Biology subjects

Ferrero, S.

Publications and source records attributed to Ferrero, S..

4 recordsLinked to original sources

bioRxiv2026

Computationally hybridized pathogenic mammarenavirus receptor binding domains reveal cryptic variants that elicit cross-neutralizing immune responses

The pathogenic mammarenaviruses, Machupo (MACV) and Junin (JUNV), are under evolutionary pressure to leverage human transferrin receptor 1 (hTfR1) for cellular entry while evading host immune responses during zoonosis. We now structurally and functionally investigate cryptic, computationally hybridized JUNV-MACV GP1 sequence variants. We then evaluate the ability of those variants to facilitate internalization of pseudotyped virus-like particles (PVs) into human cells and their recognition by neutralizing antibodies, including plasma from JUNV convalescent patients. We further compare the cryoEM structures of hTfR1-bound MACV GP1 to those of two functional hTfR1-bound MACV-JUNV hybrid GP1 variants that enable robust PV internalization and are also recognized by cross-neutralizing antibodies. Immunization with these variants demonstrates they and other hybrid GP1 sequences can elicit cross-reactive, neutralizing antibodies, supporting a model in which sequence adaptation within GP1 balances receptor recognition with immune evasion. This may inform the rational design of broadly neutralizing GP1-targeted antiviral therapies.

biophysics↗

bioRxiv2025

Topology-Encoded Polarity in Oppositely Charged Binary IDPP Condensates: Multiphase Organization from Non-Coacervating Partners as a Minimal Model of Complex Coacervation

Synthetic condensates provide a way to engineer compartmentalized microenvironments that mimic the properties and functions of natural ones, yet the principles that govern their phase behavior and internal organization remain incompletely defined. Introducing charged residues into intrinsically disordered protein polymers (IDPPs) with LCST phase behavior typically suppresses phase separation under physiological conditions. Here we show that pairing two such oppositely charged IDPPs restores and programs LCST-driven liquid-liquid phase separation (LLPS), enabling a minimalist two-component platform for constructing synthetic condensates whose formation, size, and internal organization are encoded directly in sequence. LLPS emerges from an asymmetric, entropy-driven interplay between hydrophobic collapse, solvent reorganization, and salt-bridge topology. The balance between inter- and intrachain ionic pairing leads to distinct dense-phase microenvironments with tunable residual charge and micropolarity, thereby controlling condensate formation, and miscibility and the emergence of single-phase or multiphase protein condensates. The condensate interior further alters the ionization thermodynamics of charged residues shifting their apparent pKa and enabling tunable pH responses. Systems dominated by interchain salt bridges form low-polarity condensates that mix uniformly with hydrophobic partners, whereas molecular architectures favoring intrachain pairing retain residual charge and, in the presence of hydrophobic partners, undergo spontaneous internal demixing into multiphase assemblies. These findings establish a mechanistic, sequence-level framework for encoding phase behavior, micropolarity, and mesoscale organization in synthetic condensates, and demonstrate how minimalistic LCST-IDPP pairs can be engineered to create programmable microenvironments, opening avenues toward engineered condensates with higher-order organization and adaptive capabilities.

biophysics↗

bioRxiv2021

Evidence, evolution and pattern of contractile elements in villous vascular walls and stroma of human placentas of premature infants of different gestational ages. An immuno-morphologic comparative study.

The contractile elements of the human placenta villous tree represent a topic of interest and many issues persist still open. Histology of the stroma and muscular wall and their evolution, in relation with the gestational age, remains to be clarified for a deeper understanding of the adaptive potential and pathogenetic mechanisms. In our study, 56 premature placentas (21-36 wks) were considered, sub-divided into four groups based on age of gestation and compared to 23 at-term placentas (37-40 wks). All cases were tested with anti-smooth muscle actin (SMA) and anti-desmin antibodies to identify the contractile elements in the stroma and in vascular walls of villi. SMA and desmin staining show evident decreased expressions during the pregnancy (temporal variation) and from proximal to distal part of the villous tree (spatial variation) being higher in the stem villi. Both pre-term and at-term placentas showed persisting, although variable, positivity for SMA and desmin staining in the stroma and in the vessel walls of the mature intermediate and terminal villi. This represents an unexpected finding and nothing alike has been previously reported in literature. Both highly premature and term placentas seem to maintain contractile components within each type of villi, represented by both myofibroblasts and mature smooth muscular cells. These components may be present in both villous vascular walls and stroma, albeit with different staining intensity. This finding allows us to imagine an active function in the regulation of the blood flow, not only in stem and intermediate immature villi but even in smaller villi.

