approaches. Our results show that this polybasic peptide partitions into the membrane interfacial region with affinity and binding density that are directly related to surface charge. SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it does cause saturable alterations in lipid packing. Most notably, SS-31 modulates the surface electrostatic properties of model and mitochondrial membranes, which could play a significant role in the mitoprotective properties of this compound. As a proof of concept, we show that SS-31 alters ion distribution at the membrane interface with implications for maintaining mitochondrial membranes subject to divalent cation (calcium) stress. Taken together, these results support a mechanism of action in which SS peptides interact with lipid bilayers and alter the biophysical (primarily electrostatic) properties of mitochondrial membranes as their primary mechanism of action. Understanding this molecular mechanism is key to the development of future compound variants with enhanced efficacy.\n\nSignificanceSzeto-Schiller (SS) peptides are among the most promising therapeutic compounds for mitochondrial dysfunction. However, the molecular target(s) and the mechanism of action of SS peptides are poorly understood. In this study, we evaluate the interaction of the lead compound SS-31 (Elamipretide) with mitochondrial and synthetic model membranes using a host of biophysical techniques. Our results show that SS-31 membrane interaction is driven largely by the negative surface charge of mitochondrial membranes and that SS-31 alters lipid bilayer properties, most notably electrostatics at the membrane interface. This work supports a mechanism in which SS peptides act on a key physical property of mitochondrial membranes rather than with a specific protein complex, consistent with the exceptionally broad therapeutic efficacy of these compounds.

biophysics↗