developmental biology↗

bioRxiv2020

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.

ObjectivesTwo of the main target tissues of SARS-coronavirus 2 are the oral cavity pharynx-larynx epithelium, the main virus entry site, and the lung epithelium. The virus enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. Herein we aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity-pharynx-larynx and lung tissues as well as neoplastic tissues from the same histological areas. The information provided in this study may contribute to better understanding of SARS-coronavirus 2 ability to interact with different biological systems and contributes to cumulative knowledge on potential mechanisms to inhibit its diffusion. Materials and MethodsThe study has been conducted using The Cancer Genome Atlas (TCGA) and the Regina Elena Institute (IRE) databases and validated by experimental model in HNSCC and Lung cancer cells. Data from one COVID19 positive patient who was operated on for HNSCC was also included. We have analyzed 478 tumor samples and 44 normal samples from TCGA HNSCC cohort for whom both miRNA and mRNA sequencing was available. The dataset included 391 HPV- and 85 HPV+ cases, with 331 P53 mutated and 147 P53 wild type cases respectively. 352 out of 478 samples were male and 126 female. In IRE cohort we analyzed 66 tumor samples with matched normal sample for miRNA profiling and 23 tumor\normal matched samples for mRNA profiling. 45 out of 66 tumors from IRE cohort were male and 21 female, 38 were P53 mutated and 27 wild type. Most patients (63 of 66) in IRE cohort were HPV negative. Normalized TCGA HNSCC gene expression and miRNA expression data were obtained from Broad Institute TCGA Genome Data Analysis Center (http://gdac.broadinstitute.org/). mRNA expression data from IRE cohort used in this study has been deposited to NCBIs Gene Expression Omnibus and is accessible through GEO series accession number GSE107591. In order to inference about potential molecular modulation of TMPRSS2, we also included miRNAs expression for the 66 IRE cohort matched tumor and normal samples from Agilent platform. DNA methylation data for TCGA tumors were obtained from Wanderer (http://maplab.imppc.org/wanderer/). We used miRWalk and miRNet web tools for miRNA-target interaction prediction and pathway enrichment analysis. The correlation and regression analyses as well as the miRNA and gene modulation and the survival analysis were conducted using Matlab R2019. ResultsTMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues and had a prognostic value in HNSCC patients. Reduction of TMPRSS2 expression was more evident in women than in men, in TP53 mutated versus wild TP53 tumors as well as in HPV negative patients compared to HPV positive counterparts. Functionally, we assessed the multivariate effect on TMPRSS2 in a single regression model. We observed that all variables had an independent effect on TMPRSS2 in HNSCC patients with HPV negative, TP53 mutated status and with elevated TP53-dependent Myc-target genes associated with low TMPRSS2 expression. Investigation of the molecular modulation of TMPRSS2 in both HNSCC and lung cancers revealed that expression of microRNAs targeting TMPRSS2 anti-correlated in both TCGA and IRE HNSCC datasets, while there was not evidence of TMPRSS2 promoter methylation in both tumor cohorts. Interestingly, the anti-correlation between microRNAs and TMPRSS2 expression was corroborated by testing this association in a SARS-CoV-2 positive HNSCC patient. ConclusionsCollectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. The protective mechanism might occur, at least partially, through the aberrant activation of TMPRSS2 targeting microRNAs; thereby providing strong evidence on the role of non-coding RNA molecule in host viral infection. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

cancer biology↗